ORCID Profile
0000-0002-8602-8519
Current Organisation
University of South Australia
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Animal Developmental and Reproductive Biology | Cell Development, Proliferation and Death | Zoology | Animal Physiology - Systems | Characterisation of Biological Macromolecules | Biochemistry and Cell Biology | Medicinal and Biomolecular Chemistry | Colloid and Surface Chemistry | Physiology | Physiology Not Elsewhere Classified | Biologically Active Molecules | Pharmaceutical Sciences | Structural Chemistry and Spectroscopy | Biochemistry and Cell Biology not elsewhere classified | Functional Materials | Mineral Processing/Beneficiation | Materials Engineering | Cell Development (Incl. Cell Division And Apoptosis) | Genetic Development (Incl. Sex Determination) | Crop and Pasture Biochemistry and Physiology |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences | Cardiovascular system and diseases | Livestock not elsewhere classified | Biological sciences | Concentrating processes of other base metal ores | Land and water management | Clinical health not specific to particular organs, diseases and conditions | Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences | Treatments (e.g. chemicals, antibiotics)
Related Links
Publications
Development of an optical fiber‐based redox monitoring system for tissue metabolism
Publisher: Wiley
Date: 25-01-2022
Abstract: An optical redox ratio can potentially be used to report on the dynamics of cell and tissue metabolism and define altered metabolic conditions for different pathologies. While there are methods to measure the optical redox ratio, they are not particularly suited to real‐time in situ or in vivo analysis. Here, we have developed a fiber‐optic system to measure redox ratios in cells and tissues and two mathematical models to enable real‐time, in vivo redox measurements. The optical redox ratios in tissue explants are correlated directly with endogenous NADH/FAD fluorescence emissions. We apply the mathematical models to the two‐photon microscopy data and show consistent results. We also used our fiber‐optic system to measure redox in different tissues and show consistent results between the two models, hence demonstrating proof‐of‐principle. This innovative redox monitoring system will have practical applications for defining different metabolic disease states.
The early origins of obesity and insulin resistance: timing, programming and mechanisms
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/IJO.2015.178
Abstract: Maternal obesity is associated with an increased risk of developing gestational diabetes mellitus and it also results in an increased risk of giving birth to a large baby with increased fat mass. Furthermore, it is also contributes to an increased risk of obesity and insulin resistance in the offspring in childhood, adolescence and adult life. It has been proposed that exposure to maternal obesity may therefore result in an 'intergenerational cycle' of obesity and insulin resistance. There is significant interest in whether exposure to maternal obesity around the time of conception alone contributes directly to poor metabolic outcomes in the offspring and whether dieting in the obese mother before pregnancy or around the time of conception has metabolic benefits for the offspring. This review focusses on experimental and clinical studies that have investigated the specific impact of exposure to maternal obesity during the periconceptional period alone or extending beyond conception on adipogenesis, lipogenesis and on insulin signalling pathways in the fat, liver and muscle of the offspring. Findings from these studies highlight the need for a better evidence base for the development of dietary interventions in obese women before pregnancy and around the time of conception to maximize the metabolic benefits and minimize the metabolic costs for the next generation.
Cardiac growth and metabolism of the fetal sheep are not vulnerable to a 10 day increase in fetal glucose and insulin concentrations during late gestation
Publisher: Elsevier BV
Date: 07-2023
A review of fundamental principles for animal models of DOHaD research: An Australian perspective
Publisher: Cambridge University Press (CUP)
Date: 30-09-2016
DOI: 10.1017/S2040174416000477
Abstract: Epidemiology formed the basis of ‘the Barker hypothesis’, the concept of ‘developmental programming’ and today’s discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.
Technique for comprehensive fetal hepatic blood flow assessment in sheep using 4D flow MRI
Publisher: Wiley
Date: 07-2020
DOI: 10.1113/JP279631
Differential gene responses 3 days following infarction in the fetal and adolescent sheep heart
Publisher: American Physiological Society
Date: 03-2020
DOI: 10.1152/PHYSIOLGENOMICS.00092.2019
Abstract: There are critical molecular mechanisms that can be activated to induce myocardial repair, and in humans this is most efficient during fetal development. The timing of heart development in relation to birth and the size/electrophysiology of the heart are similar in humans and sheep, providing a model to investigate the repair capacity of the mammalian heart and how this can be applied to adult heart repair. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in fetal (105 days gestation when cardiomyocytes are proliferative) and adolescent sheep (6 mo of age when all cardiomyocytes have switched to an adult phenotype). An ovine gene microarray was used to compare gene expression in sham and infarcted (remote, border and infarct areas) cardiac tissue from fetal and adolescent hearts. The gene response to myocardial infarction was less pronounced in fetal compared with adolescent sheep hearts and there were unique gene responses at each age. There were also region-specific changes in gene expression between each age, in the infarct tissue, tissue bordering the infarct, and tissue remote from the infarction. In total, there were 880 genes that responded to MI uniquely in the adolescent s les compared with 170 genes in the fetal response, as well as 742 overlap genes that showed concordant direction of change responses to infarction at both ages. In response to myocardial infarction, there were specific changes in genes within pathways of mitochondrial oxidation, muscle contraction, and hematopoietic cell lineages, suggesting that the control of energy utilization and immune function are critical for effective heart repair. The more restricted gene response in the fetus may be an important factor in its enhanced capacity for cardiac repair.
Structural and molecular regulation of lung maturation by intratracheal vascular endothelial growth factor administration in the normally grown and placentally restricted fetus
Publisher: Wiley
Date: 23-12-2015
DOI: 10.1113/JP271113
Evolution, development, and function of the pulmonary surfactant system in normal and perturbed environments
Publisher: Wiley
Date: 15-12-2016
DOI: 10.1002/CPHY.C150003
Abstract: Surfactant lipids and proteins form a surface active film at the air‐liquid interface of internal gas exchange organs, including swim bladders and lungs. The system is uniquely positioned to meet both the physical challenges associated with a dynamically changing internal air‐liquid interface, and the environmental challenges associated with the foreign pathogens and particles to which the internal surface is exposed. Lungs range from simple, transparent, bag‐like units to complex, multilobed, compartmentalized structures. Despite this anatomical variability, the surfactant system is remarkably conserved. Here, we discuss the evolutionary origin of the surfactant system, which likely predates lungs. We describe the evolution of surfactant structure and function in invertebrates and vertebrates. We focus on changes in lipid and protein composition and surfactant function from its antiadhesive and innate immune to its alveolar stability and structural integrity functions. We discuss the biochemical, hormonal, autonomic, and mechanical factors that regulate normal surfactant secretion in mature animals. We present an analysis of the ontogeny of surfactant development among the vertebrates and the contribution of different regulatory mechanisms that control this development. We also discuss environmental (oxygen), hormonal and biochemical (glucocorticoids and glucose) and pollutant (maternal smoking, alcohol, and common “recreational” drugs) effects that impact surfactant development. On the adult surfactant system, we focus on environmental variables including temperature, pressure, and hypoxia that have shaped its evolution and we discuss the resultant biochemical, biophysical, and cellular adaptations. Finally, we discuss the effect of major modern gaseous and particulate pollutants on the lung and surfactant system. © 2016 American Physiological Society. Compr Physiol 6:363‐422, 2016.
Feasibility of MRI assessment of maternal–fetal oxygen transport and consumption relative to maternal position in healthy late gestational pregnancies
Publisher: Wiley
Date: 31-10-2023
DOI: 10.1113/JP285097
Maternal Dietary Restriction During the Periconceptional Period in Normal-Weight or Obese Ewes Results in Adrenocortical Hypertrophy, an Up-Regulation of the JAK/STAT and Down-Regulation of the IGF1R Signaling Pathways in the Adrenal of the Postnatal Lamb
Publisher: The Endocrine Society
Date: 12-2013
DOI: 10.1210/EN.2013-1414
Abstract: Maternal dietary restriction during the periconceptional period results in an increase in adrenal growth and in the cortisol stress response in the offspring. The intraadrenal mechanisms that result in the programming of these changes are not clear. Activation of the IGF and the signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways regulate adrenal growth. We have used an embryo transfer model in sheep to investigate the impact of exposure to either dietary restriction in normal or obese mothers or to maternal obesity during the periconceptional period on adrenal growth and function in the offspring. We assessed the adrenal abundance of key signaling molecules in the IGF-I and Janus kinase/STAT/SOCS pathways including IGF-I receptor, IGF-II receptor, Akt, mammalian target of rapamycin, ribosomal protein S6, eukaryotic translation initiation factor 4E-binding protein 1, eukaryotic translation initiation factor 4E, STAT1, STAT3, STAT5, SOCS1, and SOCS3 in female and male postnatal lambs. Maternal dietary restriction in the periconceptional period resulted in the hypertrophy of the adrenocortical cells in the zona fasciculata-reticularis and an up-regulation in STAT1, phospho-STAT1, and phospho-STAT3 (Ser727) abundance and a down-regulation in IGF-I receptor, Akt, and phospho-Akt abundance in the adrenal cortex of the postnatal lamb. These studies highlight that weight loss around the time of conception, independent of the starting maternal body weight, results in the activation of the adrenal Janus kinase/STAT pathway and adrenocortical hypertrophy. Thus, signals of adversity around the time of conception have a long-term impact on the mechanisms that regulate adrenocortical growth.
Gene expression allelic imbalance in ovine brown adipose tissue impacts energy homeostasis
Publisher: Public Library of Science (PLoS)
Date: 30-06-2017
Modifying Maternal Sleep Position in Late Pregnancy Through Positional Therapy: A Feasibility Study
Publisher: American Academy of Sleep Medicine (AASM)
Date: 15-08-2018
DOI: 10.5664/JCSM.7280
Placental glucocorticoid receptor isoforms in a sheep model of maternal allergic asthma
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.PLACENTA.2019.06.380
Abstract: Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep model of asthma. Nine known GR isoforms were detected. There was a significant increase in the expression of placental GR isoforms that are known to have low trans-activational activity in other species including GR A, GR P and GRγ which may result in a pro-inflammatory environment in the presence of allergic asthma.
Is there a dirty side to personal care products?
Publisher: The Endocrine Society
Date: 07-2016
DOI: 10.1210/EN.2016-1378
Drugs, chemicals and nutrition during pregnancy: impact on fetal, neonatal and adult health
Publisher: Cambridge University Press (CUP)
Date: 03-07-2012
Differential Effects of Exposure to Maternal Obesity or Maternal Weight Loss during the Periconceptional Period in the Sheep on Insulin Signalling Molecules in Skeletal Muscle of the Offspring at 4 Mo
Publisher: Public Library of Science (PLoS)
Date: 26-12-2013
Impact of periconceptional and preimplantation undernutrition on factors regulating myogenesis and protein synthesis in muscle of singleton and twin fetal sheep
Publisher: Wiley
Date: 08-2015
DOI: 10.14814/PHY2.12495
Seeing the fetus from a DOHaD perspective: discussion paper from the advanced imaging techniques of DOHaD applications workshop held at the 2019 DOHaD World Congress
Publisher: Cambridge University Press (CUP)
Date: 21-09-2020
DOI: 10.1017/S2040174420000884
Abstract: Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
Intrauterine growth restriction may reduce hepatic drug metabolism in the early neonatal period
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.PHRS.2018.06.003
Abstract: The effects of intrauterine growth restriction (IUGR) extend well into postnatal life. IUGR is associated with an increased risk of adverse health outcomes, which often leads to greater medication usage. Many medications require hepatic metabolism for activation or clearance, but hepatic function may be altered in IUGR fetuses. Using a sheep model of IUGR, we determined the impact of IUGR on hepatic drug metabolism and drug transporter expression, both important mediators of fetal drug exposure, in late gestation and in neonatal life. In the late gestation fetus, IUGR decreased the gene expression of uptake drug transporter OATPC and increased P-glycoprotein protein expression in the liver, but there was no change in the activity of the drug metabolising enzymes CYP3A4 or CYP2D6. In contrast, at 3 weeks of age, CYP3A4 activity was reduced in the livers of lambs born with low birth weight (LBW), indicating that LBW results in changes to drug metabolising capacity in neonatal life. Together, these results suggest that IUGR may reduce hepatic drug metabolism in fetal and neonatal life through different mechanisms.
Exposure to rosiglitazone, a PPAR-? agonist, in late gestation reduces the abundance of factors regulating cardiac metabolism and cardiomyocyte size in the sheep fetus
Publisher: American Physiological Society
Date: 15-03-2014
DOI: 10.1152/AJPREGU.00431.2013
Abstract: It is unknown whether cardiomyocyte hypertrophy and the transition to fatty acid oxidation as the main source of energy after birth is dependent on the maturation of the cardiomyocytes' metabolic system, or on the limitation of substrate availability before birth. This study aimed to investigate whether intrafetal administration of a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, during late gestation can stimulate the expression of factors regulating cardiac growth and metabolism in preparation for birth, and the consequences of cardiac contractility in the fetal sheep at ∼140 days gestation. The mRNA expression and protein abundance of key factors regulating growth and metabolism were quantified using quantitative RT-PCR and Western blot analysis, respectively. Cardiac contractility was determined by measuring the Ca 2+ sensitivity and maximum Ca 2+ -activated force of skinned cardiomyocyte bundles. Rosiglitazone-treated fetuses had a lower cardiac abundance of insulin-signaling molecules, including insulin receptor-β, insulin receptor substrate-1 (IRS-1), phospho-IRS-1 (Tyr-895), phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, PI3K catalytic subunit p110α, phospho-3-phosphoinositide-dependent protein kinase 1 (Ser-241), protein kinase B (Akt-1), phospho-Akt (Ser-273), PKCζ, phospho-PKCζ(Thr-410), Akt substrate 160 kDa (AS160), phospho-AS160 (Thr-642), and glucose transporter type-4. Additionally, cardiac abundance of regulators of fatty acid β-oxidation, including adiponectin receptor 1, AMPKα, phospho-AMPKα (Thr-172), phospho-acetyl CoA carboxylase (Ser-79), carnitine palmitoyltransferase-1, and PGC-1α was lower in the rosiglitazone-treated group. Rosiglitazone administration also resulted in a decrease in cardiomyocyte size. Rosiglitazone administration in the late-gestation sheep fetus resulted in a decreased abundance of factors regulating cardiac glucose uptake, fatty acid β-oxidation, and cardiomyocyte size. These findings suggest that activation of PPAR-γ using rosiglitazone does not promote the maturation of cardiomyocytes rather, it may decrease cardiac metabolism and compromise cardiac health later in life.
Acute resveratrol exposure does not impact hemodynamics of the fetal sheep
Publisher: Wiley
Date: 06-2023
DOI: 10.14814/PHY2.15749
Abstract: Babies born growth restricted are at an increased risk of both poor short‐and long‐term outcomes. Current interventions to improve fetal growth are ineffective and do not lower the lifetime risk of poor health status. Maternal resveratrol (RSV) treatment increases uterine artery blood flow, fetal oxygenation, and fetal weight. However, studies suggest that diets high in polyphenols such as RSV may impair fetal hemodynamics. We aimed to characterize the effect of RSV on fetal hemodynamics to further assess its safety as an intervention strategy. Pregnant ewes underwent magnetic resonance imaging (MRI) scans to measure blood flow and oxygenation within the fetal circulation using phase contrast‐MRI and T 2 oximetry. Blood flow and oxygenation measures were performed in a basal state and then repeated while the fetus was exposed to RSV. Fetal blood pressure and heart rate were not different between states. RSV did not impact fetal oxygen delivery (DO 2 ) or consumption (VO 2 ). Blood flow and oxygen delivery throughout the major vessels of the fetal circulation were not different between basal and RSV states. As such, acute exposure of the fetus to RSV does not directly impact fetal hemodynamics. This strengthens the rationale for the use of RSV as an intervention strategy against fetal growth restriction.
Placentome- and sex-specific differences in glucocorticoids and their receptor variants in the growth restricted sheep
Publisher: Elsevier BV
Date: 09-2023
The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signalling in skeletal muscle
Publisher: Wiley
Date: 27-08-2009
Maternal nutrient restriction alters Ca2+ handling properties and contractile function of isolated left ventricle bundles in male but not female Juvenile rats
Publisher: Public Library of Science (PLoS)
Date: 25-09-2015
IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb
Publisher: American Physiological Society
Date: 04-2015
DOI: 10.1152/AJPREGU.00346.2014
Abstract: The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (G αq ) or αs (G αs ). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. S les from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate G αq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.
