ORCID Profile
0000-0003-1930-8358
Current Organisation
Western University
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Publisher: David Publishing Company
Date: 28-07-2019
Publisher: Bioscientifica
Date: 22-04-2008
DOI: 10.1677/JOE-07-0481
Abstract: Ovine GH (oGH) is synthesized in placental tissue during maximal placental growth and development. Our objectives were to localize oGH mRNA in the placenta, and study the impact of exogenous GH on twin pregnancies during the normal window (35–55 days of gestational age dGA) of placental expression. In situ hybridization localized oGH mRNA in uterine luminal epithelium but not in tissues of fetal origin. While maternal GH and IGF-I concentrations were increased ( P .001) approximately tenfold, uterine, uterine fluid, placental, and fetal weights were unaffected by treatment at either 55 or 135 dGA. Fetal length, liver weight, and liver weight per kg of body weight were unaffected by maternal GH treatment. However, in the cotyledon, IGF-binding protein (BP)-1 and IGFBP-4 mRNA concentrations were increased ( P .05), while IGFBP-2 mRNA was decreased ( P .05). The concentration of mRNA for IGFBP-3 was unaffected by treatment. Within the caruncle, IGFBP-1 mRNA was decreased ( P .05), while IGFBP-3 and IGFBP-4 mRNA were increased ( P .05), and IGFBP-2 mRNA was unchanged due to GH treatment. While our data indicate that elevated maternal GH and IGF-I concentrations during early and mid-gestation do not enhance placental and fetal growth in twin pregnancies, localization of GH mRNA in uterine luminal epithelium could explain GHs transitory expression from 35 to 55 dGA, since by the end of this period the majority of the uterine luminal epithelium has fused with chorionic binucleate cells forming the placental syncytium.
Publisher: Wiley
Date: 27-10-2013
Abstract: Fructose is an increasingly common constituent of the Westernized diet due to cost and production efficiencies. Although an integral component of our pre-industrial revolution diet, over the past two decades human and animal studies have highlighted that excessive fructose intake appears to be associated with adverse metabolic effects. Excessive intake of fructose is the combined result of increased total energy consumption and increased portion sizes of foods, which often incorporate the fructose-containing sugars sucrose and high-fructose corn-syrup (HFCS). The adverse metabolic effects following excessive fructose consumption have become a hot topic in mainstream media and there is now rigorous scientific debate regarding periods of exposure, dosage levels, interactive effects with other sugars and fats and mechanisms underlying the actions of fructose. There is still a degree of controversy regarding the extent to which sugars such as sucrose and HFCS have contributed to the current epidemic of obesity and diabetes. Furthermore, an increasing number of infants are being exposed to sugar-sweetened food and beverages before birth and during early postnatal life, highlighting the importance of determining the long-term effects of this perinatal exposure on the developing offspring. There are limited human observational and controlled studies identifying associations of excessive sweetened food and beverage consumption with poor pregnancy outcomes. Animal research has demonstrated an increased incidence of gestational diabetes as well as altered maternal, fetal and offspring metabolic function, although the long-term effects and the mechanism underlying these perturbations are ill defined. This review aims to understand the role of early life fructose exposure in modifying postnatal risk of disease in the offspring, focusing on fructose intake during pregnancy and in early postnatal life.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2021
DOI: 10.1038/S41390-021-01491-W
Abstract: Intrauterine growth restriction and low birth weight (LBW) have been widely reported as an independent risk factor for adult hypercholesterolaemia and increased hepatic cholesterol in a sex-specific manner. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. Hepatic cholesterol, transcriptome, cholesterol homoeostasis regulatory proteins, and antioxidant markers were studied in UPI-induced LBW and normal birth weight (NBW) male and female guinea pigs at 150 days. Hepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "cholesterol metabolism" was an enriched pathway in LBW males but not in females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. UPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. Low birth weight (LBW) is a risk factor for increased hepatic cholesterol. Uteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. UPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. These changes, at the current age studied, were sex-specific, only being observed in LBW males and not in LBW females. These programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age.
Publisher: Bioscientifica
Date: 04-2007
DOI: 10.1530/REP-06-0294
Abstract: Overnourishing pregnant adolescent sheep promotes maternal growth but reduces placental mass, lamb birth weight and circulating progesterone. This study aimed to determine whether altered progesterone reflected transcript abundance for StAR (cholesterol transporter) and the steroidogenic enzymes ( Cyp11A1 , Hsd3b and Cyp17 ). Circulating and placental expression of ovine placental lactogen (oPL) was also investigated. Adolescent ewes with singleton pregnancies were fed high (H) or moderate (M) nutrient intake diets to restrict or support placental growth. Experiment 1: peripheral progesterone and oPL concentrations were measured in H ( n =7) and M ( n =6) animals across gestation (days 7–140). Experiment 2: progesterone was measured to mid- (day 81 M: n =11, H: n =13) or late gestation (day 130 M: n =21, H: n =22), placental oPL, StAR and steroidogenic enzymes were measured by qPCR and oPL protein by immunohistochemistry. Experiment 1: in H vs M animals, term placental ( P .05), total cotyledon ( P .01) and foetal size ( P .05) were reduced. Circulating oPL and progesterone were reduced at mid- ( P .001, P .01) and late gestation ( P .01, P .05) and oPL detection was delayed ( P .01). Experiment 2: placental oPL was not altered by nutrition. In day 81 H animals, progesterone levels were reduced ( P .001) but not related to placental or foetal size. Moreover, placental steroidogenic enzymes were unaffected. Day 130 progesterone ( P .001) and Cyp11A1 ( P .05) were reduced in H animals with intrauterine growth restriction (H+IUGR). Reduced mid-gestation peripheral oPL and progesterone may reflect altered placental differentiation and/or increased hepatic clearance respectively. Restricted placental growth and reduced biosynthesis may account for reduced progesterone in day 130 H+IUGR ewes.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/327638
Publisher: Wiley
Date: 29-06-2011
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.
Publisher: American Physiological Society
Date: 12-2011
DOI: 10.1152/AJPREGU.00274.2011
Abstract: This study examined perturbed aortic development and subsequent wall stiffening as a link to later cardiovascular disease. Placental insufficiency was induced in pregnant guinea pigs at midgestation by uterine artery ligation. Near term, fetuses were killed and defined as normal birth weight (NBW), low birth weight (LBW), and intrauterine growth restricted (IUGR). Offspring were classified according to birth weight and killed in adulthood. Collagen and elastin content of aortas were analyzed using Sirius red and orcein staining, respectively. Immunofluorescence was used for detection of α-actin and nonmuscle myosin heavy chain (MHC-B), a marker of synthetic-type vascular smooth muscle cells (VSMCs). Ex vivo generation of length-tension curves was performed with aortic rings from adult offspring. Relative elastic fiber content was decreased by 10% in LBW and 14% in IUGR compared with NBW fetuses. In adulthood, relative elastic fiber content was 51% lower in LBW vs. NBW, and the number of elastic laminae adjusted for wall thickness was 25% lower in LBW ( P 0.01). The percent area stained for MHC-B was sixfold higher in LBW vs. NBW fetuses ( P 0.0001) and threefold higher in LBW vs. NBW adult offspring ( P 0.05). The increase in MHC-B in LBW offspring concurred with a 41% increase in total collagen content and a 33 and 56% increase in relative and total α-actin content, respectively ( P 0.05). Thus aortic wall stiffening in adulthood can be traced to altered matrix composition established under suboptimal intrauterine conditions that is lified postnatally by the activity of synthetic VSMCs.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2010
Publisher: Cold Spring Harbor Laboratory
Date: 14-10-2021
DOI: 10.1101/2021.10.13.464235
Abstract: Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male ‘lean’ offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high fat-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism promoting mitochondrial overload.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.PLACENTA.2014.04.019
Abstract: To elucidate how obstetric conditions are associated with atypical placental weight ratios (PWR)s in infants born: (a) ≥37 weeks gestation (b) at ≥33 but <37 weeks gestation and (c) <33 weeks gestation. The study included all in-hospital singleton births in London, Ontario between June 1, 2006 and March 31, 2011. PWR was assessed as 90th percentile by gestational age-specific local population standards. Multivariable analysis was carried out using multinomial logistic regression with blockwise variable entry in order of temporality. Baseline factors and maternal obstetric conditions associated with PWR 90th percentile were: underweight, overweight and obese BMIs, smoking, preecl sia, placenta previa, and placental abruption. In particular, indicators of hypoxia and altered placental function were generally associated with elevated PWR at all gestations. An association between obstetric conditions associated with fetal hypoxia and PWR ≥90th percentile was illustrated. The multivariable findings suggest that the PWR is similarly increased regardless of the etiology of the hypoxia.
Publisher: Elsevier
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 13-02-2013
DOI: 10.1038/PR.2013.30
Abstract: This study examines the relationship between placental amino acid (AA) transport and fetal AA demand in an ovine fetal growth restriction (FGR) model in which placental underdevelopment induces fetal hypoxemia and hypoglycemia. Umbilical uptakes of AA, oxygen, glucose, and lactate were measured near term in eight experimental ewes (FGR group) and in eight controls (C group). The FGR group demonstrated significantly reduced umbilical uptakes of oxygen, glucose, lactate, and 11 AAs per kg fetus. The combined uptake of glucose, lactate, and AAs, expressed as nutrient/oxygen quotients, was reduced almost to 1.00 (FGR: 1.05 vs. C: 1.32, P ≤ 0.02). In contrast to a decrease in umbilical glucose concentration, all but one of the AAs that were transported from placenta to fetus demonstrated normal or elevated fetal concentrations, and five of the essential AAs were transported against a significantly higher feto/maternal (F/M) concentration ratio. This ratio peaked at the lowest fetal oxygen levels. We conclude that, in the hypoxic FGR fetus, the reduction in AA uptake is not due to a disproportionally small placental AA transport capacity. It is the consequence of decreased fetal oxidative metabolism and growth rate, which together reduce fetal AA demand.
Publisher: Frontiers Media SA
Date: 17-05-2021
DOI: 10.3389/FENDO.2021.612888
Abstract: Intrauterine growth restriction (IUGR) of the fetus, resulting from placental insufficiency (PI), is characterized by low fetal oxygen and nutrient concentrations that stunt growth rates of metabolic organs. Numerous animal models of IUGR recapitulate pathophysiological conditions found in human fetuses with IUGR. These models provide insight into metabolic dysfunction in skeletal muscle and liver. For ex le, cellular energy production and metabolic rate are decreased in the skeletal muscle and liver of IUGR fetuses. These metabolic adaptations demonstrate that fundamental processes in mitochondria, such as substrate utilization and oxidative phosphorylation, are tempered in response to low oxygen and nutrient availability. As a central metabolic organelle, mitochondria coordinate cellular metabolism by coupling oxygen consumption to substrate utilization in concert with tissue energy demand and accretion. In IUGR fetuses, reducing mitochondrial metabolic capacity in response to nutrient restriction is advantageous to ensure fetal survival. If permanent, however, these adaptations may predispose IUGR fetuses toward metabolic diseases throughout life. Furthermore, these mitochondrial defects may underscore developmental programming that results in the sequela of metabolic pathologies. In this review, we examine how reduced nutrient availability in IUGR fetuses impacts skeletal muscle and liver substrate catabolism, and discuss how enzymatic processes governing mitochondrial function, such as the tricarboxylic acid cycle and electron transport chain, are regulated. Understanding how deficiencies in oxygen and substrate metabolism in response to placental restriction regulate skeletal muscle and liver metabolism is essential given the importance of these tissues in the development of later lifer metabolic dysfunction.
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.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.EARLHUMDEV.2021.105511
Abstract: We determined the impact of gestational age (GA) from near term to term to post-term on birth lacental weight ratio and cord oxygen values with implications for placental transport efficiency for oxygen, fetal O A hospital database was used to obtain birth lacental weight ratios, cord PO Birth lacental weight ratio and umbilical venous O Fetal O
Publisher: MDPI AG
Date: 04-06-2016
DOI: 10.3390/NU8060342
Publisher: MDPI AG
Date: 12-02-2015
DOI: 10.3390/NU7021202
Publisher: Informa UK Limited
Date: 17-05-2012
DOI: 10.3109/14767058.2012.684165
Abstract: To establish gender-specific differences in maternal and fetal immune response in healthy human fetuses at term. Forty-five women with elective caesarean sections for uncomplicated singleton pregnancies were recruited for two studies. Using a multiplex biomarker immunoassay system, unstimulated maternal and fetal plasma concentrations of interleukin (IL)-1β, IL-1ra, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, and tumor necrosis factor (TNF)-α were measured from one study population. Lipopolysaccharide (LPS)-stimulated cytokine response was measured in a second study. There were no significant gender differences in either maternal or fetal unstimulated plasma cytokine concentrations, but concentrations of the proinflammatory cytokines IL-1β and IL-6 were significantly greater in male fetal LPS-stimulated s les than in female fetal s les. Blood of male fetuses mounts a larger pro-inflammatory response to lipopolysaccharide (LPS). This heightened response could be a critical pathway in promoting premature rupture of membranes (PPROM) and may be associated with life long differential gender response to infection.
Publisher: Elsevier BV
Date: 03-2017
Publisher: Cold Spring Harbor Laboratory
Date: 16-02-2022
DOI: 10.1101/2022.02.15.480604
Abstract: Pre-existing and gestationally-developed diabetes mellitus have been linked with impaired metabolic function in placental villous trophoblast cells, that is thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia as an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that have been found to be impaired in diabetic placentae. Therefore, the current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased triglyceride and glycogen nutrient stores. However, specific functional readouts of metabolic enzyme activity and mitochondrial oxidative respiratory activity were not altered. We speculated that increased glycogen content may reduce free glucose available for oxidation and subsequently protect trophoblast cells from mitochondrial damage during acute high glucose exposures. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. Hyperglycemic exposure was associated with an altered transcriptomic profile (e.g. increased expression of ACSL1 (+1.36 fold-change (FC), HSD11B2 (+1.35 FC), and RPS6KA5 (+1.32 FC)), and metabolome profile (e.g. increased levels lactate (+2.72 FC), malonate (+3.74 FC), and riboflavin (+3.68 FC)) in BeWo cytotrophoblasts that further highlighted trophoblast metabolic function is modulated independently by hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolic function and nutrient storage, and these data continue to expand our knowledge on the mechanisms governing the development of placental dysfunction.
Publisher: American Physiological Society
Date: 06-2001
DOI: 10.1152/JAPPL.2001.90.6.2420
Abstract: Heat exposure early in ovine pregnancy results in placental insufficiency and intrauterine growth restriction (PI-IUGR). We hypothesized that heat exposure in this model disrupts placental structure and reduces placental endothelial nitric oxide synthase (eNOS) protein expression. We measured eNOS protein content and performed immunohistochemistry for eNOS in placentas from thermoneutral (TN) and hyperthermic (HT) animals killed at midgestation (90 days). Placental histomorphometry was compared between groups. Compared with the TN controls, the HT group showed reduced delivery weights (457 ± 49 vs. 631 ± 21 g P 0.05) and a trend for reduced placentome weights (288 ± 61 vs. 554 ± 122 g P = 0.09). Cotyledon eNOS protein content was reduced by 50% in the HT group ( P 0.03). eNOS localized similarly to the vascular endothelium and binucleated cells (BNCs) within the trophoblast of both experimental groups. HT cotyledons showed a reduction in the ratio of fetal to maternal stromal tissue (1.36 ± 0.36 vs. 3.59 ± 1.2 P≤ 0.03). We conclude that eNOS protein expression is reduced in this model of PI-IUGR and that eNOS localizes to both vascular endothelium and the BNC. We speculate that disruption of normal vascular development and BNC eNOS production and function leads to abnormal placental vascular tone and blood flow in this model of PI-IUGR.
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0002-9378(99)70098-0
Abstract: This study was undertaken to assess the accuracy of triplex ultrasonographic measurement of venous umbilical blood flow in comparison with the steady-state diffusion technique and to determine the impact of cotyledon weight and number on umbilical blood flow. Six late-gestation ewes with long-term catheter placement were studied for venous umbilical blood flow with the ethanol steady-state diffusion technique and with triplex-mode ultrasonography (color Doppler, pulsed-wave Doppler, and real-time ultrasonography). At necropsy the number and weight of the cotyledons serving each umbilical vein were recorded. Umbilical blood flow determined by triplex-mode ultrasonography (207. 5 +/- 8.6 mL. kg(-1) fetus. min(-1)) was virtually identical to that determined with the steady-state diffusion technique (208.1 +/- 7.3 mL. kg(-1) fetus. min(-1) P =.9). When values were normalized for the weight or number of cotyledons serving each vein, there was no difference in umbilical blood flow between small and large umbilical veins in all the sheep. Our study validates the accuracy of the triplex ultrasonographic method and provides justification for its use in future human investigations. In absolute terms umbilical blood flow frequently differs between the 2 veins. When expressed per number or mass of cotyledons, however, the umbilical blood flows are similar.