Chronic Hypoxemia in Late Gestation Decreases Cardiomyocyte Number but Does Not Change Expression of Hypoxia-Responsive Genes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-08-2014
Abstract: Placental insufficiency is the leading cause of intrauterine growth restriction in the developed world and results in chronic hypoxemia in the fetus. Oxygen is essential for fetal heart development, but a hypoxemic environment in utero can permanently alter development of cardiomyocytes. The present study aimed to investigate the effect of placental restriction and chronic hypoxemia on total number of cardiomyocytes, cardiomyocyte apoptosis, total length of coronary capillaries, and expression of genes regulated by hypoxia. We induced experimental placental restriction from conception, which resulted in fetal growth restriction and chronic hypoxemia. Fetal hearts in the placental restriction group had fewer cardiomyocytes, but interestingly, there was no difference in the percentage of apoptotic cardiomyocytes the abundance of the transcription factor that mediates hypoxia‐induced apoptosis, p53 or expression of apoptotic genes Bax and Bcl2 . Likewise, there was no difference in the abundance of autophagy regulator beclin 1 or expression of autophagic genes BECN1 , BNIP3 , LAMP1 , and MAP1LC3B . Furthermore, fetuses exposed to normoxemia (control) or chronic hypoxemia ( placental restriction ) had similar mRNA expression of a suite of hypoxia‐inducible factor target genes, which are essential for angiogenesis ( VEGF , Flt1 , Ang1 , Ang2 , and Tie2 ), vasodilation ( iNOS and Adm ), and glycolysis ( GLUT1 and GLUT3 ). In addition, there was no change in the expression of PKC‐ε, a cardioprotective gene with transcription regulated by hypoxia in a manner independent of hypoxia‐inducible factors. There was an increased capillary length density but no difference in the total length of capillaries in the hearts of the chronically hypoxemic fetuses. The lack of upregulation of hypoxia target genes in response to chronic hypoxemia in the fetal heart in late gestation may be due to a decrease in the number of cardiomyocytes (decreased oxygen demand) and the maintenance of the total length of capillaries. Consequently, these adaptive responses in the fetal heart may maintain a normal oxygen tension within the cardiomyocyte of the chronically hypoxemic fetus in late gestation.
Feasibility of detecting myocardial infarction in the sheep fetus using late gadolinium enhancement CMR imaging
Publisher: Springer Science and Business Media LLC
Date: 13-09-2017
COVID-19: can we treat the mother without harming her baby?
Publisher: Cambridge University Press (CUP)
Date: 25-01-2021
DOI: 10.1017/S2040174420001403
Abstract: Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.
Regulation of lung maturation by prolyl hydroxylase domain inhibition in the lung of the normally grown and placentally restricted fetus in late gestation
Publisher: American Physiological Society
Date: 06-2016
DOI: 10.1152/AJPREGU.00469.2015
Abstract: Intrauterine growth restriction induced by placental restriction (PR) in sheep leads to chronic hypoxemia and reduced surfactant maturation. The underlying molecular mechanism involves altered regulation of hypoxia signaling by increased prolyl hydroxylase domain (PHD) expression. Here, we evaluated the effect of intratracheal administration of the PHD inhibitor dimethyloxalylglycine (DMOG) on functional, molecular, and structural determinants of lung maturation in the control and PR sheep fetus. There was no effect of DMOG on fetal blood pressure or fetal breathing movements. DMOG reduced lung expression of genes regulating hypoxia signaling ( HIF-3α, ACE1), antioxidant defense ( CAT), lung liquid reabsorption ( SCNN1-A, ATP1-A1, AQP-1, AQP-5), and surfactant maturation ( SFTP-A, SFTP-B, SFTP-C, PCYT1A, LPCAT, ABCA3, LAMP3) in control fetuses. There were very few effects of DMOG on gene expression in the PR fetal lung (reduced lung expression of angiogenic factor ADM, water channel AQP-5, and increased expression of glucose transporter SLC2A1). DMOG administration in controls reduced total lung lavage phosphatidylcholine to the same degree as in PR fetuses. These changes appear to be regulated at the molecular level as there was no effect of DMOG on the percent tissue, air space, or numerical density of SFTP-B positive cells in the control and PR lung. Hence, DMOG administration mimics the effects of PR in reducing surfactant maturation in the lung of control fetuses. The limited responsiveness of the PR fetal lung suggests a potential biochemical limit or reduced plasticity to respond to changes in regulation of hypoxia signaling following exposure to chronic hypoxemia in utero.
Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes
Publisher: Springer Science and Business Media LLC
Date: 07-2004
Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart
Publisher: Wiley
Date: 20-05-2018
DOI: 10.1113/JP275806
Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses
Publisher: American Physiological Society
Date: 15-01-2016
DOI: 10.1152/AJPENDO.00600.2014
Abstract: We have investigated the effects of embryo number and maternal undernutrition imposed either around the time of conception or before implantation on hepatic lipid metabolism in the sheep fetus. We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid β-oxidation regulators, PGC-1α ( P 0.05), PDK2 ( P 0.01), and PDK4 ( P 0.01) mRNA expression in singleton and twin fetuses at 135–138 days gestation. In singletons, there was also lower hepatic PDK4 ( P 0.01), CPT-1 ( P 0.01), and PKCζ ( P 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 ( P 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser 485 ) ( P 0.01), p-PDPK-1 (Ser 41 ) ( P 0.05), and PKCζ ( P 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 ( P 0.001) and CPT-1 ( P 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid β-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis.
Feasibility of ventricular volumetry by cardiovascular MRI to assess cardiac function in the fetal sheep
Publisher: Wiley
Date: 02-06-2020
DOI: 10.1113/JP279054
Does poor fetal growth influence the extent of fetal exposure to maternal medications?
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PHRS.2018.02.001
Abstract: A large proportion of women are prescribed a medication during pregnancy, and the conditions requiring treatment with these medicines are often also associated with placental dysfunction and abnormal fetal growth. For the fetus, exposure to maternal illness or medications can alter fetal growth trajectory, which is a key indicator of fetal and postnatal wellbeing. There is a large amount of human and animal evidence highlighting the hormonal and/or metabolic changes that occur in both the mother and the fetus as a result of maternal illness or either excessive or restricted fetal growth. These changes can affect the expression of drug metabolising enzymes and drug transporters in the both the mother and her fetus, and may ultimately alter fetal drug exposure. This review aims to explore the complex and multidirectional interplay between maternal illness, fetal growth trajectory, maternal drug treatment, and fetal drug exposure.
IUGR decreases cardiomyocyte endowment and alters cardiac metabolism in a sex- and cause-of-IUGR-specific manner
Publisher: American Physiological Society
Date: 07-2018
DOI: 10.1152/AJPREGU.00180.2017
Abstract: Intrauterine growth restriction (IUGR) increases the risk of ischemic heart disease in adulthood. Studies in rats suggest cardiac vulnerability is more pronounced in males and in offspring that were exposed to hypoxia in utero. Therefore, we aimed to test the hypotheses that 1) IUGR adolescent males, but not females, have fewer cardiomyocytes and altered expression of cardiometabolic genes compared with controls and 2) IUGR due to hypoxia has a greater effect on these parameters compared with IUGR due to nutrient restriction. IUGR was induced in guinea pigs by maternal hypoxia (MH 10% O 2 , n = 9) or maternal nutrient restriction (MNR ~30% reduction in food intake, n = 9) in the second half of pregnancy and compared with control ( n = 11). At 120 days of age, postmortem was performed and the left ventricle perfusion fixed for stereological determination of cardiomyocyte number or snap frozen to determine the abundance of cardiometabolic genes and proteins by quantitative RT-PCR and Western blotting, respectively. MH reduced the number of cardiomyocytes in female ( P 0.05), but not male or MNR, adolescent offspring. Furthermore, IUGR males had decreased expression of genes responsible for fatty acid activation in the sarcoplasm ( FACS) and transport into the mitochondria ( AMPK-a 2 and ACC P 0.05) and females exposed to MH had increased activation hosphorylation of AMP-activated protein kinase-α ( P 0.05). We postulate that the changes in cardiomyocyte endowment and cardiac gene expression observed in the present study are a direct result of in utero programming, as offspring at this age did not suffer from obesity, hypertension, or left ventricular hypertrophy.
An MRI approach to assess placental function in healthy humans and sheep
Publisher: Wiley
Date: 29-03-2021
DOI: 10.1113/JP281002
Abstract: Human placental function is evaluated using non‐invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental by MRI was ∼4 ml min −1 kg −1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental , which involves the quantification of maternal‐ and fetal‐placental blood flows, fetal oxygen delivery and , and the oxygen gradient between uterine‐ and umbilical‐venous blood, providing a comprehensive assessment of placental function with clinical potential. It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( ) and in vitro studies do not reflect true metabolism in utero . Here we propose an MRI method to non‐invasively quantify in utero placental and fetal oxygen delivery ( ) and in healthy humans and sheep. Women ( n = 20) and Merino sheep ( n = 10 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively mean ± SD). Blood flow (phase‐contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine‐ and umbilical‐placental vessels, allowing calculation of uteroplacental and fetal and . Maternal (ml min −1 kg −1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal (ml min −1 kg −1 fetus uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281 fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal ratio did not change with age (human, P = 0.256 sheep, P = 0.121). Human umbilical blood flow (ml min −1 kg −1 fetus) decreased with advancing age ( P = 0.008), while fetal was preserved through an increase in oxygen extraction ( P = 0.046). By contrast, sheep fetal was preserved through stable umbilical flow (ml min −1 kg −1 P = 0.443) and oxygen extraction ( P = 0.582). MRI derived measurements of uteroplacental and fetal between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical ‘placental function test’.
Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep
Publisher: American Physiological Society
Date: 05-2014
DOI: 10.1152/AJPENDO.00553.2013
Abstract: This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN −60 to 7 days) or preimplantation (PIUN 0–7 days) undernutrition at 136–138 days of gestation (term = 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA ( P 0.01) and protein abundance and the protein abundance of IRS-1 ( P 0.01), p110β ( P 0.05), PTEN ( P 0.05), CREB ( P 0.01), and pCREB (Ser 133 P 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 ( P 0.01), p85 ( P 0.01), p110β ( P 0.001), PTEN ( P 0.01), Akt2 ( P 0.01), p-Akt (Ser 473 P 0.01), and p-FOXO-1 (Thr24) ( P 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA ( P 0.01) but, paradoxically, an increase in PEPCK-C protein ( P 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs.
Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus
Publisher: American Physiological Society
Date: 04-2010
DOI: 10.1152/AJPLUNG.00226.2009
Abstract: Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 ± 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight SD from the mean of control fetuses and a mean gestational Pa O 2 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational Pa O 2 was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.
Maternal undernutrition alters fat cell size distribution, but not lipogenic gene expression, in the visceral fat of the late gestation guinea pig fetus
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.PLACENTA.2010.07.014
Abstract: This study investigated the development of adipose tissue in the guinea pig and the impact of maternal undernutrition on the structural and functional characteristics of perirenal adipose tissue in the dam and fetus. Date-mated guinea pigs were provided with either ad libitum feed (Control, C) or 85% of food intake per body weight of the Controls (Undernutrition, UN). Maternal (C, n = 6 UN, n = 7) perirenal adipose tissue (PAT) was collected at 60 d gestation and fetal PAT was collected at 50 d (C, n = 4) and 60 d (C, n = 8 and UN, n = 7) gestation (term, 69 d). The expression of stearoyl-CoA desaturase (SCD-1), fatty acid synthase (FAS), lipoprotein lipase (LPL), leptin and glycerol 3 phosphate dehydrogenase (G3PDH) mRNA and glucose transporters 1 and 4 (GLUT1 and GLUT4) was determined by Real Time PCR. There was no effect of maternal UN on total or relative PAT mass in the pregnant dam. There was an increase in G3PDH, but not LPL, leptin, FAS or GLUT4 mRNA expression, in UN dams compared to Controls (P < 0.05). In the fetal guinea pig there was no effect of maternal UN on total or relative PAT mass, however, the UN fetuses had a higher percentage of larger lipid locules in their PAT compared to Controls (P < 0.05). The expression of FAS, LPL, SCD-1, leptin, G3PDH and GLUT4 mRNA in PAT was not different between the Control and UN fetuses. These results support previous studies which have demonstrated that maternal undernutrition is associated with an increased accumulation of visceral adipose tissue in utero, and extend them by showing that maternal undernutrition results in early changes in the size distribution of lipid locules in visceral fat depots that precede changes in lipogenic gene expression.
Differential Response to Injury in Fetal and Adolescent Sheep Hearts in the Immediate Post-myocardial Infarction Period
Publisher: Frontiers Media SA
Date: 05-03-2019
Does a growth-restricted fetus have fewer cardiomyocytes than a normally grown fetus?
Publisher: Informa UK Limited
Date: 07-2012
DOI: 10.1586/EOG.12.30
Normal human and sheep fetal vessel oxygen saturations by T2 magnetic resonance imaging
Publisher: Wiley
Date: 29-05-2020
DOI: 10.1113/JP279725
Mature Surfactant Protein-B Expression by Immunohistochemistry as a Marker for Surfactant System Development in the Fetal Sheep Lung
Publisher: SAGE Publications
Date: 21-08-2015
Abstract: Evaluation of the number of type II alveolar epithelial cells (AECs) is an important measure of the lung’s ability to produce surfactant. Immunohistochemical staining of these cells in lung tissue commonly uses antibodies directed against mature surfactant protein (SP)-C, which is regarded as a reliable SP marker of type II AECs in rodents. There has been no study demonstrating reliable markers for surfactant system maturation by immunohistochemistry in the fetal sheep lung despite being widely used as a model to study lung development. Here we examine staining of a panel of surfactant pro-proteins (pro–SP-B and pro–SP-C) and mature proteins (SP-B and SP-C) in the fetal sheep lung during late gestation in the saccular/alveolar phase of development (120, 130, and 140 days), with term being 150 ± 3 days, to identify the most reliable marker of surfactant producing cells in this species. Results from this study indicate that during late gestation, use of anti-SP-B antibodies in the sheep lung yields significantly higher cell counts in the alveolar epithelium than SP-C antibodies. Furthermore, this study highlights that mature SP-B antibodies are more reliable markers than SP-C antibodies to evaluate surfactant maturation in the fetal sheep lung by immunohistochemistry.
Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
DOI: 10.1038/S41390-021-01489-4
Abstract: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1 , hypoxia signaling genes ( HIF-2α , HIF-3α , ADM , and EGLN-3 ), genes regulating sodium movement ( SCNN1-A , SCNN1-B , ATP1-A1 , and ATP1-B1 ), surfactant maturation ( SFTP-B and ABCA3 ), and airway remodeling ( ELN ). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.
Australian perspectives: outcomes from the 2015 Australia and New Zealand Developmental Origins of Health and Disease (ANZ DOHaD) scientific meeting
Publisher: Cambridge University Press (CUP)
Date: 30-09-2016
Label-free imaging of healthy and infarcted fetal sheep hearts by two-photon microscopy
Publisher: Wiley
Date: 02-05-2018
Abstract: Coronary heart disease is one of the largest causes of death worldwide, making this a significant health care issue. A critical problem for the adult human heart is that it does not undergo effective repair in response to damage, leaving patients with a poor prognosis. Unlike the adult, fetal hearts have the ability to repair after myocardial damage. Using two-photon microscopy, we have visualised the morphological and metabolic changes following myocardial infarction in sheep fetuses, to characterise response to cardiac injury in a mammalian model. Following myocardial infarction, fetal hearts showed no significant increase in collagen deposition in the region of the infarction, when compared to either the surrounding tissue or shams. In contrast, metabolic activity (i. e. NAD(P)H and FAD) was significantly reduced in the region of myocardial infarction, when compared to either the surrounding tissue or sham hearts. For comparison, we also imaged two hearts from preadolescent sheep (sham and myocardial infarction) and showed highly ordered collagen deposition with decreased metabolic activity within the infarcted area. Therefore, two-photon imaging had the capacity to image both morphological and metabolic changes in response to myocardial infarction and showed differences in the response with age. Picture: Two-photon imaging of myocardial infarction (b and d) enabled the visualisation of increased collagen (blue Em=431 nm) and changes in other tissue autofluorescence (green Em=489-606 nm) in fetal (a and b) and preadolescent (c and d) hearts, compared to shams (a and c). The excitation wavelength was 840 nm. Scale bars: 10 μm.
Limited fetal metabolism of rosiglitazone: elimination via the maternal compartment in the pregnant ewe
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.REPROTOX.2016.04.008
Abstract: Despite the fact that fetal drug exposure is common, the disposition of drugs in the fetus is poorly understood. This study aimed to investigate fetal placental and non-placental disposition of rosiglitazone in the pregnant ewe. Steady state was reached after day 5 of fetal infusion, and were ∼1.8 fold higher than maternal concentrations (P<0.001). The AUC for fetal rosiglitazone concentration throughout the infusion was inversely correlated with placental and fetal weight. Metabolic activity of the fetal liver microsomes were ∼25 fold lower than maternal microsomes (P<0.001). The findings suggest that trans-placental transfer is the major route through which rosiglitazone is cleared from the fetal compartment, while non-placental hepatic elimination makes only a minor contribution. This supports a limited capacity of the fetus for eliminating this class of drugs, and highlights the potential for drug toxicity when administering pharmacotherapy to the mother/fetus in human pregnancy.