Publisher: Routledge
Date: 02-01-2018
Publisher: SAGE Publications
Date: 08-2010
Abstract: In an ovine model of placental insufficiency-induced intrauterine growth retardation (PI-IUGR), characterized by hypoxia, hypoglycemia and a significant reduction in fetal weight, we assessed alterations in fetal and placental polyols. Arterial maternal–fetal concentration differences of glucose and mannose were greater in the PI-IUGR fetus glucose: C ( n = 7), 2.68 ± 0.14 mmol/L versus PI-IUGR ( n = 9), 3.18 ± 0.16 mmol/L ( P 0.02) and mannose: C, 42.9 ± 8.1 μmol/L versus PI-IUGR, 68.5 ± 19.1 μmol/L ( P 0.001). For PI-IUGR fetuses, fetal arterial plasma myo-inositol concentrations were significantly increased ( P 0.001). The concentrations of sorbitol, glucose and fructose were significantly reduced ( P 0.03, 0.01, 0.02, respectively). The cotyledons of IUGR placentas had a significantly increased concentration of myo-inositol ( P 0.003) and decreased concentrations of sorbitol, fructose and glycerol ( P 0.01, 0.02, 0.01, respectively). Fetal hepatic concentrations of sorbitol ( P 0.001) and fructose ( P 0.03) were also significantly reduced. These profound changes in both placental and fetal concentrations of polyols and sugars in sheep PI-IUGR pregnancies support the conclusion that within the PI-IUGR placenta there is an increased flux through the glucose 6-P:inositol 1-P cyclase system and decreased flux through the polyol dehydrogenase system, leading to increased placental myo-inositol production and decreased sorbitol production. The decreased placental supply of sorbitol to the fetal liver may lead to decreased fetal hepatic fructose production. These observations highlight that, in association with hypoxic and hypoglycemic PI-IUGR fetuses, there are major placental and fetal alterations in polyol production. The manner in which these alterations in fetoplacental carbohydrate metabolism contribute to the pathophysiology of PI-IUGR is currently unknown.
Publisher: Cold Spring Harbor Laboratory
Date: 06-02-2021
DOI: 10.1101/2021.02.05.429612
Abstract: Alterations in glycolysis and oxidative pathways are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo , non-invasive technologies to understand the development of hepatic metabolic aberrations in lean NAFLD. To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) MRI techniques to investigate effects of a chronic, life-long exposure to the Western Diet (WD) in a model of NAFLD and identify cellular metabolite changes and correlations related to enzyme activity. It is hypothesized that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. Prospective POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: 28 male guinea pigs were weaned onto a control diet or WD. 3T T1, T2, IDEAL, broadband PRESS MRS. Median PDFF was calculated in the liver and hind limbs. [1- 13 C]pyruvate dynamic MRS in the liver was quantified by the time to peak (TTP), calculated as the time from pyruvate peak to metabolite peak. After a recovery period, animals were euthanized, and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. Unpaired Student’s t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. Life-long WD consumption resulted in significantly higher liver PDFF correlated with elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD, corresponding with increased liver triglyceride levels characteristic of lean NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD livers.
Publisher: Cambridge University Press (CUP)
Date: 23-06-2020
DOI: 10.1017/S2040174420000483
Abstract: Currently, there is limited knowledge on how health care providers perceive and understand the Developmental Origins of Health and Disease (DOHaD), which may impact how they inform patients and their families throughout the perinatal period. This qualitative descriptive study explored if and how health care providers counsel on in utero programming and future health outcomes with parents, both preconception and during pregnancy. One-on-one, semi-structured interviews were conducted with 23 health care providers from varying health disciplines including obstetrics and gynaecology, midwifery, paediatrics, endocrinology and internal medicine. Audiotaped interviews were transcribed verbatim and analysed using inductive thematic analysis. Three themes were identified: Knowledge about DOHaD, Counselling on DOHaD in Practice Settings and Impact of DOHaD on Health. Health care providers not only expressed excitement over the potential health benefits of DOHaD counselling but also indicated barriers to knowledge translation, including a lack of knowledge among providers and a disconnect between basic scientists and practitioners. All health care providers expressed concerns on how and when to introduce the concept of DOHaD when counselling patients and called for the development of practice guidelines. Counselling on DOHaD needs to be framed in a way that is empowering, minimising the potential of coercion and guilt. More interaction and collaboration are needed between health care providers and researchers to identify strategies to support knowledge translation generated from DOHaD research into practice settings.
Publisher: Springer Science and Business Media LLC
Date: 12-2005
DOI: 10.1203/01.PDR.0000185266.23265.87
Abstract: Fetal growth restriction (FGR) is associated with increased perinatal morbidity and mortality, and often results from functional placental insufficiency. Placentation requires extensive vasculogenesis and subsequent angiogenesis, in both maternal and fetal tissues. Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are angiogenic growth factors expressed in the placenta, and compete for binding to a common receptor, Tunica interna endothelial cell kinase-2 (Tie-2). Our objective was to examine Ang-1, Ang-2 and Tie-2 expression in ovine placental tissue obtained from normal and FGR pregnancies throughout gestation. Fetal cotyledon and maternal caruncle tissue concentrations of Ang-1, Ang-2 and Tie-2 mRNA were assessed by real-time reverse transcriptase-polymerase chain reaction and protein concentrations were assessed by Western immunoblot analysis, at 55, 90 and 135 d gestational age (dGA). Concentrations of Ang-1, Ang-2 and Tie-2 mRNA in FGR fetal cotyledons were increased at 55 dGA, and Tie-2 mRNA concentrations were decreased in FGR fetal cotyledons and maternal caruncles at 135 dGA. Immunoblot analysis demonstrated increased concentrations of Ang-2 in the fetal cotyledon at 55 dGA, and lower concentrations at 135 dGA. In contrast, concentrations of Tie-2 were increased at 90 dGA, but tended to decrease at 135 dGA in FGR maternal caruncles. The changes observed during early- to mid-gestation may result in increased branching angiogenesis, but may also set the stage for increased nonbranching angiogenesis during late gestation, altered placental architecture and placental insufficiency that result in FGR.
Publisher: Elsevier BV
Date: 07-2018
Publisher: Elsevier BV
Date: 12-2003
Publisher: Wiley
Date: 02-02-2016
DOI: 10.1113/JP271467
Publisher: Wiley
Date: 05-2005
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.
Publisher: Elsevier BV
Date: 12-2003
Publisher: Wiley
Date: 31-07-2015
DOI: 10.1002/JMRI.25009
Abstract: To test the feasibility of hyperpolarized [1-(13) C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport. Seven pregnant guinea pigs with a total of 30 placentae and fetuses were anesthetized and scanned at 3T. T1 -weighted (1) H images were obtained from the maternal abdomen. An 80 mM solution of hyperpolarized [1-(13) C]pyruvate (hereafter referred to as pyruvate) was injected into a vein in the maternal foot. Time-resolved 3D (13) C images were acquired starting 10 seconds after the beginning of bolus injection and every 10 seconds after to 50 seconds. The pregnant guinea pigs were recovered after imaging. Regions of interest (ROIs) were drawn around the maternal heart and each placenta and fetal liver in all slices in the (1) H images. These ROIs were copied to the (13) C images and were used to calculate the sum of the pyruvate and lactate signal intensities for each organ. The signal intensities were normalized by the volume of the organ and the maximum signal in the maternal heart. No adverse events were observed in the pregnant guinea pigs and natural pupping occurred at term (∼68 days). Pyruvate signal was observed in all 30 placentae, and lactate, a by-product of pyruvate metabolism, was also observed in all placentae. The maximum pyruvate and lactate signals in placentae occurred at 20 seconds. In addition to the observation of pyruvate and lactate signals in the placentae, both pyruvate and lactate signals were observed in all fetal livers. The maximum pyruvate and lactate signals in the fetal livers occurred at 10 seconds and 20 seconds, respectively. This work demonstrates the feasibility of using hyperpolarized [1-(13) C]pyruvate MRI to noninvasively examine fetoplacental metabolism and transport of pyruvate in guinea pigs. Hyperpolarized (13) C MRI may provide a novel method for longitudinal studies of fetoplacental abnormalities.
Publisher: Springer Science and Business Media LLC
Date: 04-1999
Publisher: MDPI AG
Date: 25-07-2023
Abstract: Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs) palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin-layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in β-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advice and implementing dietary interventions to maintain appropriate placental function by limiting excessive exposure to saturated NEFAs remain crucial in managing at-risk obese and GDM pregnancies.
Publisher: Springer Science and Business Media LLC
Date: 02-2016
Abstract: We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs on pregnancy outcomes, maternal/fetal growth parameters, and blood analytes to further characterize the utility of this model for inducing fetal growth restriction (FGR). Thirty guinea pig sows were fed ad libitum (Control) or 70% of the control diet prepregnant switching to 90% at midpregnancy (MNR). Animals were necropsied near term with weights obtained on all sows, fetuses, and placenta. Fetal blood s ling and organ dissection were undertaken in appropriate for gestational age (AGA) fetuses from Control litters and FGR fetuses from MNR litters using > or < 80 g which approximated the 10th percentile for the population weight distribution of the Control fetuses. MNR fetal demise rates (1/43) were extremely low in contrast to that seen with uterine artery ligation/ablation models, albeit with increased preterm delivery in MNR sows (3 of 15). We confirm that MNR fetuses are smaller and have increased placental/fetal weight ratios as often seen in human FGR infants. We provide justification for using a fetal weight threshold for categorizing AGA Control and FGR-MNR cohorts reducing population variance, and show that FGR-MNR fetuses have asymmetrical organ growth, and are polycythemic and hypoglycemic which are also well associated with moderate FGR in humans. These findings further support the utility of moderate MNR in guinea pigs for inducing FGR with many similarities to that in humans with moderate growth restriction whether resulting from maternal undernourishment or placental insufficiency.
Publisher: Bioscientifica
Date: 05-04-2019
Publisher: Public Library of Science (PLoS)
Date: 15-02-2018
Publisher: Georg Thieme Verlag KG
Date: 05-2011
Abstract: The metabolic syndrome (or syndrome X) is a constellation of risk factors including insulin resistance, hypertension, dyslipidemia, and central obesity that predispose to the development of cardiovascular disease and type 2 diabetes in adult life. Insulin resistance is believed to be a critical pathophysiological event early in the disease process, impacting both skeletal muscle metabolic function and vascular responses. Adverse changes in insulin sensitivity have been found to originate in utero for instance, prenatal events such as placental insufficiency/oxidative stress leading to altered fetal growth trajectories are associated with increased rates of metabolic syndrome in adult life. Such intrauterine insults result in reduced skeletal muscle mass in conjunction with altered insulin signaling, decreased oxidative fibers, and impaired mitochondrial function. These developmental disturbances set the stage for development of muscle triglyceride accumulation and depressed insulin sensitivity in childhood. Abnormalities of vascular structure and function arising from deprived intrauterine conditions that are exacerbated by insulin resistance account for the progression of hypertension from childhood to adulthood. Arterial changes initiated in utero include reduced endothelial nitric oxide (NO) bioavailability, vascular smooth muscle cell proliferation and inflammation, events leading to endothelial dysfunction, and atherosclerosis that are present in those destined for metabolic syndrome. In addition, the hypertensive phenotype that is a hallmark of metabolic syndrome may also be traced to blunted kidney development and renin-angiotensin system activation in growth-restricted offspring. The summative impact of these intrauterine programmed changes in terms of influencing adult health and disease encompasses dietary and lifestyle factors introduced postnatally. Establishing novel therapeutic interventions aimed at preventing and/or reducing in utero-induced insulin resistance and vascular dysfunction warrants investigation because the numbers of low birthweight babies continue to increase.
Publisher: Elsevier BV
Date: 12-2001
Publisher: Wiley
Date: 14-10-2022
DOI: 10.1002/JMRI.28482
Abstract: Fetal myelination assessment is important for understanding neurodevelopment and neurodegeneration. Myelin water imaging (MWI) quantifies myelin water fraction (MWF), a validated marker for myelin content, and has been used to assess brain myelin in children and neonates. To demonstrate that MWI can quantify MWF in fetal guinea pigs (GPs). Animal model. Nine pregnant, Dunkin-Hartley GPs with 31 fetuses (mean ± standard deviation = 60 ± 1.5 days gestation). 3D spoiled gradient echo and balanced steady-state free precession sequences at 3.0 T. MWF maps were reconstructed for maternal and fetal GP brains using the multicomponent driven equilibrium single pulse observation of T Linear regression between MWF and MBP stain intensity (SI) of all four regions (coefficient of determination, R The mean MWF of the analyzed regions are as follows (mean ± standard deviation): 0.338 + 0.016 (maternal CC), 0.340 ± 0.017 (maternal FOR), 0.214 ± 0.016 (fetal CC), and 0.305 ± 0.025 (fetal FOR). MWF correlated with MBP SI in all regions (R This study demonstrated the feasibility of MWI in assessing fetal brain myelin content. 2 Technical Efficacy: Stage 1.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/181257
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2020
DOI: 10.1101/2020.02.21.959320
Abstract: Premature senescence in low birth weight rodents is associated with later life metabolic disease, including the development of insulin resistance. Telomerase, a reverse transcriptase enzyme with telomeric and non-telomeric functions, is present at high levels during development to maintain and repair long telomere lengths and to protect cells from oxidative stress-induced growth arrest. Adverse In utero environments are often associated with increased reactive oxygen species (ROS), and ROS have been documented to impair/alter telomerase function. We postulate that telomerase protects cells against oxidative stress-induced damage, and its inhibition could lead to premature senescence. A primary cell line of fetal guinea pig muscle cells was differentiated under high (20%) and low (1-2%) oxygen concentrations and telomerase activity was pharmacologically inhibited using a synthetic tea catechin. Following 48 hours, ROS detection was conducted with MitoSOX, Mitotracker and 6-carboxy-2’,7’-dichlorodihydrofluorescein diacetate staining. Cells cultured at 20% O 2 and treated with a telomerase activity inhibitor displayed reduced cell growth rates and increased levels of senescence markers, including p21 and p53. Telomeric DNA damage, measured by phosphorylated-γH2A.X staining at telomeres, was significantly increased in cells cultured at all oxygen concentrations with telomerase inhibition. Telomerase inhibition altered metabolic signaling (e.g. mTOR, p66Shc) and increased mitochondrial ROS levels. Telomerase may protect cells during development from adverse in utero environments that cause premature senescence.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/PR.2017.92
Abstract: BackgroundWe determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney, and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and vascular endothelial growth factor (VEGF) protein levels, and for HP-1 immunoreactivity (IR).ResultsFGR-MNR fetuses were 36% smaller with asymmetrical growth restriction compared to controls. EPO and VEGF protein levels were increased in the female FGR-MNR fetuses, providing support for hypoxic stimulus and linkage to increased erythropoiesis, but not in the male FGR-MNR fetuses, possibly reflecting a weaker link between oxygenation and erythropoiesis. HP-1 IR was increased in the liver and kidneys of both male and female FGR-MNR fetuses as an index of local tissue hypoxia, but with no changes in the placenta.ConclusionChronic hypoxia is likely to be an important signaling mechanism for the decreased fetal growth seen with maternal undernutrition and appears to be post-placental in nature.
Publisher: MDPI AG
Date: 29-11-2021
DOI: 10.3390/NU13124315
Abstract: Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.
Publisher: Springer Science and Business Media LLC
Date: 11-2006
Publisher: MDPI AG
Date: 17-01-2022
DOI: 10.3390/IJMS23020999
Abstract: Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2022
DOI: 10.1186/S13293-022-00445-Z
Abstract: We determined the effect of fetal sex on birth lacental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal–placental growth differences. A hospital database was used to obtain birth lacental weight, cord PO 2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA 34 weeks ( N = 69,836). Oxygen saturation was calculated from the cord PO 2 and pH data, while fractional O 2 extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth lacental weight, cord PO 2 , O 2 saturation, and fractional O 2 extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. Birth lacental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O 2 extraction was increased in females confirming increased O 2 consumption relative to delivery. Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O 2 consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth lacental weights.