Automated Proteomics Workflows for High-Throughput Library Generation and Biomarker Detection Using Data-Independent Acquisition
Publisher: American Chemical Society (ACS)
Date: 23-05-2023
Fetal cardiovascular response to acute hypoxia during maternal anesthesia
Publisher: Wiley
Date: 02-2020
DOI: 10.14814/PHY2.14365
Impact of chronic hypoxemia on blood flow to the brain, heart, and adrenal gland in the late-gestation IUGR sheep fetus
Publisher: American Physiological Society
Date: 02-2015
DOI: 10.1152/AJPREGU.00036.2014
Abstract: In the fetus, there is a redistribution of cardiac output in response to acute hypoxemia, to maintain perfusion of key organs, including the brain, heart, and adrenal glands. There may be a similar redistribution of cardiac output in the chronically hypoxemic, intrauterine growth-restricted fetus. Surgical removal of uterine caruncles in nonpregnant ewe results in the restriction of placental growth (PR) and intrauterine growth. Vascular catheters were implanted in seven control and six PR fetal sheep, and blood flow to organs was determined using microspheres. Placental and fetal weight was significantly reduced in the PR group. Despite an increase in the relative brain weight in the PR group, there was no difference in blood flow to the brain between the groups, although PR fetuses had higher blood flow to the temporal lobe. Adrenal blood flow was significantly higher in PR fetuses, and there was a direct relationship between mean gestational Pa O 2 and blood flow to the adrenal gland. There was no change in blood flow, but a decrease in oxygen and glucose delivery to the heart in the PR fetuses. In another group, there was a decrease in femoral artery blood flow in the PR compared with the Control group, and this may support blood flow changes to the adrenal and temporal lobe. In contrast to the response to acute hypoxemia, these data show that there is a redistribution of blood flow to the adrenals and temporal lobe, but not the heart or whole brain, in chronically hypoxemic PR fetuses in late gestation.
Fetal heart growth: IGF-1 and sex
Publisher: Informa UK Limited
Date: 05-2009
DOI: 10.1586/EOG.09.8
Akt signaling as a mediator of cardiac adaptation to low birth weight
Publisher: Bioscientifica
Date: 05-2017
DOI: 10.1530/JOE-17-0039
Abstract: Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT 1 R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT 1 receptor via angiotensin signaling pathways both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.
Maternal obesity mediated predisposition to respiratory complications at birth and in later life: understanding the implications of the obesogenic intrauterine environment
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.PRRV.2016.10.003
Abstract: More women than not are entering pregnancy either overweight or obese. This presents a significant health care burden with respect to maternal morbidities and offspring complications at birth and in later life. In recent years it has also become clear that maternal obesity is an even greater global health problem than anticipated, because the effects are not limited to the mother but are also programmed in the fetus, known as the 'intergenerational cycle of obestiy'. Despite a large body of epidemiological evidence reporting outcomes of obese pregnancies, including offspring respiratory complications, much less is known about the molecular effects of maternal obesity on fetal lung development. This review focuses on the influence of altered substrate supply associated with the obesogenic intrauterine environment on fetal lung development. Understanding the molecular mechanisms contributing to altered fetal lung development will lead to improved respiratory outcomes for offspring at birth and in later life.
ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis
Publisher: Cold Spring Harbor Laboratory
Date: 12-2017
Abstract: The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B ( ARID5B ) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2–4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC . Importantly, ARID5B is required for the survival and growth of T-ALL cells , and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis.
Prenatal exposure to selective serotonin reuptake inhibitors and risk of childhood overweight
Publisher: Cambridge University Press (CUP)
Date: 09-01-2012
DOI: 10.1017/S2040174411000808
Abstract: The objective was to investigate the association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and overweight in offspring at 4–5 years of age. We conducted a retrospective cohort study using linked records from the Women's and Children's Health Network in South Australia, Australia. Women were eligible to participate if they gave birth to singleton, live-born infants between September 2000 and December 2005. Women were excluded if they received a dispensing for an antidepressant other than SSRIs or an antipsychotic or an anti-epileptic or had a chronic medical condition. Of the 6560 eligible women, 71 received a dispensing for an SSRI (exposed), 204 had a reported psychiatric illness but did not receive a dispensing for any antidepressant (untreated psychiatric illness) and 6285 did not have a reported psychiatric illness and did not receive a dispensing for any antidepressant (unexposed). Childhood overweight was classified as a body mass index th percentile, based on age and sex. At 4–5 years of age, female offspring of exposed mothers were less likely to be overweight compared with female offspring of mothers with an untreated psychiatric illness [adjusted Prevalence Ratio (aPR) 0.23 95% confidence interval (CI) 0.05–0.98] and female offspring of unexposed mothers (aPR 0.27 0.07–0.99). No association with overweight was observed among male offspring of exposed mothers compared with male offspring of mothers with an untreated psychiatric illness (aPR 1.17 0.54–2.51) and male offspring of unexposed mothers (aPR 0.93 0.52–1.67). Further research is required to confirm these findings and examine the potential mechanisms behind the sex-specific differences.
Methodological challenges in using routinely collected health data to investigate long-term effects of medication use during pregnancy
Publisher: SAGE Publications
Date: 20-12-2012
Abstract: To date, the investigation of teratogenic effects of medications has largely focused on physical alterations present at birth (i.e. malformations) as opposed to functional alterations (i.e. neurodevelopment, metabolic function) that may not be apparent at birth but could influence an in idual’s health and risk of disease in later life. The use of routinely collected health data represents one approach to better identifying, quantifying, and understanding the long-term risks or benefits of medication use during pregnancy. As such, the objective of this review was to identify and explore opportunities and challenges associated with using routinely collected health data to examine long-term effects of medication use during pregnancy. Drawing on published research several key methodological issues associated with their use in investigating long-term outcomes are reviewed. While significant opportunities exist to make greater use of routinely collected health data, there are a number of key challenges. Identified challenges relate to aspects of study design and analysis, and include obtaining access to data, the ability to match records across datasets and over long periods of time, how medication exposures are ascertained and classified, issues around loss to follow-up how outcomes are ascertained and classified, and the careful interpretation of results in light of study and data limitations. Understanding key challenges associated with using routinely collected health data to investigate long-term effects of medication use during pregnancy is essential in supporting their appropriate use and interpretation, which will contribute to improving the quality of research undertaken and ensure the reliability of results obtained.
The Development of the Pulmonary Surfactant System
Publisher: Elsevier
Date: 2014
Maternal Undernutrition Increases Fibrosis in the Late Gestation Fetal Heart
Publisher: Elsevier BV
Date: 2017
Glycine at hypoglossal motor nucleus: genioglossus activity, CO2 responses, and the additive effects of GABA
Publisher: American Physiological Society
Date: 11-2002
DOI: 10.1152/JAPPLPHYSIOL.00464.2002
Abstract: There is evidence for glycine and GABA A -receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo, and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA A - receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001–10 mM), or muscimol (0.1 μM). Increasing glycine at the HMN produced graded suppression of GG activity ( P 0.001), although the GG still responded to stimulation with 7% inspired CO 2 ( P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.
The Australian Early Origins of Hypertension Workshop: A celebration of the scientific contributions made by Emeritus Scientia Professor Eugenie R Lumbers AM and Professor Caroline McMillen
Publisher: Cambridge University Press (CUP)
Date: 30-08-2013
Fetal hemodynamics and cardiac streaming assessed by 4D flow cardiovascular magnetic resonance in fetal sheep 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
Early origins of heart disease: Low birth weight and the role of the insulin-like growth factor system in cardiac hypertrophy
Publisher: Wiley
Date: 29-10-2012
DOI: 10.1111/J.1440-1681.2012.05743.X
Abstract: Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life. In fetal life, the insulin-like growth factor (IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy. A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy. The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways.
The impact of maternal asthma during pregnancy on offspring retinal microvascular structure and its relationship to placental growth factor production in utero
Publisher: Wiley
Date: 14-05-2020
DOI: 10.1111/MICC.12622
Changes in cardiac troponins with gestational age explain changes in cardiac muscle contractility in the sheep fetus
Publisher: American Physiological Society
Date: 07-2011
DOI: 10.1152/JAPPLPHYSIOL.00067.2011
Abstract: The development of the adult cardiac troponin complex in conjunction with changes in cardiac function and cardiomyocyte binucleation has not been systematically characterized during fetal life in a species where maturation of the cardiomyocytes occurs prenatally as it does in the human. The aim of this study was to correlate the expression of each of the major adult troponin isoforms (T, I, and C) during late gestation (term of 150 days) to changes in both Ca 2+ sensitivity and maximum Ca 2+ -activated force of the contractile apparatus and the maturation of cardiomyocytes. The percentage of mononucleated cardiomyocytes in the right ventricle decreased with gestational age to 46% by 137–142 days of gestation. The length of binucleated cardiomyocytes did not change with gestational age, but the length of binucleated cardiomyocytes relative to heart weight decreased with gestational age. There was no change in the expression of adult cardiac troponin T with increasing gestation. The contractile apparatus was significantly more sensitive to Ca 2+ at 90 days compared with either 132 or 139 days of gestation, consistent with an ∼30% increase in the expression of adult cardiac troponin I between 90 and 110 days of gestation. Maximum Ca 2+ -activated force significantly increased from 90 days compared with 130 days consistent with an increase of ∼40% in cardiac troponin C protein expression. These data show that increased adult cardiac troponin I and C protein expression across late gestation is consistent with reduced Ca 2+ sensitivity and increased maximum Ca 2+ -activated force. Furthermore, changes in cardiac troponin C, not I, protein expression track with the timing of cardiomyocyte binucleation.
Investigating Intracellular Localisation and Cytotoxicity Trends for Neutral and Cationic Iridium Tetrazolato Complexes in Live Cells
Publisher: Wiley
Date: 07-08-2017
Abstract: A family of five neutral cyclometalated iridium(III) tetrazolato complexes and their methylated cationic analogues have been synthesised and characterised. The complexes are distinguished by variations of the substituents or degree of π conjugation on either the phenylpyridine or tetrazolato ligands. The photophysical properties of these species have been evaluated in organic and aqueous media, revealing predominantly a solvatochromic emission originating from mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity. These emissions are characterised by typically long excited-state lifetimes (∼hundreds of ns), and quantum yields around 5-10 % in aqueous media. Methylation of the complexes caused a systematic red-shift of the emission profiles. The behaviour and the effects of the different complexes were then examined in cells. The neutral species localised mostly in the endoplasmic reticulum and lipid droplets, whereas the majority of the cationic complexes localised in the mitochondria. The amount of complexes found within cells does not depend on lipophilicity, which potentially suggests erse uptake mechanisms. Methylated analogues were found to be more cytotoxic compared to the neutral species, a behaviour that might to be linked to a combination of uptake and intracellular localisation.
Simple HPLC method for determination of rosiglitazone in sheep plasma and amniotic fluid and its application in a pregnant sheep model
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JPBA.2011.01.026
Abstract: This paper describes the development of a sensitive high performance liquid chromatography (HPLC) method for quantification of rosiglitazone in sheep plasma and amniotic fluid. S les were prepared by liquid-liquid extraction using tert-butyl methyl ether, and rosiglitazone was quantitated by HPLC using a C18 column and fluorescence detector with an excitation wavelength of 247 nm and emission wavelength of 367 nm. The mobile phase consisted of ammonium acetate (10 mM, pH 5.2) and acetonitrile (56.5:43.5, v/v) with a flow rate of 1 ml/min. Ketoconazole was used as the internal standard (IS). The plasma calibration curve was linear over the range of 2.5-250 ng/ml (mean r2=0.9940±0.0024 n=6) with accuracy of 99.4-102.8% over the calibration range. The intra-day and inter-day coefficient of variation (%CV, percent coefficient of variation) were in the range of 0.01-8.68% in sheep plasma. Similar performance was achieved for amniotic fluid. The described method was successfully applied to quantitate rosiglitazone concentrations in the pregnant ewe and her fetus.
Differential effects of late gestation maternal overnutrition on the regulation of surfactant maturation in fetal and postnatal life
Publisher: Wiley
Date: 24-08-2017
DOI: 10.1113/JP274528
Maternal undernutrition reduces P-glycoprotein in guinea pig placenta and developing brain in late gestation
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.REPROTOX.2012.01.013
Abstract: Poor nutrition is a major cause of fetal growth restriction which increases neonatal morbidity and mortality, as well as the risk of adult onset diseases. The objective of the study was to determine the effect of maternal undernutrition on P-glycoprotein (P-gp) expression in the placenta and the brain of both the mother and the fetus. Maternal undernutrition in guinea pigs caused placental restriction, and thus decreased fetal weight. Pups in the maternal undernutrition (UN) group had fewer capillaries in the placenta and more capillaries in the brain of the fetus. Placental, maternal and fetal brain MDR1 mRNA expression was the same in the Control and UN groups. Maternal undernutrition resulted in a significant decrease in P-gp protein expression in the placenta and fetal brain, but not the maternal brain. These findings indicate that maternal undernutrition may impact on fetal exposure to drugs administered to the mother during pregnancy due to changes in placental transfer.
MRI Characterization of blood flow and oxygen delivery in the fetal sheep whilst exposed to sildenafil citrate
Publisher: S. Karger AG
Date: 2022
DOI: 10.1159/000526972
Abstract: b i Introduction: /i /b Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. b i Methods: /i /b At 116–117 days gestational age (term, 150 days), pregnant Merino ewes ( i n /i = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T sub /sub oximetry. b i Results: /i /b Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. b i Conclusion: /i /b SC induces alterations to pulmonary haemodynamics i in utero /i a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.
Investigating Outcomes Following the Use of Selective Serotonin Reuptake Inhibitors for Treating Depression in Pregnancy
Publisher: Springer Science and Business Media LLC
Date: 11-2011
DOI: 10.2165/11593130-000000000-00000
Abstract: The aim of this review was to critically appraise the existing literature with a particular focus on identifying methodological issues associated with studying outcomes following the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Existing studies evaluating outcomes following prenatal SSRI exposure suffer from a number of important methodological limitations that should be taken into account when interpreting their results. The contradictory results obtained from prospective and retrospective cohort studies and case-control studies could be accounted for by dissimilarity between study populations, selection bias, detection bias, confounding, or differences in underlying maternal illness, data sources used, exposure classification, follow-up and statistical power/analysis. Only a small number of studies actually account for underlying maternal illness and how this may lead to adverse pregnancy outcomes. Even when such information is available, studies that include data on maternal illness have small s le sizes, limiting the statistical power to identify statistically and clinically relevant associations. Pregnancy outcomes may be confounded by the higher incidence of smoking, alcohol consumption and substance abuse frequently encountered amongst those suffering from depression, factors that are often insufficiently controlled for. While evidence of associations between prenatal SSRI exposure and adverse pregnancy outcomes are conflicting, there is an urgent need to evaluate how the particular SSRI used, the dose, timing and duration of use, genetics (maternal, paternal and/or fetal), concomitant medication use, maternal characteristics and underlying maternal illness all interact to alter pregnancy outcomes.
Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissuein the sheep fetus
Publisher: American Physiological Society
Date: 15-10-2013
DOI: 10.1152/AJPENDO.00180.2013
Abstract: Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We hypothesized that maternal undernutrition during the periconceptional (PCUN: −60 to 7 days) and/or preimplantation (PIUN: 0–7 days) periods would result in a decrease in UCP1 expression and the abundance of insulin signaling molecules and an increase in the abundance of factors that regulate adipogenesis and lipogenesis in fetal perirenal adipose tissue (PAT) and that these effects would be different in singletons and twins. Maternal PCUN and PIUN resulted in a decrease in UCP1 expression in PAT, and PIUN resulted in higher circulating insulin concentrations, an increased abundance of pPKCζ and PDK4, and a decreased abundance of Akt1, phosphorylated mTOR, and PPARγ in PAT in singleton and twin fetuses. In singletons, there was also a decrease in the abundance of p110β in PAT in the PCUN and PIUN groups and an increase in total AMPKα in PAT in the PIUN group. In twins, however, there was an increase in the abundance of mTOR in the PCUN group and an increase in PDK2 and decrease in total AMPKα in the PIUN group. Thus exposure to periconceptional undernutrition programs changes in the thermogenic capacity and the insulin and fatty acid oxidation signaling pathway in visceral fat, and these effects are different in singletons and twins. These findings are important, as the thermogenic capacity of brown fat and the insulin sensitivity of visceral fat are important determinants of the risk of developing obesity and an insulin resistance phenotype in later life.
Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity
Publisher: Springer Science and Business Media LLC
Date: 22-12-2010
DOI: 10.1007/S00467-009-1407-3
Abstract: There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant.
Impact and mechanisms of fetal physiological programming
Publisher: American Physiological Society
Date: 2005
Considerations in selecting postoperative analgesia for pregnant sheep following fetal instrumentation surgery
Publisher: Oxford University Press (OUP)
Date: 25-06-2019
DOI: 10.1093/AF/VFZ019
Periconceptional undernutrition in normal and overweight ewes leads to increased adrenal growth and epigenetic changes in adrenal IGF2/H19 gene in offspring
Publisher: Wiley
Date: 06-04-2010
DOI: 10.1096/FJ.09-154294
Abstract: Adverse conditions in early life result in increased activation of the hypothalamo-pituitary-adrenal axis and in stress responsiveness in offspring. We have developed a model in which "donor" ewes are either normally nourished or overnourished prior to a period of dietary restriction, before transfer of the embryo at 6-7 d after conception to a ewe of normal weight and nutritional history. A moderate restriction of energy intake during the periconceptional period in both normal weight and overweight ewes resulted in increased adrenal mass in male and female lambs and an increased cortisol response to stress in female lambs. The increase in adrenal weight in lambs exposed to periconceptional undernutrition was associated with a decrease in the adrenal mRNA expression of IGF2 and decreased methylation in the proximal CTCF-binding site in the differentially methylated region of the IGF2/H19 gene. Thus, weight loss in both normal and overweight mothers during the periconceptional period results in epigenetic modification of IGF2 in the adrenal gland, adrenal overgrowth, and increased vulnerability to stress in offspring. Determining the appropriate approach to weight loss in the periconceptional period may therefore be important in overweight or obese women seeking to become pregnant.
Impact of maternal late gestation undernutrition on surfactant maturation, pulmonary blood flow and oxygen delivery measured by magnetic resonance imaging in the sheep fetus
Publisher: Wiley
Date: 22-09-2021
DOI: 10.1113/JP281292
Abstract: Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero . The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery ( ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 to 140 days’ gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial compared to control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins ( SFTP ) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery and to the fetal lung. There was a negative relationship between left pulmonary artery flow and to the left lung with SFTP‐B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. image Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signalling pathways involved in fetal lung development, pulmonary haemodynamics and oxygen delivery in sheep using a combination of molecular and magnetic resonance imaging (MRI) techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial . Surfactant maturation was not affected however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary haemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with surfactant protein B mRNA and protein expression in late gestation.
Label‐free imaging of redox status and collagen deposition showing metabolic differences in the heart
Publisher: Wiley
Date: 28-11-2018
Abstract: The heart has high metabolic demand to maintain function. The primary source of energy supply to support correct contractile muscle function differs between a fetus and an adult. In fetal life, ATP is primarily generated by glycolysis and lactate oxidation, whereas following birth, there is a shift towards a reliance on mitochondrial metabolism and fatty acid oxidation. This change in metabolic status is an adaptation to different fuel availability, oxygenation and growth patterns. In this study, we have employed 2-photon excitation fluorescence microscopy to define the relationship between two critical metabolic cofactors nicotinamide adenine dinucleotide(P)H and flavin adenine dinucleotide, effectively utilizing a redox ratio to differentiate between the metabolic status in fetal (proliferative) and adult (quiescent/hypertrophic) hearts. Two-photon imaging was also used to visually confirm the known increase in collagen deposition in the adult heart. The changes observed were consistent with a hypertrophic growth profile and greater availability of fatty acids in the adult heart, compared to the proliferative fetal heart. Two-photon excitation fluorescence microscopy is therefore a convenient imaging technology that enables the monitoring of striated muscle architecture and the metabolic status of heart tissue. This imaging technology can potentially be employed to visualize cardiac and other muscle pathologies.
Do improvements in clinical practice guidelines alter pregnancy outcomes in asthmatic women? A single-center retrospective cohort study
Publisher: Informa UK Limited
Date: 20-04-2023
Mitochondrial imaging in live or fixed tissues using a luminescent iridium complex
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41598-018-24672-W
Abstract: Mitochondrial morphology is important for the function of this critical organelle and, accordingly, altered mitochondrial structure is exhibited in many pathologies. Imaging of mitochondria can therefore provide important information about disease presence and progression. However, mitochondrial imaging is currently limited by the availability of agents that have the capacity to image mitochondrial morphology in both live and fixed s les. This can be particularly problematic in clinical studies or large, multi-centre cohort studies, where tissue archiving by fixation is often more practical. We previously reported the synthesis of an iridium coordination complex [Ir( ppy ) 2 ( MeTzPyPhCN )] + where ppy is a cyclometalated 2-phenylpyridine and TzPyPhCN is the 5-(5-(4-cyanophen-1-yl)pyrid-2-yl)tetrazolate ligand and showed that this complex (herein referred to as IraZolve-Mito) has a high specificity for mitochondria in live cells. Here we demonstrate that IraZolve-Mito can also effectively stain mitochondria in both live and fixed tissue s les. The staining protocol proposed is versatile, providing a universal procedure for cell biologists and pathologists to visualise mitochondria.
Investigating outcomes associated with medication use during pregnancy: A review of methodological challenges and observational study designs
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.REPROTOX.2012.01.006
Abstract: In the absence of randomised controlled trials, knowledge of outcomes associated with medication use during pregnancy is dependent on observational studies. Numerous observational study designs exist, with the decision on which is most appropriate depending on a number of factors, including the exposure and outcome under investigation and knowledge of key methodological issues. This review provides an overview of the key methodological issues involved in undertaking observational studies to investigate medication use during pregnancy, including selection bias, exposure and outcome classification, information bias, confounding and statistical analysis. This review also discusses observational study types used to investigate outcomes associated with medication use during pregnancy and summarises their relative strengths and weaknesses. Knowledge of the strengths, weaknesses and methodological issues associated with observational studies can assist clinicians in making assessments about the validity and applicability of results presented in order to provide the best recommendations to patients.
Effect of periconceptional nutrition on the growth, behaviour and survival of the neonatal lamb
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.ANIREPROSCI.2015.06.017
Abstract: Periconceptional nutrition (PCN) can influence foetal hypothalamo-pituitary adrenal (HPA) axis function and alter cortisol secretion with possible consequences for maturation and growth of major organs, gestation length and behaviour. We examined effects of PCN on phenotype and survival of the neonatal lamb in 466 Merino ewes allocated to treatments providing 70%, 100% and 150% respectively, of maintenance requirements for 17 days prior and 6 days after insemination. Gestation length and birth weight for lambs in PCN treatment groups was similar (P > 0.05) but low PCN decreased the size of the neonate (crown-rump-length and metacarpal length P < 0.05). A subset of lambs euthanased at 5 days of age further showed that low PCN decreased the amount of peri-renal fat (P < 0.05) and increased liver mass (P < 0.05) while high PCN increased neck thymus and ovary mass (P < 0.05). Neonatal lambs from low PCN ewes returned faster to their mothers after release (P < 0.05) and contacted the udder in the shortest time (P < 0.05). Significant interactions between PCN treatment and sex (P < 0.05) and between PCN treatment and ewe age (P < 0.05) were also observed for time lambs took to follow the ewe. Survival of lambs was similar but potential differences may have been masked by favourable weather conditions. In conclusion, this study provides evidence of significant changes in lamb growth and development dependent on PCN and, for the first time, links these changes with significant changes in behaviour of the neonate. The impact of these effects on lamb survival and potential reproductive capacity of female offspring remains to be determined.
Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fe
Publisher: Cambridge University Press (CUP)
Date: 30-08-2013
DOI: 10.1017/S2040174413000378
Abstract: Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo–pituitary–adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of ‘periconceptional’ undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and ‘early preimplantation’ undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11β-hydroxysteroid dehydrogenase type 1 and 2 (11βHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136–138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 1 7 region of the GR gene. In twin fetuses, the pituitary 11βHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.
Contractile and Ca2+-handling properties of the right ventricular papillary muscle in the late-gestation sheep fetus
Publisher: American Physiological Society
Date: 09-2006
DOI: 10.1152/JAPPLPHYSIOL.00214.2006
Abstract: The force-generating capacity of cardiomyocytes rapidly changes during gestation and early postnatal life coinciding with a transition in cardiomyocyte nucleation in both mice and rats. Changes in nucleation, in turn, appear to coincide with important changes in the excitation-contraction coupling architecture. However, it is not clear whether similar changes are observed in other mammals in which this transition occurs prenatally, such as sheep. Using small (70–300 μM diameter) chemically skinned cardiomyocyte bundles from the right ventricular papillary muscle of sheep fetuses at 126–132 and 137–140 days (d) gestational age (GA), we aimed to examine whether changes in cardiomyocyte nucleation during late gestation coincided with developmental changes in excitation-contraction coupling parameters (e.g., Ca 2+ uptake, Ca 2+ release, and force development). All experiments were conducted at room temperature (23 ± 1°C). We found that the proportion of mononucleate cardiomyocytes decreased significantly with GA (126–132d, 45.7 ± 4.7%, n = 7 137–140d, 32.8 ± 1.6%, n = 6 P 0.05). When we then examined force development between the two groups, there was no significant difference in either the maximal Ca 2+ -activated force (6.73 ± 1.54 mN/mm 2 , n = 14 vs. 6.55 ± 1.25 mN/mm 2 , n = 7, respectively) or the Ca 2+ sensitivity of the contractile apparatus (pCa at 50% maximum Ca 2+ -activated force: 126–132d, 6.17 ± 0.06, n = 14 137–140d, 6.24 ± 0.08, n = 7). However, sarcoplasmic reticulum (SR) Ca 2+ uptake rates (but not Ca 2+ release) increased with GA ( P 0.05). These data reveal that during late gestation in sheep when there is a major transition in cardiomyocyte nucleation, SR Ca 2+ uptake rates increase, which would influence total SR Ca 2+ content and force production.
MitoQ as an antenatal antioxidant treatment improves markers of lung maturation in healthy and hypoxic pregnancy
Publisher: Wiley
Date: 19-07-2023
DOI: 10.1113/JP284786
Abstract: Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. However, whether antenatal antioxidant therapy confers any benefit on lung development in complicated pregnancies has not yet been investigated. Here, we tested the hypothesis that maternal antenatal treatment with MitoQ will protect the developing lung in hypoxic pregnancy in sheep, a species with similar fetal lung developmental milestones as humans. Maternal treatment with MitoQ during late gestation promoted fetal pulmonary surfactant maturation and an increase in the expression of lung mitochondrial complexes III and V independent of oxygenation. Maternal treatment with MitoQ in hypoxic pregnancy also increased the expression of genes regulating liquid reabsorption in the fetal lung. These data support the hypothesis tested and suggest that MitoQ as an antenatal targeted antioxidant treatment may improve lung maturation in the late gestation fetus. image Chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. MitoQ is a targeted antioxidant that uses the cell and the mitochondrial membrane potential to accumulate within the mitochondria. Treatment of healthy or hypoxic pregnancy with MitoQ, increases the expression of key molecules involved in surfactant maturation, lung liquid reabsorption and in mitochondrial proteins driving ATP synthesis in the fetal sheep lung. There were no detrimental effects of MitoQ treatment alone on the molecular components measured in the present study, suggesting that maternal antioxidant treatment has no effect on other components of normal maturation of the surfactant system.
Placental insufficiency induces a sexually dimorphic response in the expression of cardiac growth and metabolic signalling molecules upon exposure to a postnatal western diet in guinea pigs
Publisher: Cambridge University Press (CUP)
Date: 26-07-2022
DOI: 10.1017/S204017442100043X
Abstract: There is a strong relationship between low birth weight (LBW) and an increased risk of developing cardiovascular disease (CVD). In postnatal life, LBW offspring are becoming more commonly exposed to the additional independent CVD risk factors, such as an obesogenic diet. However, how an already detrimentally programmed LBW myocardium responds to a secondary insult, such as an obesogenic diet (western diet WD), during postnatal life is ill defined. Herein, we aimed to determine in a pre-clinical guinea pig model of CVD, both the independent and interactive effects of LBW and a postnatal WD on the molecular pathways that regulate cardiac growth and metabolism. Uterine artery ablation was used to induce placental insufficiency (PI) in pregnant guinea pigs to generate LBW offspring. Normal birth weight (NBW) and LBW offspring were weaned onto either a Control diet or WD. At ˜145 days after birth (young adulthood), male and female offspring were humanely killed, the heart weighed and left ventricle tissue collected. The mRNA expression of signalling molecules involved in a pathological hypertrophic and fibrotic response was increased in the myocardium of LBW male, but not female offspring, fed a WD as was the mRNA expression of transcription factors involved in fatty acid oxidation. The mRNA expression of glucose transporters was downregulated by LBW and WD in male, but not female hearts. This study has highlighted a sexually dimorphic cardiac pathological hypertrophic and fibrotic response to the secondary insult of postnatal WD consumption in LBW offspring.
Bright lights down under: Metal ion complexes turning the spotlight on metabolic processes at the cellular level
Publisher: Elsevier BV
Date: 11-2018
Low birth weight activates the renin-angiotensin system, but limits cardiac angiogenesis in early postnatal life
Publisher: Wiley
Date: 02-2015
DOI: 10.14814/PHY2.12270
Antidepressant use and gestational hypertension: does evidence support causality?
Publisher: Wiley
Date: 08-04-2013
Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb
Publisher: Wiley
Date: 29-09-2011
Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
Publisher: Frontiers Media SA
Date: 10-06-2020
Maternal sleep during pregnancy and poor fetal outcomes: A scoping review of the literature with meta-analysis
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.SMRV.2018.03.004
Abstract: There is a wealth of evidence to say that sleep impacts maternal health during pregnancy, however, little has been published on fetal health and maternal sleep. This scoping review summarises current literature on maternal sleep including sleep disordered breathing, sleep quality, sleep duration and supine sleep position, as these relate to fetal outcomes specifically birth weight, growth, preterm birth and stillbirth. An overall interpretation of the studies evaluated shows that events occurring during maternal sleep such as obstructive sleep apnea, sleep disruption and sleep position may have a negative effect on the fetus resulting in altered growth, gestational length and even death. These effects are biologically and physically plausible. In conclusion, there is limited and often conflicting information on maternal sleep and fetal outcomes. However, existing evidence suggests that this is an important area for future research. This area is ripe for investigation if there is to be reduction in the physical, emotional, and financial burden of poor fetal outcomes related to maternal sleep.
Impact of resveratrol‐mediated increase in uterine artery blood flow on fetal haemodynamics, blood pressure and oxygenation in sheep
Publisher: Wiley
Date: 16-03-2021
DOI: 10.1113/EP089237
The impact of intrauterine growth restriction on cytochrome P450 enzyme expression and activity
Publisher: Elsevier BV
Date: 09-2020
Long term impact of prenatal exposure to SSRIs on growth and body weight in childhood: Evidence from animal and human studies
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.REPROTOX.2012.03.003
Abstract: Prenatal exposure to SSRIs has the potential to alter fetal 5-HT signalling during critical periods of development: the long-term consequences of which have not been well studied. Of particular interest are the potential long-term effects of prenatal SSRI exposure on growth and body weight in later life, given the role of the serotonergic system in regulating food intake and body weight. Animal studies demonstrate that changes in 5-HT homeostasis during critical periods of fetal development can lead to sex-specific molecular and functional alterations in the serotonergic and HPA systems, leading to an increased risk of overweight in male, but not female, offspring in later life. This review highlights the evidence and the need for studies in humans to determine whether prenatal SSRI exposure is associated with alterations in child growth and body weight and the importance of delineating these effects from those of the underlying maternal illness.
Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats
Publisher: Wiley
Date: 11-2003
Periconceptional nutrition and the early programming of a life of obesity or adversity
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.PBIOMOLBIO.2010.12.004
Abstract: Women entering pregnancy with a high body weight and fat mass have babies at increased risk of becoming overweight or obese in childhood and later life. It is not known, whether exposure to a high level of maternal nutrition before pregnancy and exposure to a high transplacental nutrient supply in later pregnancy act through similar mechanisms to program later obesity. Using the pregnant sheep we have shown that maternal overnutrition in late pregnancy results in an upregulation of PPARγ activated genes in fetal visceral fat and a subsequent increase in the mass of subcutaneous fat in the postnatal lamb. Exposure to maternal overnutrition during the periconceptional period alone, however, results in an increase in total body fat mass in female lambs only with a dominant effect on visceral fat depots. Thus the early programming of later obesity may result from 'two hits', the first occurring as a result of maternal overnutrition during the periconceptional period and the second occurring as a result of increased fetal nutrition in late pregnancy. Whilst a short period of dietary restriction during the periconceptional period reverses the impact of periconceptional overnutrition on the programming of obesity, it also results in an increased lamb adrenal weight and cortisol stress response, together with changes in the epigenetic state of the insulin like growth factor 2 (IGF2) gene in the adrenal. Thus, not all of the effects of dietary restriction in overweight or obese mother in the periconceptional period may be beneficial in the longer term.
Maternal-placental-fetal drug metabolism is altered by late gestation undernutrition in the pregnant ewe
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.LFS.2022.120521
Abstract: Maternal undernutrition during pregnancy disrupts both fetal growth and development with perturbations to certain physiological processes within the maternal-fetal-placental unit, including metabolic function. However, it is unknown if hypoglycemia during pregnancy alters maternal-fetal-placental drug metabolism as mediated by cytochrome P450 (CYP) enzymes. Despite this, hypoglycemia reduces CYP enzyme activity in non-pregnant animals. We therefore hypothesised that in a sheep model of hypoglycemia induced by late gestation undernutrition (LGUN), maternal-fetal-placental CYP activity would be reduced, and that fetal glucose infusion (LGUN+G) would rescue reduced CYP activity. At 115d gestation (term, 150d), ewes were allocated to control (100% metabolic energy requirement (MER) n = 11), LGUN (50% MER n = 7) or LGUN+G (50% MER + fetal glucose infusion n = 6) and maintained on their diets until post-mortem. Maternal-fetal-placental CYP activity assays were performed at 131-133d gestation. Microsomes were isolated from placenta and fetal liver collected at 139-142d gestation and incubated with CYP-specific probe drugs. Metabolite concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). CYP2C19 and CYP3A were undetectable in placenta or fetal liver, and CYP1A2 was undetectable in the fetal liver. Placental-specific CYP1A2 and CYP2D6 activity and hepatic-specific CYP2D6 activity were unaffected by LGUN. Maternal-fetal-placental CYP1A2 activity was reduced in response to LGUN in the maternal compartment only. Reduced maternal-fetal-placental CYP1A2 activity, but not placental-specific CYP1A2 activity, may lead to the developing fetus being exposed to increased concentrations of CYP1A2-specific substrates and suggests further consideration of drug dosing is required in instances of late gestation maternal undernutrition.