Publisher: Wiley
Date: 10-05-2021
DOI: 10.1002/JMRI.27677
Abstract: Alterations in glycolysis are central to the increasing incidence of non‐alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non‐invasive technologies to understand the development of hepatic metabolic aberrations. To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life‐long exposure to the Western diet (WD) in an animal model resulting in NAFLD to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. Prospective. Twenty‐eight male guinea pigs weaned onto a control diet ( N = 14) or WD ( N = 14). 3 T T1‐weighted gradient echo, T2‐weighted spin‐echo, three‐dimensional gradient multi‐echo fat‐water separation (IDEAL‐IQ), and broadband point‐resolved spectroscopy (PRESS) chemical‐shift sequences. Median PDFF was calculated in the liver and hind limbs. [1‐ 13 C]pyruvate dynamic MRS in the liver was quantified by the time‐to‐peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. Unpaired Student's t ‐tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. Life‐long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life‐long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD‐exposed livers. 2 1
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.AJOG.2007.07.016
Abstract: To determine: 1) placental eNOS mRNA concentration across gestation in normal ovine pregnancy and in an ovine model of intrauterine growth restriction (IUGR), and 2) placental eNOS protein concentration in early ovine pregnancy. A total of 24 sheep were studied with 12 ewes placed in hyperthermic (HT) conditions to induce IUGR and 12 were kept in control conditions. HT and control animals underwent euthanasia at 3 developmental time points (55, 95, & 130 days gestational age dGA) in ovine placental & fetal development. Compared to controls, HT pregnancies showed 1) no differences in fetal weights at 55 dGA and 95dGA with significant reductions at 130 dGA, 2) significantly smaller placentae at 95 and 130 dGA with a trend for a reduction at 55 dGA, 3) significant decreases in cotyledon eNOS mRNA at 95 and 130 dGA, 4) a significant increase in caruncle eNOS mRNA expression at 130 dGA, 5) significant increase in eNOS protein in the caruncle, but not in the cotyledon at 55 dGA. Placental eNOS concentration is transcriptionally regulated at mid-gestation, while additional post-transcriptional regulation is also involved during early and late gestation in this model of placental and fetal growth restriction.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.PLACENTA.2018.05.011
Abstract: Abnormal maternal lipid profiles, a hallmark of increased maternal adiposity, are associated with pregnancy complications such as preecl sia and gestational diabetes, and offspring long-term metabolic health is impacted as the consequence of altered fetal growth, physiology and often iatrogenic prematurity. The metabolic changes associated with maternal obesity and/or the consumption of a high-fat diet effecting maternal lipid profiles and metabolism have also been documented to specifically affect placental function and may underlie changes in fetal development and life course disease risk. The placenta plays a critical role in mediating nutritional signals between the fetus and the mother. As obesity rates in women of reproductive age continue to increase, it is becoming evident that inclusion of new technologies that allow for a better understanding of early changes in placental lipid transport and metabolism, non-invasively in maternal circulation, maternal tissues, placenta, fetal circulation and fetal tissues are needed to aid timely clinical diagnosis and treatment for obesity-associated diseases. This review describes pregnancy lipid homeostasis, with specific reference to changes arising from altered maternal body composition on placental and fetal lipid transport and metabolism. Current technologies for lipid assessments, such as metabolomics and lipidomics may be impacted by labour or mode of delivery and are only reflective of a single time point. This review further addresses how established and novel technologies for assessing lipids and their metabolism non-invasively and during the course of pregnancy may guide future research into the effect of maternal metabolic health on pregnancy outcome, placenta and fetus.
Publisher: PeerJ
Date: 02-01-2017
Publisher: Cambridge University Press (CUP)
Date: 02-07-2013
DOI: 10.1017/S2040174413000299
Abstract: This study determined the effect of chronic intrauterine hypoxia on collagen deposition in the fetal sheep heart. Moderate or severe hypoxia was induced by placental embolization in chronically catheterized fetal sheep for 15 days starting at gestational day 116 ± 2 (term ∼147 days). The fetal right and left ventricle were evaluated for collagen content using a Sirius red dye and for changes in signaling components of pathways involved in collagen synthesis and remodeling using quantitative polymerase chain reaction and Western blot. In severely hypoxic fetuses ( n = 6), there was a two-fold increase ( P 0.05) in the percentage staining for collagen in the right ventricle, compared with control ( n = 6), whereas collagen content was not altered in the moderate group ( n = 4). Procollagen I and III mRNA levels were increased in the right ventricle, two-fold ( P 0.05) and three-fold ( P 0.05), respectively, in the severe group relative to control. These changes were paralleled by a two-fold increase ( P 0.05) in mRNA levels of the pro-fibrotic cytokine, transforming growth factor β (TGF-β 1 ), in the right ventricle. In the right ventricle, the mRNA levels of matrix metalloproteinase 2 (MMP-2) and its activator, membrane-type MMP (MTI-MMP) were increased five-fold ( P = 0.06) and three-fold ( P 0.05), respectively, relative to control. Protein levels of TGF-β were increased in the left ventricle ( P 0.05). Thus, up-regulated collagen synthesis leading to increased collagen content occurs in the chronically hypoxic fetal heart and may contribute to the right ventricular diastolic and systolic dysfunction reported in human intrauterine growth restriction fetuses.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41523-021-00346-1
Abstract: The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group , we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
Publisher: Public Library of Science (PLoS)
Date: 17-03-2023
DOI: 10.1371/JOURNAL.PONE.0283118
Abstract: Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia is an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that are altered in term diabetic placentae. The current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1 , HSD11B2 , RPS6KA5 , and LAP3 and reduced mRNA expression of CYP2F1 , and HK2 , concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction.
Publisher: Elsevier BV
Date: 04-2007
Publisher: Elsevier BV
Date: 02-2001
Publisher: MDPI AG
Date: 27-08-2021
DOI: 10.3390/MPS4030058
Abstract: One of the greatest challenges to the development and implementation of pregnancy therapeutics is the ability to rigorously test treatments in clinically relevant animal models. Guinea pigs offer a unique advantage in studying the placenta, fetal development, and reproductive health as they have similar developmental milestones to humans, both throughout gestation and following birth. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe a methodology to efficiently and accurately time mate guinea pigs, and provide a picture representation of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a reliable approach to timed mating in the guinea pig.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1038/S41523-020-0155-1
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JNUTBIO.2019.02.009
Abstract: Uteroplacental insufficiency-induced low birth weight (LBW) and postnatal high saturated fat/high sucrose-fructose diet (Western Diet, WD) consumption have been independently associated with the development of hepatic steatosis, while their additive effect on fatty acid, acylcarnitine and amino acid profiles in early adulthood have not been widely reported. We employed LBW, generated via uterine artery ablation, and normal birth weight (NBW) male guinea pigs fed either a WD or control diet (CD) from weaning to postnatal day 150 (early adulthood). Hepatic steatosis was absent in CD-fed offspring, while NBW/WD offspring displayed macrovesicular steatosis and LBW/WD offspring exhibited microvesicular steatosis, both occurring in a lean phenotype. Life-long consumption of the WD, irrespective of birth weight, was associated with an increase in hepatic medium- and long-chain saturated fatty acids, monounsaturated fatty acids, acylcarnitines, reduced oxidative phosphorylation complex III activity and polyunsaturated fatty acids, and molecular evidence of disrupted hepatic insulin signaling. In NBW/WD, hepatic C15:1 and C16:1n-6 fatty acids in phospholipids, C16, C18 and C18:1 acylcarnitines, concentrations of aspartate, phenylalanine, tyrosine and tryptophan and expression of carnitine palmitoyltransferase 1 alpha (CPT1α) and uncoupling protein 2 (UCP2) genes were elevated compared to LBW/WD livers. Our results suggest that LBW and life-long WD combined are influential in promoting hepatic microvesicular steatosis in conjunction with a specific mitochondrial gene expression and metabolomic profile in early adulthood.