Does the intrauterine growth-restricted fetus benefit from antenatal glucocorticoids?
Publisher: Informa UK Limited
Date: 03-2010
DOI: 10.1586/EOG.10.4
The Periconceptional Environment and Cardiovascular Disease: Does In Vitro Embryo Culture and Transfer Influence Cardiovascular Development and Health?
Publisher: MDPI AG
Date: 18-02-2015
DOI: 10.3390/NU7031378
Periconceptional Undernutrition Programs Changes in Insulin-Signaling Molecules and MicroRNAs in Skeletal Muscle in Singleton and Twin Fetal Sheep1
Publisher: Oxford University Press (OUP)
Date: 2014
DOI: 10.1095/BIOLREPROD.113.109751
Abstract: Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We determined the effect of maternal undernutrition in the periconceptional period (PCUN, i.e., 60 days prior to 6 days after conception) and the preimplantation period (PIUN, i.e., 0-6 days after conception) on mRNA expression and protein abundance of key insulin-signaling molecules as well as the global microRNA expression in quadriceps muscle of singleton and twin fetal sheep in late gestation. In singleton fetuses, exposure to PCUN resulted in lower protein abundance of PIK3CB (P < 0.01), PRKCZ (P < 0.05), and pPRKCZ (Thr410) (P < 0.05) in skeletal muscle compared to controls. In PIUN singletons, there was a higher protein abundance of IRS1 (P < 0.05), PDPK1 (P < 0.05), and SLC2A4 (P < 0.05) compared to controls. In twins, PCUN resulted in higher protein abundance of IRS1 (P < 0.05), AKT2 (P < 0.05), PDPK1 (P < 0.05), and PRKCZ (P < 0.001), while PIUN also resulted in higher protein abundance of IRS1 (P < 0.05), PRKCZ (P < 0.001), and SLC2A4 (P < 0.05) in fetal muscle compared to controls. There were specific patterns of the types and direction of changes in the expression of 22 microRNAs in skeletal muscle after exposure to PCUN or PIUN and clear differences in these patterns between singleton and twin pregnancies. These findings provide evidence that maternal undernutrition around the time of conception induces changes in the expression of microRNAs, which may play a role in altering the abundance of the key insulin-signaling molecules in skeletal muscle and in the association between PCUN undernutrition and insulin resistance in adult life.
Subgroup Discovery for Election Analysis: A Case Study in Descriptive Data Mining
Publisher: Springer Berlin Heidelberg
Date: 2010
Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/327638
Regulation of fetal lung development in response to maternal overnutrition
Publisher: Wiley
Date: 27-10-2013
Abstract: With the worldwide obesity epidemic, the proportion of women entering pregnancy overweight or obese has increased significantly in recent years. Babies born to obese women are at an increased risk of respiratory complications at birth and in childhood. In addition to maternal diabetes, there are a number of metabolic changes that the fetus of an overnourished mother experiences in utero that may modulate lung development and represent the mechanisms underlying the increased risk of respiratory complications. Herein we highlight a series of factors associated with the intrauterine environment of an overnourished mother that may impact on fetal lung development and lead to an increased risk of complications at birth or in postnatal life.
Improving pregnancy outcomes in humans through studies in sheep.
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00391.2017
Abstract: Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
Development of a method to determine cytochrome P450 1A2, 2C9, 2D6 and 3A4 activity sheep hepatic microsomes
Publisher: Elsevier BV
Date: 11-2020
Risk of Respiratory Distress Syndrome and Efficacy of Glucocorticoids: Are They the Same in the Normally Grown and Growth-Restricted Infant?
Publisher: Springer Science and Business Media LLC
Date: 11-2016
Abstract: Administration of glucocorticoids (GCs) to women at risk of preterm delivery reduces the newborn's risk of respiratory distress syndrome (RDS) by 35% to 40% however, not all infants respond to this treatment. Fetal growth restriction (FGR) increases the risk of prematurity, perinatal morbidity, and mortality. This review aims to synthesize current evidence reporting the difference in RDS risk between FGR and normally grown infants (Question 1) and whether antenatal GC administration reduces the risk of RDS morbidity in FGR infants (Question 2). Systematic searches were performed, and after screening, a total of 27 and 9 citations were eligible for inclusion for Questions 1 and 2, respectively. In order to answer the two questions, odds ratios and 95% confidence intervals were calculated for all studies. The evidence was equivocal for a difference in risk of RDS in FGR compared with normally grown infants. Despite antenatal GC administration, there was evidence suggesting that the risk of RDS persists in FGR infants. The range of risk of RDS morbidity observed between studies is likely influenced by the definitions (RDS and FGR), gestational age, and small s le sizes of FGR infants evaluated. In addition, RDS morbidity may be related to the heterogeneous nature of FGR etiologies (including maternal, placental, and/or fetal factors). Further understanding of RDS morbidity and responsiveness to current treatments in FGR infants at a range of gestational ages, larger s le sizes, and stratification according to the specific etiology of FGR, may lead to improved respiratory outcomes at birth in this obstetric subpopulation.
Hepatic cytochrome P450 function is reduced by life-long Western diet consumption in guinea pig independent of birth weight
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.LFS.2021.120133
Abstract: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of triglycerides and cholesterol within the liver and dysregulation of specific hepatic cytochrome P450 (CYPs) activity. CYPs are involved in the metabolism of endogenous and exogenous chemicals. Hepatic CYP activity is dysregulated in human studies and animal models of a Western diet (WD) or low birth weight (LBW) independently, but the additive effects of LBW and postnatal WD consumption are unknown. As such, the aim of this study was to determine the independent and combined effect of birthweight and postnatal diet on hepatic CYP activity in a guinea pig model. LBW was generated via uterine artery ablation at mid gestation (term = 70 days gestation). Normal birthweight (NBW) and LBW pups were allocated either a control diet (CD) or WD at weaning. After 4 months of dietary intervention, guinea pigs were humanely killed, and liver tissue collected for biochemical and functional hepatic CYP activity analyses. Independent of birthweight, functional activity of CYP3A was significantly reduced in female and male WD compared to CD animals (female, P < 0.0001 male, P = 0.004). Likewise, CYP1A2 activity was significantly reduced in male WD compared to CD animals (P = 0.020) but this same reduction was not observed in females. Diet, but not birthweight, significantly altered hepatic CYP activity in both sexes, and the effect of diet appeared to be greater in males. These findings may have clinical implications for the management of NAFLD and associated co-morbidities between the sexes.
Fetal growth restriction and hypertension in the offspring: mechanistic links and therapeutic directions
Publisher: Elsevier BV
Date: 09-2020
Maternal periconceptional and first trimester protein restriction in beef heifers: effects on placental parameters and fetal and neonatal calf development
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/RD19017
Abstract: Few studies have investigated the effects of nutrition during the periconception and early gestation periods on fetal and placental development in cattle. In this study, nulliparous yearling heifers (n=360) were in idually fed a diet high or low in protein (HPeri and LPeri) beginning 60 days before conception. From 24 to 98 days after conception, half of each treatment group was changed to the alternative high- or low-protein diet (HPost and LPost) yielding four groups in a 2×2 factorial design. A subset of heifers (n=46) was necropsied at 98 days after conception and fetoplacental development assessed. Placentome number and volume decreased in response to LPeri and LPost diets respectively. Absolute lung, pancreas, septum and ventricle weights decreased in LPost versus HPost fetuses, whereas the post-conception diet altered absolute and relative liver and brain weights depending on sex. Similarly, changes in fetal hepatic gene expression of factors regulating growth, glucose output and lipid metabolism were induced by protein restriction in a sex-specific manner. At term, neonatal calf and placental measures were not different. Protein restriction of heifers during the periconception and early gestation periods alters fetoplacental development and hepatic gene expression. These changes may contribute to functional consequences for progeny, but this may not be apparent from gross morphometry at birth.
Antenatal steroids and the IUGR fetus: are exposure and physiological effects on the lung and cardiovascular system the same as in normally grown fetuses?
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/839656
Abstract: Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia.
Nutrition in Pregnancy: Optimising Maternal Diet and Fetal Adaptations to Altered Nutrient Supply
Publisher: MDPI AG
Date: 04-06-2016
DOI: 10.3390/NU8060342
253 IMPACT OF LOW BIRTH WEIGHT ON THE EXPRESSION OF THE RENIN-ANGIOTENSIN SYSTEM, FACTORS WHICH REGULATE AUTOPHAGY, FIBROSIS AND CAPILLARY DENSITY IN THE HEART DURING EARLY POSTNATAL LIFE
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2012
Cerebral blood flow during spontaneous and cholinergically induced behavioral states in the sheep fetus
Publisher: Springer Science and Business Media LLC
Date: 05-2005
Recent developments on the role of epigenetics in obesity and metabolic disease
Publisher: Springer Science and Business Media LLC
Date: 11-07-2015
Cardiorespiratory consequences of intrauterine growth restriction: Influence of timing, severity and duration of hypoxaemia
Publisher: Elsevier BV
Date: 07-2020
Maternal undernutrition around the time of conception and embryo number each impact on the abundance of key regulators of cardiac growth and metabolism in the fetal sheep heart
Publisher: Cambridge University Press (CUP)
Date: 05-08-2013
DOI: 10.1017/S2040174413000354
Abstract: Poor maternal nutrition before and during pregnancy is associated with an increased risk of cardiovascular disease in later life. To determine the impact of maternal undernutrition during the periconceptional (PCUN: −45 days to 6 days) and preimplantation (PIUN: 0–6 days) periods on cardiac growth and metabolism, we have quantified the mRNA and protein abundance of key regulators of cardiac growth and metabolism in the left ventricle of the sheep fetus in late gestation. The cardiac protein abundance of AMP-activated protein kinase (AMPK), phospho-acetyl CoA carboxykinase (ACC) and pyruvate dehydrogenase kinase-4 (PDK-4) were decreased, whereas ACC was increased in singletons in the PCUN and PIUN groups. In twins, however, cardiac ACC was decreased in the PCUN and PIUN groups, and carnitine palmitoyltransferase-1 (CPT-1) was increased in the PIUN group. In singletons, the cardiac abundance of insulin receptor β (IRβ) was decreased in the PCUN group, and phosphoinositide-dependent protein kinase-1 (PDPK-1) was decreased in the PCUN and PIUN groups. In twins, however, the cardiac abundance of IRβ and phospho-Akt substrate 160kDa (pAS160) were increased in the PIUN group. The cardiac abundance of insulin-like growth factor-2 receptor (IGF-2R), protein kinase C alpha (PKCα) and mammalian target of rapamycin (mTOR) were decreased in PCUN and PIUN singletons and extracellular-signal-regulated kinase (ERK) was also decreased in the PIUN singletons. In contrast, in twins, cardiac abundance of IGF-2R and PKCα were increased in the PCUN and PIUN groups, phospho-ribosomal protein S6 (pRPS6) was increased in the PCUN group, and ERK and eukaryotic initiation factor 4E (eIF4E) were also increased in the PIUN fetuses. In conclusion, maternal undernutrition limited to around the time of conception is sufficient to alter the abundance of key factors regulating cardiac growth and metabolism and this may increase the propensity for cardiovascular diseases in later life.
Prenatal exposure to selective serotonin reuptake inhibitors and childhood overweight at 7 years of age
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.ANNEPIDEM.2013.08.005
Abstract: To investigate a possible association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and childhood overweight at 7 years of age. Information on pregnancy exposures and prevalence of childhood overweight at 7 years of age was obtained from the Danish National Birth Cohort. Overweight was classified as body mass index >85th percentile, based on age and sex. Based on an a priori hypothesis, we conducted analyses stratified by child sex to examine sex-specific differences. Of eligible pregnant women, 127 reported using an SSRI, 490 reported having a psychiatric illness but no psychotropic medication use, and 35,568 reported no psychiatric illness and no psychotropic medication use. In comparison to children of mothers with a psychiatric illness but no SSRI use during pregnancy, prenatal SSRI exposure overall was not associated with an increased risk of childhood overweight (adjusted prevalence ratio [aPR] 1.12 95% confidence interval 0.71 to 1.77). However, when stratified according to child sex, an increased risk was observed among males (aPR 1.78 95% CI, 1.01 to 3.12) but not females (aPR 0.86 95% CI, 0.37 to 1.99). In contrast, female children of mothers with a psychiatric illness but no SSRI use during pregnancy were more likely to be overweight than female children of unexposed mothers (aPR 1.45 95% CI, 1.05 to 2.02). This association was not mirrored among males (aPR 1.06 95% CI, 0.76 to 1.50). We observed the potential for opposing sex-specific differences in the long-term effects of prenatal exposure to SSRI use and/or maternal psychiatric illness on childhood overweight. Limitations of the present study suggest that further research in this area may be warranted with larger s le sizes and longer follow-up.
Intrauterine Growth Restriction and Differential Patterns of Hepatic Growth and Expression of IGF1, PCK2, and HSDL1 mRNA in the Sheep Fetus in Late Gestation1
Publisher: Oxford University Press (OUP)
Date: 06-2009
Normalisation of surfactant protein -A and -B expression in the lungs of low birth weight lambs by 21 days old
Publisher: Public Library of Science (PLoS)
Date: 26-09-2017
Preclinical models of maternal asthma and progeny outcomes: a scoping review protocol
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-05-2023
Alteration of cardiac glucose metabolism in association to low birth weight: experimental evidence in lambs with left ventricular hypertrophy
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.METABOL.2013.06.013
Abstract: Intrauterine growth restriction that results in low birth weight (LBW) has been linked to the onset of pathological cardiac hypertrophy. An altered transition from a fetal to an adult energy metabolism phenotype, with increased reliance on glucose rather than fatty acids for energy production, could help explain this connection. We have therefore investigated cardiac metabolism in relation to left ventricular hypertrophy in LBW lambs, at 21days after birth. The expression of regulatory molecules involved in cardiac glucose and fatty acid metabolism was measured using real-time PCR and Western blotting. A section of the left ventricle was fixed for Periodic Acid Schiff staining to determine tissue glycogen content. There was increased abundance of insulin signalling pathway proteins (phospho-insulin receptor, insulin receptor and phospho-Akt) and the glucose transporter (GLUT)-1, but no change in GLUT-4 or glycogen content in the heart of LBW compared to ABW lambs. There was, however, increased abundance of cardiac pyruvate dehydrogenase kinase 4 (PDK-4) in LBW compared to ABW lambs. There were no significant changes in the mRNA expression of components of the peroxisome proliferator activated receptor regulatory complex or proteins involved in fatty acid metabolism. We concluded that LBW induced left ventricular hypertrophy was associated with increased GLUT-1 and PDK-4, suggesting increased glucose uptake, but decreased efficacy for the conversion of glucose to ATP. A reduced capacity for energy conversion could have significant implications for vulnerability to cardiovascular disease in adults who are born LBW.
Effect of Environment and Aging on the Pulmonary Surfactant System
Publisher: Elsevier
Date: 2014
A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth
Publisher: Wiley
Date: 13-03-2023
DOI: 10.1113/JP284137
Abstract: Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease. image
The reliance on α‐adrenergic receptor stimuli for blood pressure regulation in the chronically hypoxaemic fetus is not dependent on post‐ganglionic activation
Publisher: Wiley
Date: 27-12-2020
DOI: 10.1113/JP280693
Second-harmonic generation and two-photon-excited autofluorescence microscopy of cardiomyocytes: Quantification of cell volume and myosin filaments
Publisher: SPIE-Intl Soc Optical Eng
Date: 2008
DOI: 10.1117/1.3027970
Abstract: The ability to quantify changes in cardiomyocyte and myosin volume across gestation and in response to intrauterine insults will lead to a better understanding of the link between low birth weight and an increased risk of heart disease in adult life. We present the use of second-harmonic generation (SHG) and two-photon excitation autofluorescence (TPEF) microscopy to image unstained isolated fetal cardiomyocytes. The simultaneous collection of these two images provides a wealth of information on the morphology of cardiomyocytes. The SHG signal provides high-contrast images of myosin filaments and the TPEF signal can be used to clearly visualize cell morphology. A potential issue may arise if SHG microscopy is performed exclusively due to the lack of sensitivity to distinguish between mononucleated and binucleated cardiomyocytes. However, TPEF microscopy has the ability to efficiently separate the two types of cardiomyocytes. In addition, quantitative analysis of the SHG and TPEF images enables quantification of myosin filament level and accurate determination of cell volume. In short, we demonstrate that advanced nonlinear optical microscopy can be used to answer key physiological questions in the early origins of adult health with increased accuracy and speed compared to previously used methods.
Minimal changes in telomere length after a 12-week dietary intervention with almonds in mid-age to older, overweight, and obese Australians: results of a randomised clinical trial
Publisher: Cambridge University Press (CUP)
Date: 11-05-2022
DOI: 10.1017/S0007114521001549
Abstract: Diet is a modifiable risk factor for chronic disease and a potential modulator of telomere length (TL). The study aim was to investigate associations between diet quality and TL in Australian adults after a 12-week dietary intervention with an almond-enriched diet (AED). Participants (overweight/obese, 50–80 years) were randomised to an AED ( n 62) or isoenergetic nut-free diet (NFD, n 62) for 12 weeks. Diet quality was assessed using a Dietary Guideline Index (DGI), applied to weighed food records, that consists of ten components reflecting adequacy, variety and quality of core food components and discretionary choices within the diet. TL was measured by quantitative PCR in s les of lymphocytes, neutrophils, and whole blood. There were no significant associations between DGI scores and TL at baseline. Diet quality improved with AED and decreased with NFD after 12 weeks (change from baseline AED + 9·8 %, NFD − 14·3 % P 0·001). TL increased in neutrophils (+9·6 bp, P = 0·009) and decreased in whole blood, to a trivial extent (–12·1 bp, P = 0·001), and was unchanged in lymphocytes. Changes did not differ between intervention groups. There were no significant relationships between changes in diet quality scores and changes in lymphocyte, neutrophil or whole blood TL. The inclusion of almonds in the diet improved diet quality scores but had no impact on TL mid-age to older Australian adults. Future studies should investigate the impact of more substantial dietary changes over longer periods of time.
Placental MRI Predicts Fetal Oxygenation and Growth Rates in Sheep and Human Pregnancy
Publisher: Wiley
Date: 28-08-2022
Abstract: Magnetic resonance imaging (MRI) assessment of fetal blood oxygen saturation (SO 2 ) can transform the clinical management of high‐risk pregnancies affected by fetal growth restriction (FGR). Here, a novel MRI method assesses the feasibility of identifying normally grown and FGR fetuses in sheep and is then applied to humans. MRI scans are performed in pregnant ewes at 110 and 140 days (term = 150d) gestation and in pregnant women at 28 +3 ± 2 +5 weeks to measure feto‐placental SO 2 . Birth weight is collected and, in sheep, fetal blood SO 2 is measured with a blood gas analyzer (BGA). Fetal arterial SO 2 measured by BGA predicts fetal birth weight in sheep and distinguishes between fetuses that are normally grown, small for gestational age, and FGR. MRI feto‐placental SO 2 in late gestation is related to fetal blood SO 2 measured by BGA and body weight. In sheep, MRI feto‐placental SO 2 in mid‐gestation is related to fetal SO 2 later in gestation. MRI feto‐placental SO 2 distinguishes between normally grown and FGR fetuses, as well as distinguishing FGR fetuses with and without normal Doppler in humans. Thus, a multi‐compartment placental MRI model detects low placental SO 2 and distinguishes between small hypoxemic fetuses and normally grown fetuses.
Characterisation of cytochrome P450 isoenzyme activity in sheep liver and placental microsomes
Publisher: Elsevier BV
Date: 2023
Early origins of heart disease: Low birth weight and determinants of cardiomyocyte endowment
Publisher: Wiley
Date: 28-08-2012
DOI: 10.1111/J.1440-1681.2011.05649.X
Abstract: 1. World-wide epidemiological and experimental animal studies demonstrate that adversity in fetal life, resulting in intrauterine growth restriction, programmes the offspring for a greater susceptibility to ischaemic heart disease and heart failure in adult life. 2. After cardiogenesis, cardiomyocyte endowment is determined by a range of hormones and signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of multinucleation/terminal differentiation. 3. The small fetus may have reduced cardiomyocyte endowment owing to the impact of a suboptimal intrauterine environment on the signalling pathways that regulate cardiomyocyte proliferation, apoptosis and the timing of terminal differentiation.
GABA(A) receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM not REM sleep
Publisher: Wiley
Date: 28-02-2003
Impact of the Addition of a Centrifugal Pump in a Preterm Miniature Pig Model of the Artificial Placenta
Publisher: Frontiers Media SA
Date: 22-07-2022
DOI: 10.3389/FPHYS.2022.925772
Abstract: The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit ( n = 12 98 ± 4 days 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.
Introduction: Celebrating Emeritus Scientia Professor Eugenie R Lumbers AM and Professor Caroline McMillen
Publisher: Wiley
Date: 27-10-2013
The role of miRNA regulation in fetal cardiomyocytes, cardiac maturation and the risk of heart disease in adults
Publisher: Wiley
Date: 28-06-2018
DOI: 10.1113/JP276072
Antidepressant Use in Late Gestation and Breastfeeding Rates at Discharge from Hospital
Publisher: SAGE Publications
Date: 12-2016
Abstract: Few studies have investigated breastfeeding outcomes among women exposed to antidepressants. This study aimed to evaluate the association between antidepressant use in late gestation and maternal psychiatric illness on breastfeeding rates at discharge from hospital. The authors conducted a retrospective cohort study of 32,662 women delivering live-born singletons between January 2001 and December 2008. Electronic hospital records were used to obtain data on antidepressant exposure during late gestation and whether mothers were breastfeeding at discharge from hospital following delivery. Five hundred seventy-five women received a dispensing for an antidepressant in late gestation (exposed), 1,552 did not receive a dispensing for an antidepressant but had a reported psychiatric illness (disease comparison), and 30,535 served as nonexposed controls. Exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital compared with nonexposed women, adjusted odds ratio ( AOR) = 0.63, 95% confidence interval (CI) [0.50-0.80], but no statistically significant difference was observed when compared with women in the disease comparison group, AOR = 0.83, 95% CI [0.65-1.07]. In stratified analyses, compared with women in the disease comparison group, exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital if their neonate was delivered at term, AOR = 0.73, 95% CI [0.55-0.98], but not preterm, AOR = 1.24, 95% CI [0.66-2.32]. While antidepressant use is associated with a reduction in breastfeeding rates, this association appears to be strongly influenced by factors such as underlying maternal psychiatric illness. Overall, these results highlight that these women may benefit from additional education and support to improve breastfeeding rates.
Restriction of placental function alters heart development in the sheep fetus
Publisher: American Physiological Society
Date: 07-2007
DOI: 10.1152/AJPREGU.00798.2006
Abstract: Placental insufficiency, resulting in restriction of fetal substrate supply, is a major cause of intrauterine growth restriction (IUGR) and increased neonatal morbidity. Fetal adaptations to placental restriction maintain the growth of key organs, including the heart, but the impact of these adaptations on in idual cardiomyocytes is unknown. Placental and hence fetal growth restriction was induced in fetal sheep by removing the majority of caruncles in the ewe before mating (placental restriction, PR). Vascular surgery was performed on 13 control and 11 PR fetuses at 110–125 days of gestation (term: 150 ± 3 days). PR fetuses with a mean gestational Po 2 17 mmHg were defined as hypoxic. At postmortem ( or days), fetal hearts were collected, and cardiomyocytes were isolated and fixed. Proliferating cardiomyocytes were counted by immunohistochemistry of Ki67 protein. Cardiomyocytes were stained with methylene blue to visualize the nuclei, and the proportion of mononucleated cells and length and width of cardiomyocytes were measured. PR resulted in chronic fetal hypoxia, IUGR, and elevated plasma cortisol concentrations. Although there was no difference in relative heart weights between control and PR fetuses, there was an increase in the proportion of mononucleated cardiomyocytes in PR fetuses. Whereas mononucleated and binucleated cardiomyocytes were smaller, the relative size of cardiomyocytes when expressed relative to heart weight was larger in PR compared with control fetuses. The increase in the relative proportion of mononucleated cardiomyocytes and the relative sparing of the growth of in idual cardiomyocytes in the growth-restricted fetus are adaptations that may have long-term consequences for heart development in postnatal life.
PPARγ activation in late gestation does not promote surfactant maturation in the fetal sheep lung
Publisher: Cambridge University Press (CUP)
Date: 07-01-2021
DOI: 10.1017/S204017442000135X
Abstract: Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ , surfactant proteins ( SFTP-A, -B, -C , and -D ), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1 . Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B . However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.
Australian perspectives: outcomes from the 2016 ANZ DOHaD Scientific Meeting
Publisher: Cambridge University Press (CUP)
Date: 26-09-2017
Chronic hypoxaemia as a molecular regulator of fetal lung development: implications for risk of respiratory complications at birth
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.PRRV.2016.08.011
Abstract: Exposure to altered intrauterine conditions during pregnancy influences both fetal growth and organ development. Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction (IUGR) that may influence the risk of infants experiencing respiratory complications at birth. There are a variety of signalling pathways that contribute to normal fetal lung development at the molecular level. The specific molecular effects of chronic hypoxaemia associated with IUGR on lung development are likely to be dependent on the specific aetiology (maternal, placental and/or fetal factors) that can alter hormone concentrations, oxygen and nutrient transport to the fetus. This review discusses molecular pathways that may contribute to altered fetal lung maturation following exposure to chronic hypoxaemia. Importantly, these studies highlight that the heterogeneity in respiratory outcomes at birth in this obstetric subpopulation are likely determined by the timing, severity and duration of chronic hypoxaemia encountered by the fetus during pregnancy.
Maternal allergic asthma during pregnancy alters fetal lung and immune development in sheep: potential mechanisms for programming asthma and allergy
Publisher: Wiley
Date: 03-07-2019
DOI: 10.1113/JP277952
Adverse intrauterine environment and cardiac miRNA expression
Publisher: MDPI AG
Date: 06-12-2017
DOI: 10.3390/IJMS18122628
Intrauterine growth restriction alters the activity of drug metabolising enzymes in the maternal-placental-fetal unit
Publisher: Elsevier BV
Date: 11-2021
Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring
Publisher: Bioscientifica
Date: 11-2013
DOI: 10.1530/REP-13-0219
Abstract: Exposure to dietary restriction during the periconceptional period in either normal or obese ewes results in increased adrenal growth and a greater cortisol response to stress in the offspring, but the mechanisms that programme these changes are not fully understood. Activation of the angiotensin type 1 receptor (AT1R) has been demonstrated to stimulate adrenal growth and steroidogenesis. We have used an embryo transfer model in the sheep to investigate the effects of exposure to dietary restriction in normal or obese mothers from before and 1 week after conception on the methylation status, expression, abundance and localisation of key components of the renin–angiotensin system (RAS) in the adrenal of post-natal lambs. Maternal dietary restriction in normal or obese ewes during the periconceptional period resulted in an increase in angiotensin-converting enzyme (ACE) and AT1R abundance in the absence of changes in the methylation status or mRNA expression of ACE and AT1R in the adrenal of the offspring. Exposure to maternal obesity alone also resulted in an increase in adrenal AT1R abundance. There was no effect of maternal dietary restriction or obesity on ACE2 and AT2R or on ERK, calcium/calmodulin-dependent kinase II abundance, and their phosphorylated forms in the lamb adrenal. Thus, weight loss around the time of conception, in both normal-weight and obese ewes, results in changes within the intra-adrenal RAS consistent with increased AT1R activation. These changes within the intra-adrenal RAS system may contribute to the greater adrenal stress response following exposure to signals of adversity in the periconceptional period.
Redox ratio in the left ventricle of the growth restricted fetus is positively correlated with cardiac output
Publisher: Wiley
Date: 16-09-2021
Abstract: Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long‐term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two‐photon microscopy and phase‐contrast MRI (PC‐MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two‐photon imaging revealed that the left ventricle of IUGR fetuses (at 140–141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC‐MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood.
Advanced imaging of fetal cardiac function
Publisher: Frontiers Media SA
Date: 23-05-2023
DOI: 10.3389/FCVM.2023.1206138
Abstract: Over recent decades, a variety of advanced imaging techniques for assessing cardiovascular physiology and cardiac function in adults and children have been applied in the fetus. In many cases, technical development has been required to allow feasibility in the fetus, while an appreciation of the unique physiology of the fetal circulation is required for proper interpretation of the findings. This review will focus on recent advances in fetal echocardiography and cardiovascular magnetic resonance (CMR), providing ex les of their application in research and clinical settings. We will also consider future directions for these technologies, including their ongoing technical development and potential clinical value.
Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant ewe and increases fetal but not cardiac growth
Publisher: Wiley
Date: 10-2019
DOI: 10.1113/JP278110
Themed issue on the DOHaD workshop on Fetal, Placental and Pediatric Imaging
Publisher: Cambridge University Press (CUP)
Date: 28-01-2021
miR-133a and Target Gene Expression in the Foetus and 6 Month Old Sheep Heart in Response to Myocardial Infarction
Publisher: Elsevier BV
Date: 08-2016
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Publisher: Informa UK Limited
Date: 02-01-2016
Early restriction of placental growth results in placental structural and gene expression changes in late gestation independent of fetal hypoxemia
Publisher: Wiley
Date: 12-2016
DOI: 10.14814/PHY2.13049
Impact of periconceptional and preimplantation undernutrition on factors regulating myogenesis and protein synthesis in muscle of singleton and twin fetal sheep.
Publisher: Apollo - University of Cambridge Repository
Date: 2020
DOI: 10.17863/CAM.56180
Exposed or not exposed? Exploring exposure classification in studies using administrative data to investigate outcomes following medication use during pregnancy
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1007/S00228-011-1154-9
Abstract: The aim of this systematic review was to examine and compare differences in the way medication exposures are classified in studies using linked administrative data to investigate outcomes following medication use during pregnancy. This was undertaken with a focus on studies investigating specific neonatal outcomes following prenatal exposure to selective serotonin reuptake inhibitors (SSRIs). We searched Medline and Embase to identify studies that used linked administrative data to investigate specific neonatal outcomes (congenital malformations, birth weight, gestational age) following prenatal exposure to SSRIs. Key factors such as dose, duration and timing of exposure were inconsistently addressed in the studies identified. In addition, there was a great deal of variability in the way medication exposures were classified and how women who stop taking their medication before or during early pregnancy are handled in analyses. Furthermore, there are issues in assuming how and when women who receive a dispensing for a medication actually take it during pregnancy. This creates a great deal of uncertainty around medication exposure during pregnancy in studies using linked administrative data, potentially resulting in biased risk estimates. There is a need for greater focus on determining the most effective and accurate way of using linked administrative data to investigate outcomes following medication use during pregnancy in an effort to minimise potential biases.
Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic
Publisher: Wiley
Date: 30-05-2018
DOI: 10.1113/JP274948
Maternal Fluoxetine Infusion Does Not Alter Fetal Endocrine and Biophysical Circadian Rhythms in Pregnant Sheep
Publisher: Springer Science and Business Media LLC
Date: 07-2005
DOI: 10.1016/J.JSGI.2005.03.001
Abstract: Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FX), commonly known as Prozac (Eli Lilly & Co, Indianapolis, IN). FX potentiates serotoninergic neurotransmission and serotonin has been implicated in the regulation of circadian rhythms. We have therefore investigated the effect of chronic administration of FX on maternal and fetal circadian rhythms in sheep. Following an initial bolus dose of 70 mg FX, an 8-day continuous infusion of FX (n = 11, 98.5 microg/kg x d) was performed. Controls (n = 13) were treated with sterile water vehicle only. Maternal and fetal plasma melatonin and prolactin concentrations were determined every 3 hours for 24 hours and then every 6 hours for 24 hours beginning on the fourth day of infusion. FX treatment did not alter either the basal or circadian rhythms of either maternal or fetal plasma melatonin and prolactin concentrations. Fetal cardiovascular and behavioral state parameters were measured continuously. While the incidence of low-voltage (LV) electrocortical (ECOG) activity was significantly reduced in fetuses in the FX group, there was no effect of FX on the diurnal rhythms in fetal arterial pressure, heart rate, breathing movements, or behavioral state. These results show that maternal FX treatment does not result in significant alterations in maternal and fetal hormonal and behavioral circadian rhythms.
The effect of placental restriction on insulin signaling and lipogenic pathways in omental adipose tissue in the postnatal lamb
Publisher: Cambridge University Press (CUP)
Date: 13-06-2013
DOI: 10.1017/S2040174413000202
Abstract: Intrauterine growth restriction (IUGR) followed by accelerated growth after birth is associated with an increased risk of abdominal (visceral) obesity and insulin resistance in adult life. The aim of the present study was to determine the impact of IUGR on mRNA expression and protein abundance of insulin signaling molecules in one of the major visceral fat depots, the omental adipose depot. IUGR was induced by placental restriction, and s les of omental adipose tissue were collected from IUGR ( n = 9, 5 males, 4 females) and Control ( n = 14, 8 males, 6 females) neonatal lambs at 21 days of age. The mRNA expression of the insulin signaling molecules, AMP-kinase (AMPK) and adipogenic/lipogenic genes was determined by qRT-PCR, and protein abundance by Western Blotting. AMPKα2 mRNA expression was increased in male IUGR lambs (0.015 ± 0.002 v. 0.0075 ± 0.0009, P 0.001). The proportion of the AMPK pool that was phosphorylated (%P-AMPK) was lower in IUGR lambs compared with Controls independent of sex (39 ± 9% v. 100 ± 18%, P 0.001). The mRNA expression and protein abundance of insulin signaling proteins and adipogenic/lipogenic genes was not different between groups. Thus, IUGR is associated with sex-specific alterations in the mRNA expression of AMPKα2 and a reduction in the percentage of the total AMPK pool that is phosphorylated in the omental adipose tissue of neonatal lambs, before the onset of visceral obesity. These molecular changes would be expected to promote lipid accumulation in the omental adipose depot and may therefore contribute to the onset of visceral adiposity in IUGR animals later in life.