Publisher: Frontiers Media SA
Date: 14-11-2014
Publisher: Wiley
Date: 11-1990
Publisher: Wiley
Date: 15-12-2014
Publisher: Bioscientifica
Date: 09-1999
Abstract: Pregnant ewes were exposed chronically to thermoneutral (TN 20+/-2 degrees C, 30% relative humidity n=8) or hyperthermic (HT 40+/-2 degrees C 12 h/day, 35+/-2 degrees C 12 h/day, 30% relative humidity, n=6) environments between days 37 and 93 of pregnancy. Ewes were killed following 56 days of exposure to either environment (days in treatment (dit)), corresponding to 93+/-1 day post coitus (dpc). Maternal core body temperatures (CBT) in HT ewes were significantly elevated above the TN ewes (HT 39.86+/-0.1 degrees C vs TN 39.20+/-0.1 degrees C P .001). Both groups of animals displayed circadian CBT, though HT ewes had elevated litudes (HT 0.181+/-0.002 degrees C vs TN 0.091+/-0.002 degrees C P .001) and increased phase shift constants (HT 2100 h vs TN 1800 h P .001). Ewes exposed to chronic heat stress had significantly reduced progesterone and ovine placental lactogen (oPL) concentrations from 72 and 62 dpc respectively (P .05), corresponding to approximately 30 dit. However, when compared with the TN ewes, HT cotyledonary tissue oPL mRNA and protein concentrations were not significantly different (P .1). Prolactin concentrations rose immediately upon entry into the HT environment, reaching concentrations approximately four times that of TN ewes, a level maintained throughout the study (HT 216.31+/-32.82 vs TN 54. 40+/-10.0 P .0001). Despite similar feed intakes and euglycemia in both groups of ewes, HT fetal body weights were significantly reduced when compared with TN fetuses (HT 514.6+/-48.7 vs TN 703. 4+/-44.8 P .05), while placental weights (HT 363.6+/-63.3 vs TN 571.2+/-95.9) were not significantly affected by 56 days of heat exposure. Furthermore, the relationship between body weight and fetal length, the ponderal index, was significantly reduced in HT fetuses (HT 3.01+/-0.13 vs TN 3.57+/-0.18 P .05). HT fetal liver weights were also significantly reduced (HT 27.31+/-4.73 vs TN 45.16+/-6.16 P .05) and as a result, the brain/liver weight ratio was increased. This study demonstrates that chronic heat exposure lowers circulating placental hormone concentrations. The observation that PL mRNA and protein contents are similar across the two treatments, suggests that reduced hormone concentrations are the result of impaired trophoblast cell development, specifically trophoblast migration. Furthermore, the impact of heat exposure during maximal placental growth is great enough to restrict early fetal development, even before the fetal maximal growth phase (100 dpc-term). These data highlight that intrauterine growth retardation (IUGR) may result primarily from placental trophoblast cell dysfunction, and secondarily from later reduced placental size.
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2020
DOI: 10.1101/2020.08.21.256255
Abstract: Guinea pig development in utero is more similar to humans than any other rodent species. As such, their importance to reproductive studies is evident, particularly those studies focused on therapeutic interventions to improve human pregnancy outcome. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe, and provide picture representation, of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a cost effective and reliable approach to timed-mating in the guinea pig.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.PLACENTA.2005.01.003
Abstract: Amino acids have multiple functions in fetoplacental development. The supply of amino acids to the fetus involves active transport across and metabolism within the trophoblast. Transport occurs through various amino acid transport systems located on both the maternal and fetal facing membranes, many of which have now been documented to be present in rat, sheep and human placentas. The capacity of the placenta to supply amino acids to the fetus develops during pregnancy through alterations in such factors as surface area and specific time-dependent transport system expression. In intrauterine growth restriction (IUGR), placental surface area and amino acid uptakes are decreased in human and experimental animal models. In an ovine model of IUGR, produced by hyperthermia-induced placental insufficiency (PI-IUGR), umbilical oxygen and essential amino acid uptake rates are significantly reduced in the most severe cases in concert with decreased fetal growth. These changes indicate that severe IUGR is likely associated with a shift in amino acid transport capacity and metabolic pathways within the fetoplacental unit. After transport across the trophoblast in normal conditions, amino acids are actively incorporated into tissue proteins or oxidized. In the sheep IUGR fetus, however, which is hypoxic, hypoglycemic and hypoinsulinemic, there appear to be net effluxes of amino acids from the liver and skeletal muscle, suggesting changes in amino acid metabolism. Potential changes may be occurring in the insulin/IGF-I signaling pathway that includes decreased production and/or activation of specific signaling proteins leading to a reduced protein synthesis in fetal tissues. Such observations in the placental insufficiency model of IUGR indicate that the combination of decreased fetoplacental amino acid uptake and disrupted insulin/IGF signaling in liver and muscle account for decreased fetal growth in IUGR.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier
Date: 2017
Publisher: The Endocrine Society
Date: 02-04-2009
DOI: 10.1210/EN.2008-1789
Publisher: Wiley
Date: 30-05-2018
DOI: 10.1113/JP274948
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/134758
Abstract: Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor- γ (PPAR γ ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.JPEDSURG.2019.01.024
Abstract: Tracheal occlusion (TO) reverses pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. Wnt signaling plays a critical role in lung development, but few studies exist. The purpose of our study was to a) confirm that our CDH rabbit model produced PH which was reversed by TO and b) determine the effects of CDH +/- TO on Wnt signaling. CDH was created in fetal rabbits at 23 days, TO at 28 days, and lung collection at 31 days. Lung body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. mRNA and miRNA expression was determined in the left lower lobe using RT-qPCR. Fifteen CDH, 15 CDH + TO, 6 sham CDH, and 15 controls survived and were included in the study. LBWR was low in CDH, while CDH + TO was similar to controls (p = 0.003). MTBD was higher in CDH fetuses and restored to control levels in CDH + TO (p < 0.001). Reference genes TOP1, SDHA, and ACTB were consistently expressed within and between treatment groups. miR-33 and MKI67 were increased, and Lgl1 was decreased in CDH + TO. TO reversed pulmonary hypoplasia and stimulated early Wnt signaling in CDH fetal rabbits. Basic science, prospective. II.
Publisher: Cold Spring Harbor Laboratory
Date: 28-07-2023
DOI: 10.1101/2023.07.25.550586
Abstract: Intrauterine growth restriction (IUGR) is an obstetrical outcome where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has previously assessed fetal myelin water fraction (MWF) and can potentially assess myelination changes associated with IUGR. Thus, this study aims to quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. Our s le consisted of 22 pregnant Dunkin-Hartley GPs with 71 fetuses (34 male) [mean ± standard deviation: 60 ± 1.2 days gestation]. Eight SPGR volumes [flip angles (α): 2° – 16°], and two sets of 8 bSSFP volumes (α: 8° – 64°), at 0° and 180° phase increments were acquired at 3.0 T. MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T 1 /T 2 (mcDESPOT). Regions of interest (ROIs) were placed in the fetal corpus callosum (CC), fornix (FOR), and parasagittal white matter (PSW). Linear regression was performed between five fetal IUGR markers [body volume (BV), body-to-pregnancy volume ratio (BPrVR), brain-to-liver VR (BLVR), brain-to-placenta VR (BPlVR), and brain-to-BVR (BBVR)] and MWF for all regions (coefficient of determination, R 2 ). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs for all three regions (α = 0.05). The MWF values are as follows: (mean ± standard deviation): 0.23 ± 0.02 (fetal CC), 0.19 ± 0.02 (fetal CC – IUGR), 0.31 ± 0.02 (fetal FOR), 0.27 ± 0.01 (fetal FOR – IUGR), 0.28 ± 0.02 (fetal PSW), and 0.24 ± 0.03 (fetal PSW – IUGR). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every region. In conclusion, the mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2018
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.EARLHUMDEV.2017.06.009
Abstract: Maternal under- and over-nutrition are known to effect fetal growth with altered placental development and nutrient transport, but whether fetal oxygenation is also altered remains unknown. To examine linkages between maternal BMI and birth weights, placental weights, and umbilical vein and artery PO Population-based cohort study. Analysis of hospital database information on all patients with pre-pregnant BMI values delivering viable, singleton infants between Jan 1, 1999 and Dec 31, 2010 (N=29,212). BMI was categorized into underweight, normal weight, overweight, and obese, with birth weights categorized into small (SGA), appropriate (AGA), and large for gestational age (LGA). Maternal BMI, birth and placental weights, umbilical vein and artery PO Underweight mothers with smaller infants and overweight/obese mothers with larger infants had disproportionately large placentas, suggesting compensatory and/or enhanced placental growth in these pregnancies. All SGA infants had lower umbilical vein and artery PO These findings support fetal hypoxemia as a common determinant of growth restriction, whether in underweight mothers and due to under-nutrition or in overweight/obese mothers and due to placental insufficiency. However, oxygen is unlikely to be the primary promotor for fetal growth in overweight/obese mothers and LGA infants, with other substrates of more importance as nutritional cues in these pregnancies.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/638476
Abstract: Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.
Publisher: Elsevier BV
Date: 12-2002
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.
Publisher: Wiley
Date: 04-2015
Publisher: Elsevier BV
Date: 05-2023
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/291846
Abstract: The placental weight ratio (PWR) is a health indicator that reflects the balance between fetal and placental growth. The PWR is defined as the placental weight ided by the birth weight, and it changes across gestation. Its ranges are not well established. We aimed to establish PWR distributions by gestational age and to investigate whether the PWR distributions vary by fetal growth adequacy, small, average, and large for gestational age (SGA, AGA, and LGA). The data came from a hospital based retrospective cohort, using all births at two London, Ontario hospitals in the past 10 years. All women who delivered a live singleton infant between 22 and 42 weeks of gestation were included ( n = 41441 ) . Nonparametric quantile regression was used to fit the curves. The results demonstrate decreasing PWR and dispersion, with increasing gestational age. A higher proportion of SGA infants have extreme PWRs than AGA and LGA, especially at lower gestational ages. On average, SGA infants had higher PWRs than AGA and LGA infants. The overall curves offer population standards for use in research studies. The curves stratified by fetal growth adequacy are the first of their kind, and they demonstrate that PWR differs for SGA and LGA infants. Corrigendum to “Population-Based Placental Weight Ratio Distributions”
Publisher: Springer Science and Business Media LLC
Date: 2002
DOI: 10.1385/ENDO:19:1:23
Publisher: Elsevier BV
Date: 08-2002
Abstract: Our purpose was to test the hypothesis that the intra-amniotic injection of a retroviral vector producer cell line into pregnant sheep will result in retrovirus-mediated transduction and stable gene transfer to the ovine fetus. Thirteen pregnant ewes at various gestational ages underwent amniocentesis and injection of cells producing the retrovirus vector LIRESgeo, which is derived from Maloney murine leukemia virus and encodes Escherichia coli LacZ (beta-galactosidase) as a marker gene. Pregnant ewes and fetuses were killed, and amniotic fluid, placenta, and fetal tissues were collected and assayed for transgene expression 7 to 77 days after intraamniotic injection. In addition, serum was collected and analyzed for evidence of specific immune responses against the producer cells, and amniotic fluid was collected and analyzed for deleterious effects on producer cell viability, vector production, and vector transduction. Only 1 of 10 fetuses exposed to the retroviral producer cells demonstrated beta-galactosidase activity that correlated with positive immunohistochemistry for LacZ in lung, trachea, pancreas, and small intestine. However, the presence of the LacZ gene could not be confirmed by polymerase chain reaction. Thus, we could not confirm transduction after any of the injections. The retroviral producer cells survived well in amniotic fluid and continued to produce high levels of retroviral vector after intra-amniotic injection, although amniotic fluid inhibited the transducing activity of the vector in a manner dependent on gestational age. Intra-amniotic retroviral gene transfer with the use of these hotropic producer cells does not result in reproducible gene transfer in the ovine fetus although amniotic fluid sustains producer cell viability and vector production. Possible reasons for the inefficient transduction are discussed.
Publisher: American Physiological Society
Date: 03-2021
DOI: 10.1152/AJPREGU.00249.2020
Abstract: Migratory birds may benefit from diets rich in polyunsaturated fatty acids (PUFAs) that could improve exercise performance. Previous investigations suggest that different types of birds may respond differently to PUFA. We established muscle myocyte cell culture models from muscle satellite cells of a migratory passerine songbird (yellow-rumped warbler, Setophaga coronata coronata) and a nonpasserine shorebird (sanderling, Calidris alba). We differentiated and treated avian myotubes and immortalized murine C 2 C 12 myotubes with n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and with monounsaturated oleic acid (OA) to compare effects on aerobic performance, metabolic enzyme activities, key fatty acid (FA) transporters, and expression of peroxisome proliferator-activated receptors (PPARs). Sanderling and C 2 C 12 myotubes increased expression of PPARs with n-3 PUFA treatments, whereas expression was unchanged in yellow-rumped warblers. Both sanderlings and yellow-rumped warblers increased expression of fatty acid transporters, whereas C 2 C 12 cells decreased expression following n-3 PUFA treatments. Only yellow-rumped warbler myotubes increased expression of some metabolic enzymes, whereas the sanderling and C 2 C 12 cells were unchanged. PUFA supplementation in C 2 C 12 myotubes increased mitochondrial respiratory chain efficiency, whereas sanderlings increased proton leak-associated respiration and maximal respiration (measurements were not made in warblers). This research indicates that songbirds and shorebirds respond differently to n-3 PUFA and provides support for the hypothesis that n-3 PUFA increase the aerobic capacity of migrant shorebird muscle, which may improve overall endurance flight performance.
Publisher: MDPI AG
Date: 05-03-2019
DOI: 10.3390/ANI9030080
Abstract: Weaning stress can negatively impact a pig’s performance dietary supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) reduces inflammatory stress and promotes nursery pig’s health and growth. Fish oil (FO) is a major source of n-3 PUFA however, microalgae (AL) may provide an alternative source of n-3 PUFA. The aim of this study was to assess the health benefits of supplementing a plant protein-based nursery diet with 3.12% AL or 1.25% FO providing equal total n-3 PUFA compared to a control (CON) diet. Seventy-two pigs were fed experimental diets for three weeks (phases 1 and 2), followed by a common standard diet for three weeks (phase 3). Following phase 2, 8 pigs per treatment underwent a lipopolysaccharide (LPS) immune stress challenge to assess the acute-phase response and 8 pigs per treatment were vaccinated with novel antigens to assess acquired immunity. No significant differences in piglets’ growth were observed, despite decreased feed intake in FO piglets compared to AL piglets in phase 3. AL supplementation tended to reduce, and FO supplementation significantly reduced the LPS-induced fever response. The AL pigs had significantly reduced cortisol responses, increased cytokine concentrations, and increased chromogranin A concentrations compared to FO and CON pigs following LPS challenge. Results suggest that AL or FO supplementation in nursery diets differentially modulate the acute-phase response, possibly due to different n-3 PUFA profiles between the two ingredients.
Publisher: PeerJ
Date: 03-01-2017
DOI: 10.7717/PEERJ.2840
Abstract: The gastrointestinal tract (GIT) microbiota is essential to metabolic health, and the prevalence of the Western diet (WD) high in fat and sugar is increasing, with evidence highlighting a negative interaction between the GIT and WD, resulting in liver dysfunction. Additionally, an adverse in utero environment such as placental insufficiency resulting in low birth weight (LBW) offspring, contributes to an increased risk of metabolic diseases such as fatty liver infiltration and liver dysfunction in later life. We sought to understand the potential interactive effects of exposure to a WD upon growing LBW offspring. We postulated that LBW offspring when challenged with a poor postnatal diet, would display an altered microbiota and more severe liver metabolic dysfunction. The fecal microbiota of normal birth weight (NBW) and LBW young guinea pig offspring, weaned onto either a control diet (CD) or WD was determined with 16S rRNA gene next generation sequencing at young adulthood following the early rapid growth phase after weaning. A liver blood chemistry profile was also performed. The life-long consumption of WD following weaning into young adulthood resulted in increased total cholesterol, triglycerides and alanine aminotransferase levels in association with an altered GIT microbiota when compared to offspring consuming CD. Neither birth weight nor sex were associated with any significant changes in microbiota alpha ersity, by measuring the Shannon’s ersity index. One hundred forty-eight operational taxonomic units were statistically distinct between the diet groups, independent of birth weight. In the WD group, significant decreases were detected in Barnesiella, Methanobrevibacter smithii and relatives of Oscillospira guillermondii , while Butyricimonas and Bacteroides spp. were increased. These results describe the GIT microbiota in a guinea pig model of LBW and WD associated metabolic syndrome and highlight several WD specific GIT alterations associated with human metabolic disease.
Publisher: Springer Science and Business Media LLC
Date: 10-2011
Abstract: This study aimed to determine the effect of varying degrees of intermittent umbilical cord occlusion (UCO) on arterial elastin composition. Over 4 days, chronically catheterized late gestation fetal sheep received 5 total UCO per day lasting 1 min/h (mild group: n = 6), 2 min/h (moderate group: n = 4), 3 min/h (severe group n = 6) or no occlusion (control group: n = 7). Each group was evaluated for elastin content of the carotid and superior mesenteric artery (SMA), the arterial pressure response to UCO, and plasma cortisol concentration. Elastin content of the carotid artery was significantly increased by severe UCO (9.5 µg/mg versus 6.4 µg/mg P < .05) and insignificantly increased in mild and moderate groups, whereas UCO had no effect on elastin content of the SMA. This dose- and site-dependent response of the vasculature appears attributable to the hemodynamic changes that accompany UCO.