Imaging and lipidomics methods for lipid analysis in metabolic and cardiovascular disease
Publisher: Cambridge University Press (CUP)
Date: 12-07-2017
DOI: 10.1017/S2040174417000496
Abstract: Cardiometabolic diseases exhibit changes in lipid biology, which is important as lipids have critical roles in membrane architecture, signalling, hormone synthesis, homoeostasis and metabolism. However, Developmental Origins of Health and Disease studies of cardiometabolic disease rarely include analysis of lipids. This short review highlights some ex les of lipid pathology and then explores the technology available for analysing lipids, focussing on the need to develop imaging modalities for intracellular lipids. Analytical methods for studying interactions between the complex endocrine and intracellular signalling pathways that regulate lipid metabolism have been critical in expanding our understanding of how cardiometabolic diseases develop in association with obesity and dietary factors. Biochemical methods can be used to generate detailed lipid profiles to establish links between lifestyle factors and metabolic signalling pathways and determine how changes in specific lipid subtypes in plasma and homogenized tissue are associated with disease progression. New imaging modalities enable the specific visualization of intracellular lipid traffic and distribution in situ . These techniques provide a dynamic picture of the interactions between lipid storage, mobilization and signalling, which operate during normal cell function and are altered in many important diseases. The development of methods for imaging intracellular lipids can provide a dynamic real-time picture of how lipids are involved in complex signalling and other cell biology pathways and how they ultimately regulate metabolic function/homoeostasis during early development. Some imaging modalities have the potential to be adapted for in vivo applications, and may enable the direct visualization of progression of pathogenesis of cardiometabolic disease after poor growth in early life.
Let’s Talk about Placental Sex, Baby: Understanding Mechanisms That Drive Female- and Male-Specific Fetal Growth and Developmental Outcomes
Publisher: MDPI AG
Date: 15-06-2021
DOI: 10.3390/IJMS22126386
Abstract: It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific “evolutionary advantage” likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.
Systematic review: Impact of resveratrol exposure during pregnancy on maternal and fetal outcomes in animal models of human pregnancy complications—Are we ready for the clinic?
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.PHRS.2019.04.020
Abstract: Resveratrol (RSV) has been reported to have potential beneficial effects in the complicated pregnancy. Various pregnancy complications lead to a suboptimal in utero environment that impacts fetal growth during critical windows of development. Detrimental structural changes to key organ systems in utero persist into adult life and predispose offspring to an increased risk of chronic non-communicable metabolic diseases such as cardiovascular disease, diabetes and obesity. The aim of this systematic review was to determine the effect of gestational RSV exposure on both maternal and fetal outcomes. Publicly available databases (n = 8) were searched for original studies reporting maternal and/or fetal outcomes after RSV exposure during pregnancy irrespective of species. Of the 115 studies screened, 31 studies were included in this review. RSV exposure occurred for different durations across a range of species (Rats n = 18, Mice n = 7, Japanese Macaques n = 3 and Sheep n = 3), models of complicated pregnancy (eg. maternal dietary manipulations, gestational diabetes, maternal hypoxia, teratogen exposure, etc.), dosages and administration routes. Maternal and fetal outcomes differed not only based on the model of complicated pregnancy assessed but also as a result of species. Given the heterogenic nature of these studies, further investigation assessing RSV exposure during the complicated pregnancy is warranted. In order to make an informed decision regarding the use of RSV to intervene in pregnancy complications, we suggest a minimum data set for consideration in future studies.
Fetal growth restriction, nutrition, and the renin-angiotensin system-reply
Publisher: Elsevier BV
Date: 03-2021
Increased Alveolar Heparan Sulphate and Reduced Pulmonary Surfactant Amount and Function in the Mucopolysaccharidosis IIIA Mouse
Publisher: MDPI AG
Date: 08-04-2021
Abstract: Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease with significant neurological and skeletal pathologies. Respiratory dysfunction is a secondary pathology contributing to mortality in MPS IIIA patients. Pulmonary surfactant is crucial to optimal lung function and has not been investigated in MPS IIIA. We measured heparan sulphate (HS), lipids and surfactant proteins (SP) in pulmonary tissue and bronchoalveolar lavage fluid (BALF), and surfactant activity in healthy and diseased mice (20 weeks of age). Heparan sulphate, ganglioside GM3 and bis(monoacylglycero)phosphate (BMP) were increased in MPS IIIA lung tissue. There was an increase in HS and a decrease in BMP and cholesteryl esters (CE) in MPS IIIA BALF. Phospholipid composition remained unchanged, but BALF total phospholipids were reduced (49.70%) in MPS IIIA. There was a reduction in SP-A, -C and -D mRNA, SP-D protein in tissue and SP-A, -C and -D protein in BALF of MPS IIIA mice. Captive bubble surfactometry showed an increase in minimum and maximum surface tension and percent surface area compression, as well as a higher compressibility and hysteresis in MPS IIIA surfactant upon dynamic cycling. Collectively these biochemical and biophysical changes in alveolar surfactant are likely to be detrimental to lung function in MPS IIIA.
Postnatal consequences of prenatal nicotine exposure
Publisher: Cambridge University Press (CUP)
Date: 20-05-2015
Sheep models of intrauterine growth restriction: Fetal adaptations and consequences
Publisher: Wiley
Date: 21-05-2008
DOI: 10.1111/J.1440-1681.2008.04975.X
Abstract: 1. Intrauterine growth restriction (IUGR) has been associated with poor perinatal health outcomes. Animal models have been used to investigate why IUGR is associated with a poor prognosis. The sheep has been used extensively as an experimental model for IUGR with poor placental substrate supply to the fetus induced using a range of methods, including the surgical ablation of the majority of endometrial caruncles prior to conception, experimental induction of maternal hyperthermia, ligation of an umbilical artery or embolization of the placenta in late gestation and maternal overnutrition in the pregnant adolescent ewe. 2. Fetal adaptations to fetal hypoxia and hypoglycaemia include activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system and an associated increase in circulating cortisol and noradrenaline concentrations. Fetal cardiovascular responses vary according to the method used to induce placental dysfunction. 3. Although an array of experimental models has been used to induce placental dysfunction at different stages of fetal development, each leads to remarkably similar fetal growth, metabolic, neuroendocrine and cardiovascular adaptations and consequences. The extent and range of the fetal physiological adaptations to chronic placental insufficiency are determined by the duration of exposure and the degree of the severity of substrate supply restriction. 4. The present review summarizes how sheep models of IUGR have provided an increased understanding of the nature of the fetal adaptations to IUGR, their longer-term physiological consequences and how to improve clinical management of IUGR in human pregnancies.
Neonatal Outcomes After Late-Gestation Exposure to Selective Serotonin Reuptake Inhibitors
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2012
DOHaD in Indigenous populations: DOHaD, epigenetics, equity and race
Publisher: Cambridge University Press (CUP)
Date: 02-2019
Impact of maternal overnutrition on gluconeogenic factors and methylation of the phosphoenolpyruvate carboxykinase promoter in the fetal and postnatal liver
Publisher: Springer Science and Business Media LLC
Date: 14-10-2014
DOI: 10.1038/PR.2013.178
Abstract: Exposure to maternal obesity or hyperglycemia increases the risk of obesity and poor glucose tolerance in the offspring. We hypothesized that maternal overnutrition in late pregnancy would result in (i) lower methylation in the promoter region of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C PCK1) and (ii) higher expression of hepatic gluconeogenic factors in the fetal and postnatal lamb. Ewes were fed 100% (n = 18) or ~155% (n = 17) of energy requirements from 115 d gestation, and livers were collected at ~140 d gestation or 30 d postnatal age. Maternal overnutrition resulted in a decrease in hepatic expression of the mitochondrial form of PEPCK (PEPCK-M PCK2) but not of PEPCK-C or glucose-6-phosphatase (G6PHOS) before and after birth. Hepatic expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), peroxisome proliferator-activated receptor α (PPARα), PEPCK-C, G6PHOS, and 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), but not PEPCK-M, was higher in the postnatal lamb compared with that in the fetal lamb. The level of PCK1 methylation was paradoxically approximately twofold higher in the postnatal liver compared with that in the fetal liver. Maternal overnutrition programs a decrease in hepatic PEPCK-M in the offspring and as ~50% of total hepatic PEPCK is PEPCK-M, the longer-term consequences of this decrease may be significant.
Placental adaptations in growth restriction
Publisher: MDPI AG
Date: 08-01-2015
DOI: 10.3390/NU7010360
Epigenetics and human obesity
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/IJO.2014.34
Abstract: Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. This paper provides a systematic review of studies investigating the association between obesity and either global, site-specific or genome-wide methylation of DNA. Studies on the impact of pre- and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an in idual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify unfavourable epigenomic profiles.
Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues
Publisher: Wiley
Date: 23-12-2020
Abstract: The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two-photon microscopy. Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism.
Intrafetal glucose infusion alters glucocorticoid signaling and reduces surfactant protein mRNA expression in the lung of the late-gestation sheep fetus
Publisher: American Physiological Society
Date: 09-2014
DOI: 10.1152/AJPREGU.00053.2014
Abstract: Increased circulating fetal glucose and insulin concentrations are potential inhibitors of fetal lung maturation and may contribute to the pathogenesis of respiratory distress syndrome (RDS) in infants of diabetic mothers. In this study, we examined the effect of intrafetal glucose infusion on mRNA expression of glucose transporters, insulin-like growth factor signaling, glucocorticoid regulatory genes, and surfactant proteins in the lung of the late-gestation sheep fetus. The numerical density of the cells responsible for producing surfactant was determined using immunohistochemistry. Glucose infusion for 10 days did not affect mRNA expression of glucose transporters or IGFs but did decrease IGF-1R expression. There was reduced mRNA expression of the glucocorticoid-converting enzyme HSD11B-1 and the glucocorticoid receptor, potentially reducing glucocorticoid responsiveness in the fetal lung. Furthermore, surfactant protein ( SFTP) mRNA expression was reduced in the lung following glucose infusion, while the number of SFTP-B-positive cells remained unchanged. These findings suggest the presence of a glucocorticoid-mediated mechanism regulating delayed maturation of the surfactant system in the sheep fetus following glucose infusion and provide evidence for the link between abnormal glycemic control during pregnancy and the increased risk of RDS in infants of uncontrolled diabetic mothers.
DOHaD in the land down under: 11th World Congress 2019
Publisher: Cambridge University Press (CUP)
Date: 29-09-2020
The early origins of later obesity: Pathways and mechanisms
Publisher: Springer Netherlands
Date: 2009
DOI: 10.1007/978-1-4020-9173-5_8
Abstract: Excess bodyweight is the sixth most important risk factor contributing to the overall burden of disease worldwide. In excess of a billion adults and 10% of all children are now classified as overweight or obese. The main adverse consequences of obesity are the metabolic syndrome, cardiovascular disease and type 2 diabetes and a diminished average life expectancy. It has been argued that the complex pathological processes underlying obesity reflect environmental and genetic interactions, and in iduals from disadvantaged communities seem to have greater risks than more affluent in iduals partly because of fetal and postnatal programming interactions. Abundant evidence indicates that the obesity epidemic reflects progressive secular and age-related decreases in physical activity, together with passive over-consumption of energy dense foods despite neurobiological processes designed to regulate energy balance. The difficulty in treating obesity, however, highlights the deficits in our current understanding of the pathophysiology which underlies the initiation and chronic nature of this disorder. Large population based studies in Europe and North America in healthy women and in women with gestational diabetes have demonstrated that there are clear relationships between maternal and fetal nutrient supply, fetal growth patterns and the subsequent risk of obesity and glucose intolerance in childhood and adult life. In this review we discuss the impact of fetal nutrition on the biology of the developing adipocyte and brain and the growing evidence base supporting an intergenerational cycle of obesity.
Antenatal Glucocorticoid Treatment of The Growth-restricted Fetus: Benefit or Cost?
Publisher: Springer Science and Business Media LLC
Date: 06-2009
Abstract: Women at risk of preterm labor are commonly treated with antenatal glucocorticoids to reduce neonatal complications, including respiratory distress syndrome. Despite the benefits of antenatal glucocorticoid for neonatal lung function, they are associated with negative cardiovascular outcomes. Among this population, there is a group of intrauterine growth-restricted fetuses in which substrate supply is reduced and these fetuses must undergo a range of cardiovascular adaptations to survive. Interestingly, the cardiovascular changes caused by antenatal glucocorticoid in normally grown fetuses are contrary to the cardiovascular adaptations that the intrauterine growth-restricted fetus must make to survive. Hence, the possibility exists that antenatal glucocorticoid in intrauterine growth-restricted infants may compromise cardiovascular development. This review first provides an overview of general antenatal glucocorticoid effects, before outlining the effects on cardiorespiratory development in normally grown fetuses, the cardiovascular adaptations that occur in the intrauterine growth-restricted fetus and finally integrating this with the very limited evidence for the effect of antenatal glucocorticoid in intrauterine growth-restricted infants.
Maternal Obesity and the Early Origins of Childhood Obesity: Weighing Up the Benefits and Costs of Maternal Weight Loss in the Periconceptional Period for the Offspring
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/585749
Abstract: There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring.
Umbilical vein infusion of prostaglandin I2 increases ductus venosus shunting of oxygen‐rich blood but does not increase cerebral oxygen delivery in the fetal sheep
Publisher: Wiley
Date: 23-08-2020
DOI: 10.1113/JP280019
Magnetic resonance imaging of placentome development in the pregnant Ewe
Publisher: Elsevier BV
Date: 02-2021
Impact of in vitro embryo culture and transfer on blood pressure regulation in the adolescent lamb
Publisher: Cambridge University Press (CUP)
Date: 13-11-2021
DOI: 10.1017/S2040174420001014
Abstract: Nutrition during the periconceptional period influences postnatal cardiovascular health. We determined whether in vitro embryo culture and transfer, which are manipulations of the nutritional environment during the periconceptional period, dysregulate postnatal blood pressure and blood pressure regulatory mechanisms. Embryos were either transferred to an intermediate recipient ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and a methyl donor (IVCHS+M) for 6 days. Basal blood pressure was recorded at 19–20 weeks after birth. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after varying doses of phenylephrine (PE). mRNA expression of signaling molecules involved in blood pressure regulation was measured in the renal artery. Basal MAP did not differ between groups. Baroreflex sensitivity, set point, and upper plateau were also maintained in all groups after PE stimulation. Adrenergic receptors alpha-1A (αAR1A), alpha-1B (αAR1B), and angiotensin II receptor type 1 (AT1R) mRNA expression were not different from controls in the renal artery. These results suggest there is no programmed effect of ET or IVC on basal blood pressure or the baroreflex control mechanisms in adolescence, but future studies are required to determine the impact of ET and IVC on these mechanisms later in the life course when developmental programming effects may be unmasked by age.
No Evidence for an Enhanced Role of Endothelial Nitric Oxide in the Maintenance of Arterial Blood Pressure in the IUGR Sheep Fetus
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.PLACENTA.2009.05.003
Abstract: The fetus makes a number of physiological adaptations to a restriction of placental substrate supply, including a decrease in body growth and an increase in peripheral vasoconstriction which maintains mean arterial pressure (MAP) and supports a redistribution of cardiac output to key fetal organs. It is not known, however, whether chronic restriction of placental substrate supply results in an enhanced or diminished role for vasodilators such as endothelial nitric oxide in the regulation of MAP. We hypothesised that there is an increased contribution of NO to blood pressure regulation in growth restricted fetuses and that a 2h infusion of a nitric oxide synthase inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME) would result in an augmented rise in MAP in chronically hypoxemic, placentally restricted (PR, n=8) fetuses compared to controls (n=6) in late gestation. There was no difference in the increase in fetal MAP and decrease in HR during l-NAME infusion between Control and PR fetuses. In the PR group, fetuses with lower mean gestational PaO(2) had a lower increase in MAP during l-NAME infusion. Thus we have found no evidence for an enhanced role of NO in the maintenance of MAP in the chronically hypoxemic IUGR fetus.
In utero substrate restriction by placental insufficiency or maternal undernutrition decreases optical redox ratio in foetal perirenal fat
Publisher: Wiley
Date: 10-01-2021
Association of early and late maternal smoking during pregnancy with offspring body mass index at 4 to 5 years of age
Publisher: Cambridge University Press (CUP)
Date: 05-10-2015
DOI: 10.1017/S2040174415007151
Abstract: The objective was to investigate the association between early and late maternal smoking during pregnancy on offspring body mass index (BMI). We undertook a retrospective cohort study using linked records from the Women’s and Children’s Health Network in South Australia. Among a cohort of women delivering a singleton, live-born infants between January 2000 and December 2005 ( n =7658), 5961 reported not smoking during pregnancy, 297 reported quitting smoking during the first trimester of pregnancy, and 1400 reported continued smoking throughout pregnancy. Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance programme. The main outcome measure was age- and sex-specific BMI z-score. At 4 to 5 years, mean ( s.d. ) BMI z-score was 0.40 (1.05), 0.60 (1.07) and 0.65 (1.18) in children of mothers who reported never smoking, quitting smoking and continued smoking during pregnancy, respectively. Compared with the group of non-smokers, both quitting smoking and continued smoking were associated with an increase in child BMI z-score of 0.15 (95% confidence interval: 0.01–0.29) and 0.21 (0.13–0.29), respectively. A significant dose–response relationship was also observed between the number of cigarettes smoked per day on average during the second half of pregnancy and the increase in offspring BMI z-score ( P .001). In conclusion, any maternal smoking in pregnancy, even if mothers quit, is associated with an increase in offspring BMI at 4 to 5 years of age.
Maternal asthma during pregnancy and risks of allergy and asthma in progeny: a systematic review protocol
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-03-2021
Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation
Publisher: Wiley
Date: 07-05-2017
DOI: 10.1113/JP273842
Rosiglitazone Increases the Expression of Peroxisome Proliferator-Activated Receptor-gamma Target Genes in Adipose Tissue, Liver, and Skeletal Muscle in the Sheep Fetus in Late Gestation
Publisher: The Endocrine Society
Date: 11-06-2009
DOI: 10.1210/EN.2009-0462
Abstract: Exposure to maternal overnutrition increases the expression of peroxisome proliferator-activated receptor-γ (PPARγ) in adipose tissue before birth, and it has been proposed that the precocial activation of PPARγ target genes may lead to increased fat deposition in postnatal life. In this study, we determined the effect of intrafetal administration of a PPARγ agonist, rosiglitazone, on PPARγ target gene expression in fetal adipose tissue as well indirect actions of rosiglitazone on fetal liver and skeletal muscle. Osmotic pumps containing rosiglitazone (n = 7) or vehicle (15% ethanol, n = 7) were implanted into fetuses at 123–126 d gestation (term = 150 ± 3 d gestation). At 137–141 d gestation, tissues were collected and mRNA expression of PPARγ, lipoprotein lipase (LPL), adiponectin, and glycerol-3-phosphate dehydrogenase (G3PDH) in adipose tissue, PPARα and PPARγ-coactivator 1α (PGC1α) in liver and muscle and phosphoenolpyruvate carboxykinase (PEPCK) in liver determined by quantitative real-time RT-PCR. Plasma insulin concentrations were lower in rosiglitazone-treated fetuses (P & 0.02). Rosiglitazone treatment resulted in increased expression of LPL and adiponectin mRNA (P & 0.01) in fetal adipose tissue. The expression of PPARα mRNA in liver (P & 0.05) and PGC1α mRNA (P & 0.02) in skeletal muscle were also increased by rosiglitazone treatment. Rosiglitazone treatment increased expression of PPARγ target genes within fetal adipose tissue and also had direct or indirect actions on the fetal liver and muscle. The effects of activating PPARγ in fetal adipose tissue mimic those induced by prenatal overnutrition, and it is therefore possible that activation of PPARγ may be the initiating mechanism in the pathway from prenatal overnutrition to postnatal obesity.
Open or closed: Changes in ductus arteriosus flow patterns at birth using 4D flow MRI in newborn piglets
Publisher: Wiley
Date: 26-08-2021
DOI: 10.14814/PHY2.14999
Editorial: Outcomes from the 2018 Australia and New Zealand developmental origins of health and disease (ANZ DOHaD) scientific meeting
Publisher: Cambridge University Press (CUP)
Date: 20-05-2020
Restriction of placental growth results in greater hypotensive response to alpha-adrenergic blockade in fetal sheep during late gestation
Publisher: Wiley
Date: 21-02-2005
A fibre optic fluorescence sensor to measure redox level in tissues
Publisher: SPIE
Date: 02-01-2018
DOI: 10.1117/12.2283352
The Journal of Developmental Origins of Health and Disease (JDOHaD) celebrates the contribution of women in DOHaD on International Women’s Day
Publisher: Cambridge University Press (CUP)
Date: 08-03-2020
Haemodynamics and cerebral oxygenation of neonatal piglets in the immediate ex utero period supported by mechanical ventilation or ex utero oxygenator
Publisher: Wiley
Date: 04-2021
DOI: 10.1113/JP280803
Abstract: The margin of human viability has extended to the extremes of gestational age ( weeks) when the lungs are immature and ventilator‐induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air‐breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post‐oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT). Post‐transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets. The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post‐transition period. Gestational age at birth is a major predictor of wellbeing the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability ( weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm‐associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post‐transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO 2 ) decreased from in utero levels post‐transition however, cerebral regional oxygen saturation (rSO 2 ) was maintained at fetal‐like levels. OXY piglets became hypoxaemic and retained CO 2 . Whether OXY piglets are able to maintain cerebral rSO 2 under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow.
Adverse Intrauterine Environment and Cardiac miRNA Expression.
Publisher: Apollo - University of Cambridge Repository
Date: 2018
DOI: 10.17863/CAM.21877
Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: a study within the Danish National Birth Cohort
Publisher: Wiley
Date: 15-09-2015
Abstract: To investigate the impact of prenatal antidepressant exposure on behavioural problems in children at 7 years of age. Nationwide population-based study. Danish National Birth Cohort. A cohort of 49 178 pregnant women recruited between 1996 and 2002. Data obtained from computer-assisted telephone interviews twice during pregnancy were used to identify children born to: (i) depressed women who took antidepressants during pregnancy (n = 210) (ii) depressed women who did not take any antidepressants during pregnancy (n = 231) and (iii) healthy women who were not depressed (n = 48 737). Childhood behavioural problems at 7 years of age were examined using the validated Danish parent-report version of the Strengths and Difficulties Questionnaire (SDQ). SDQ scores. No associations were observed between prenatal antidepressant exposure and abnormal SDQ scores for overall problem behaviour (adjusted relative risk, aRR 1.00 95% confidence interval, 95% CI 0.49-2.05), hyperactivity/inattention (aRR 0.99 95% CI 0.56-1.75), or peer problems (aRR 1.04 95% CI 0.57-1.91). Although prenatal antidepressant exposure appeared to be associated with abnormal SDQ scores on the subscales of emotional symptoms (aRR 1.68 95% CI 1.18-2.38) and conduct problems (aRR 1.58 95% CI 1.03-2.42), these associations were significantly attenuated following adjustment for antenatal mood status (aRR 1.20 95% CI 0.85-1.70 and aRR 1.19 95% CI 0.77 1.83, respectively). Untreated prenatal depression was associated with an increased risk of all behavioural outcomes evaluated, compared with unexposed children, with significant attenuation following adjustment for antenatal mood status. The results of this study suggest that independent of maternal illness, prenatal antidepressant exposure is not associated with an increased risk of behavioural problems in children at 7 years of age. Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems.
Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus
Publisher: Wiley
Date: 03-2021
DOI: 10.14814/PHY2.14742
Activation of IGF-2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus
Publisher: Wiley
Date: 29-10-2012
The fetal sheep lung does not respond to cortisol infusion during the late canalicular phase of development
Publisher: Wiley
Date: 11-2013
DOI: 10.1002/PHY2.130
Maternal Obesity or Weight Loss Around Conception Impacts Hepatic Fatty Acid Metabolism in the Offspring
Publisher: Wiley
Date: 10-04-2014
DOI: 10.1002/OBY.20752
Abstract: To determine the impact of maternal obesity or weight loss during the periconceptional period on programming of lipid metabolism in the liver of the offspring. An embryo transfer model was used to investigate the effects of exposure to either maternal obesity and/or weight loss before and for 1-week post-conception on the abundance of key molecules regulating hepatic fatty acid oxidation and lipid synthesis in the 4-month-old lamb. Periconceptional maternal obesity resulted in decreased hepatic PPARα, PGC1α and GCN5 abundance and increased hepatic SIRT1 and AMPKα1, AMPKα2 and SREBP1 abundance in the offspring. Maternal weight loss in obese ewes did not ablate all of these effects of maternal obesity on hepatic metabolism in the lamb. Weight loss in normal weight ewes also resulted in decreased hepatic PGC1α and GCN5 and increased AMPKα2 abundance in the offspring. Exposure of the oocyte/embryo to either maternal obesity or weight loss during the periconceptional period has long term consequences for hepatic lipid metabolism. These findings highlight the sensitivity of the early embryo to maternal nutrition and the need for dietary interventions which maximize metabolic benefits and minimize metabolic costs for the next generation.
Late gestation over nutrition alters the cardiac metabolic profile
Publisher: Elsevier BV
Date: 2015
Embryo number and periconceptional undernutrition in the sheep have differential effects on adrenal epigenotype, growth, and development
Publisher: American Physiological Society
Date: 15-07-2014
DOI: 10.1152/AJPENDO.00051.2012
Abstract: Exposure to poor maternal nutrition around the time of conception results in an early prepartum activation of the fetal pituitary-adrenal axis and in increased adrenal growth and stress response after birth associated with epigenetic changes in a differentially methylated region (DMR) of adrenal IGF2/H19. We have determined the effects of maternal undernutrition during the periconceptional period (PCUN: 70% of control intake from 60 days before until 6 days after conception) and early preimplantation period (PIUN: 70% of control intake for 6 days after conception) on fetal plasma ACTH and cortisol concentrations and fetal adrenal ACTHR, StAR, 3βHSD, CYP11B, CYP17, TGFβ1, IGF1, IGF1R, IGF2, and IGF2R mRNA expression and the methylation level of sites within the DMRs of IGF2/H19 and IGF2R in the adrenal of twin and singleton fetuses at 136–138 days gestation. Being a twin resulted in a delayed prepartum increase in fetal ACTH and in a lower cortisol response to CRH in the control but not PCUN and PIUN groups. PCUN, but not PIUN, resulted in an increase in adrenal weight and CYP17 expression in singletons, a decrease in adrenal IGF2 expression in singletons, and an increase in adrenal IGF2R expression in both twins and singletons. IGF2/H19 and IGF2R DMR methylation levels and ACTHR expression were lower in the twin adrenal. Thus, exposure of the oocyte and embryo to maternal undernutrition or to the environment of a twin pregnancy have differential effects on epigenetic and other factors that regulate fetal adrenal growth and IGF2 and IGF2R expression.
Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin‐signaling pathways in the offspring
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1096/FJ.13-227918
Abstract: Our aim was to determine the effect of exposure to maternal obesity or to maternal weight loss around conception on the programming of hepatic insulin signaling in the offspring. We used an embryo transfer model in sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for 1 wk after conception on the expression of hepatic insulin-signaling and gluconeogenic factors and key miRNAs involved in insulin signaling in the offspring. We found that exposure to maternal obesity resulted in increased hepatic miR-29b (P<0.05), miR-103 (P<0.01), and miR-107 (P<0.05) expression, a decrease in IR (P<0.05), phopsho-Akt (P<0.01), and phospho-FoxO1 (P<0.01) abundance, and a paradoxical decrease in 11βHSD1 (P<0.05), PEPCK-C (P<0.01), and PEPCK-M (P<0.05) expression in lambs. These changes were ablated by a period of moderate dietary restriction imposed during the periconceptional period. Maternal dietary restriction alone also resulted in decreased abundance of a separate subset of hepatic insulin-signaling molecules, namely, IRS1 (P<0.05), PDK1 (P<0.01), phospho-PDK1 (P<0.05), and aPKCζ (P<0.05) and in decreased PEPCK-C (P<0.01) and G6Pase (P<0.01) expression in the lamb. Our findings highlight the sensitivity of the epigenome to maternal nutrition around conception and the need for dietary interventions that maximize metabolic benefits and minimize metabolic costs for the next generation.
Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats
Publisher: American Thoracic Society
Date: 15-11-2005
Prenatal development of the pulmonary surfactant system and the influence of hypoxia
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.RESP.2011.05.015
Abstract: Pulmonary surfactant fulfils erse functions at the lung air-liquid interface of all air-breathing vertebrates. Neurohormonal regulation of surfactant synthesis and secretion is highly conserved among non-mammalian amniotes. Although the pattern of surfactant lipid maturation is similar among species, the onset and completion differ dramatically. These differences are apparently not determined by phylogeny, but may relate to the timing of development of relative hypoxia as an embryo develops, which is related to birthing strategy. We have proposed that hypoxia is an evolutionary drive for differential surfactant development among species. In mammalian and non-mammalian models, hypoxia induces fetal growth restriction. Depending on the timing of the insult, this may be associated with an acceleration or deceleration of surfactant development. The hypoxic effect may be mediated via hormonal and growth factors, such as glucocorticoids and VEGF. However, the multifactorial nature of mammalian growth restriction models complicates the mechanistic interpretations. Hence, less complex oviparous animal models are required, in which hypoxia can be isolated from maternal influences.
Regulation of microRNA during cardiomyocyte maturation in sheep
Publisher: Springer Science and Business Media LLC
Date: 22-07-2015
Long-Term Effects of Prenatal SSRI Exposure on Child Growth: Weighing the Evidence
Publisher: American Psychiatric Association Publishing
Date: 11-2013
Identification of placental androgen receptor isoforms in a sheep model of maternal allergic asthma
Publisher: Elsevier BV
Date: 11
DOI: 10.1016/J.PLACENTA.2021.01.003
Abstract: Maternal asthma is known to impact intrauterine growth outcomes, which may be mediated, in part, by altered androgen signalling. Our aim was to explore whether the sheep placenta expresses androgen receptor (AR) isoforms and determine if the differential expression of AR protein isoforms is altered by maternal asthma. Four known AR isoforms were detected (AR-FL, AR-v1, AR-v7, and AR-45), and their expression and subcellular distribution was altered in the presence of maternal allergic asthma. These findings underscore the importance for in vivo models of maternal asthma to delineate molecular patterns that may contribute to feto-placental growth and development.
Feasibility of phase-contrast cine magnetic resonance imaging for measuring blood flow in the sheep fetus
Publisher: American Physiological Society
Date: 12-2019
DOI: 10.1152/AJPREGU.00273.2017
Abstract: Phase-contrast cine MRI (PC-MRI) is the gold-standard noninvasive technique for measuring vessel blood flow and has previously been applied in the human fetal circulation. We aimed to assess the feasibility of using PC-MRI to define the distribution of the fetal circulation in sheep. Fetuses were catheterized at 119–120 days of gestation (term, 150 days) and underwent MRI at ∼123 days of gestation under isoflurane anesthesia, ventilated at a [Formula: see text] of 1.0. PC-MRI was performed using a fetal arterial blood pressure catheter signal for cardiac triggering. Blood flows were measured in the major fetal vessels, including the main pulmonary artery, ascending and descending aorta, superior vena cava, ductus arteriosus, left and right pulmonary arteries, umbilical vein, ductus venosus, and common carotid artery and were indexed to estimated fetal weight. The combined ventricular output, pulmonary blood flow, and flow across the foramen ovale were calculated from vessel flows. Intraobserver and interobserver agreement and reproducibility was assessed. Blood flow measurements were successfully obtained in 61 out of 74 vessels (82.4%) interrogated in 9 fetuses. There was good intraobserver [ R = 0.998, P 0.0001 intraclass correlation (ICC) = 0.997] and interobserver agreement ( R = 0.996, P 0.0001 ICC = 0.996). Repeated MRI measurements showed good reproducibility ( R = 0.989, P = 0.0002 ICC = 0.990). We conclude that PC-MRI using fetal catheters for gating triggers is feasible in the major vessels of late gestation fetal sheep. This approach may provide a useful new tool for assessing the circulatory characteristics of fetal sheep models of human disease, including fetal growth restriction and congenital heart disease.
Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs
Publisher: Public Library of Science (PLoS)
Date: 12-05-2020
Effects of maternal hypoxia during pregnancy on bone development in offspring: A guinea pig model
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/916918
Abstract: Low birth weight is associated with reduced bone mass and density in adult life. However, effects of maternal hypoxia (MH) on offspring bone development are not known. Objective . The current study investigated the effects of fetal growth restriction induced by MH during the last half of gestation on bone structure and volume in the offspring of the fetus near term and the pup in adolescence. Methods . During 35–62-day gestation (term, 69d), guinea pigs were housed in room air (21% O 2 control) or 12% O 2 (MH). Offspring femur and tibia were collected at 62d gestation and 120d after birth. Results . MH decreased fetal birth weight but did not affect osteogenic potential pools in the fetal bone marrow. Histological analysis showed no effects of MH on tibial growth plate thickness in either fetal or postnatal offspring, although there was increased VEGF mRNA expression in the growth plate of postnatal offspring. MH did not change primary spongiosa height but lowered collagen-1 mRNA expression in postnatal offspring. There was increased mRNA expression of adipogenesis-related gene (FABP4) in bone from the MH postnatal offspring. Conclusion . MH during late gestation did not change the pool of osteogenic cells before birth or growth plate heights before and after birth. However, MH reduced expression of bone formation marker (collagen-1) and increased expression of fat formation marker (FABP4) in postnatal offspring bone.
Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus
Publisher: American Physiological Society
Date: 07-2015
DOI: 10.1152/AJPLUNG.00275.2014
Abstract: Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130–135 ( n = 19) and 139–145 ( n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain ( PHD) 2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α ( HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.
Arginine vasopressin improves cerebral perfusion following controlled haemorrhage in adult ewes
Publisher: Wiley
Date: 19-07-2019
DOI: 10.1113/JP277629
Neutral Re(I) Complex Platform for Live Intracellular Imaging
Publisher: American Chemical Society (ACS)
Date: 07-2021
Does maternal obesity change cardiomyocyte endowment?
Publisher: Informa UK Limited
Date: 2013
DOI: 10.1586/EOG.12.74
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