Publisher: MDPI AG
Date: 08-01-2015
DOI: 10.3390/NU7010360
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.VETIMM.2019.109937
Abstract: Maternal stress, such as a bacterial infection occurring in late gestation, may predispose offspring to a variety of diseases later in life. It may also alter programming of developing systems within the fetus, such as the hypothalamic-pituitary-adrenal (HPA) axis and immune system. Dietary supplementation during the last trimester of pregnancy with immune-modulating compounds may be a means of reducing potential adverse effects of maternal stress on the developing fetus. Essential omega-3 polyunsaturated fatty acids (n-3 PUFA) such as docosahexanoic acid (DHA) and eicosapentanoic acid are well-known for their immune-modulating and anti-inflammatory properties. Sources of these n-3 PUFA include fish products such as fish oil and microalgae, which may be a suitable alternative to fish-based products. The aim of this study was to determine the effect of supplementing gestating sow diets with n-3 PUFA and inducing an immune stress challenge in late gestation on piglet growth and immune responsiveness when placed on either a high- or low-quality protein diet after weaning. Forty-eight sows were fed gestation diets containing either 3.12% microalgae, 3.1% fish oil or a corn oil control diet containing 1.89% corn oil starting on gestation day (gd) 75. On gd112, half the sows in each treatment were immune stress challenged with bacterial lipopolysaccharide (LPS) endotoxin (10 μg/kg administered i.m). After farrowing, piglet BW gain was monitored weekly during lactation and pigs were weaned at 21 days of age. One week after weaning, four piglets per sow were immune stress challenged with LPS (40 μg/kg administered i.m.). At the same time, four piglets per sow were vaccinated with the novel antigens chicken ovalbumin (OVA) and Candida cellular antigen (CAA) and received booster vaccinations two weeks later. Four weeks after the initial vaccination, a transdermal hypersensitivity immune challenge was performed using the same antigens. Blood s les were also collected to quantify IgG antibody responses to both antigens. PUFA enrichment in sow blood and piglet brain was detected after sows were on feed for 40 days. Piglet growth was increased in pigs fed a high-quality diet in nursery phase 1. Concentrations of the cytokines IL-1ra, IL-6 and IL-10 were elevated in pigs fed a high-quality protein diet following LPS immune challenge. Overall, it appears that in the current study piglet nursery diet quality was more important for determining piglet health and growth than maternal diet and immune stress.
Publisher: American Physiological Society
Date: 05-2018
DOI: 10.1152/AJPREGU.00317.2017
Abstract: We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs with fetal growth restriction (FGR) on offspring body and organ weights, hypothesizing that FGR-MNR animals will show catch-up growth but with organ-specific differences. Guinea pig sows were fed ad libitum (Control) or 70% of the control diet from 4 weeks preconception, switching to 90% at midpregnancy (MNR). Control newborns g [appropriate for gestational age (AGA) n = 37] and MNR newborns g (FGR n = 37) were monitored until neonatal (~25 days) or adult (~110 days) necropsy. Birth weights and body/organ weights at necropsy were used to calculate absolute and fractional growth rates (FRs). FGR-MNR birth weights were decreased ~32% compared with the AGA-Controls. FGR-MNR neonatal whole body FRs were increased ~36% compared with Controls indicating catch-up growth, with values negatively correlated to birth weights indicating the degree of FGR leads to greater catch-up growth. However, the increase in organ FRs in the FGR-MNR neonates compared with Controls was variable, being similar for the brain and kidneys indicating comparable catch-up growth to that of the whole body and twofold increased for the liver but negligible for the heart indicating markedly increased and absent catch-up growth, respectively. While FGR-MNR body and organ weights were unchanged from the AGA-Controls by adulthood, whole body growth rates were increased. These findings confirm early catch-up growth in FGR-MNR guinea pigs but with organ-specific differences and enhanced growth rates by adulthood, which are likely to have implications for structural alterations and disease risk in later life.
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/129173
Abstract: PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C 2 C 12 muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.
Publisher: MDPI AG
Date: 31-01-2023
Abstract: Solastalgia is a term used to describe the pain and distress experienced by those witnessing their home environments destroyed or changed in unwelcome ways. Solastalgia is expected to become more prominent as climate change worsens and transforms landscapes. This scoping review examines and maps the existing literature on solastalgia in Australia, particularly focusing on Aboriginal and Torres Strait Islander experiences. Four focus questions guided the review to explore how solastalgia is conceptualized, highlight risk and protective factors, and identify strategies for addressing solastalgia. Eighteen papers met the criteria for inclusion. Overall, our results show a minimal evidence base on solastalgia in Australia with an even greater gap in exploring solastalgia from Aboriginal and Torres Strait Islander perspectives. A strong connection to home environments was suggested as both a risk and protective factor for experiencing solastalgia. Aboriginal and Torres Strait Islander peoples are considered at risk due to intimate connections to home environments, and since the invasion, have experienced mental distress resulting from significant, damaging changes to landscapes and home environments. We recommend further exploration of lived experiences of solastalgia across a greater ersity of Australian contexts, particularly amongst Aboriginal and Torres Strait Islander peoples, including a focus on practical implications.
Publisher: MDPI AG
Date: 18-01-2023
Abstract: This article assesses the accessibility of mainstream mental health services (MMHSs) in two regions of New South Wales (NSW), Australia, based on experiences and perspectives of Aboriginal young people aged 16–25. Semi-structured yarning interviews were conducted with thirteen Aboriginal young people in two regions of NSW. Thematic analysis was undertaken by all research team members to identify major themes from the data and conceptual connections between them. The identified themes from in idual analysis and coding were triangulated during several analysis meetings to finalise the key themes and findings. Aboriginal young people had no experience of engaging with early-intervention MMHSs. MMHSs were identified as inaccessible, with most participants unaware that MMHSs existed in each region. Due to MMHSs being inaccessible, many Aboriginal young people presented to emergency departments (EDs) during a crisis. Aboriginal Community Controlled Health Services (ACCHSs) were identified as key providers of accessible, culturally meaningful, and effective social and emotional wellbeing (SEWB) service support for Aboriginal young people in NSW. If health and wellbeing outcomes are to improve for Aboriginal young people in NSW, MMHSs must increase accessibility for Aboriginal young people requiring SEWB support.
Publisher: Portland Press Ltd.
Date: 10-2023
DOI: 10.1042/BSR20231060
Publisher: Cambridge University Press (CUP)
Date: 02-03-2023
DOI: 10.1017/S2040174423000053
Abstract: Intrauterine growth restriction (IUGR) exerts a negative impact on developing cardiomyocytes and emerging evidence suggests activation of oxidative stress pathways plays a key role in this altered development. Here, we provided pregnant guinea pig sows with PQQ, an aromatic tricyclic o-quinone that functions as a redox cofactor antioxidant, during the last half of gestation as a potential antioxidant intervention for IUGR-associated cardiomyopathy. Pregnant guinea pig sows were randomly assigned to receive PQQ or placebo at mid gestation and fetuses were identified as spontaneous IUGR (spIUGR) or normal growth (NG) near term yielding four cohorts: NG ± PQQ and spIUGR ± PQQ. Cross sections of fetal left and right ventricles were prepared and cardiomyocyte number, collagen deposition, proliferation (Ki67) and apoptosis (TUNEL) were analyzed. Cardiomyocyte endowment was reduced in spIUGR fetal hearts when compared to NG however, PQQ exerted a positive effect on cardiomyocyte number in spIUGR hearts. Cardiomyocytes undergoing proliferation and apoptosis were more common in spIUGR ventricles when compared with NG animals, which was significantly reduced with PQQ supplementation. Similarly, collagen deposition was increased in spIUGR ventricles and was partially rescued in PQQ-treated spIUGR animals. The negative influence of spIUGR on cardiomyocyte number, apoptosis, and collagen deposition during parturition can be suppressed by antenatal administration of PQQ to pregnant sows. These data identify a novel therapeutic intervention for irreversible spIUGR-associated cardiomyopathy.
Publisher: Public Library of Science (PLoS)
Date: 13-06-2014
Publisher: SAGE Publications
Date: 05-2006
DOI: 10.1177/153537020623100511
Abstract: Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction (IUGR) were the focus of our study. Our objective was to test the hypothesis that the fetal ovine myocardium adapts during an IUGR gestation by increasing glucose transporter protein expression, plasma membrane-bound glucose transporter protein concentrations, and insulin signal transduction protein concentrations. Growth measurements and whole heart tissue were obtained at 55 days gestational age (dGA), 90 dGA, and 135 dGA (term = 145 dGA) in fetuses from control (C) and hyperthermic (HT) pregnant sheep. Additionally, in 135 dGA animals, arterial blood was obtained and Doppler ultrasound was used to determine umbilical artery systolic (S) and diastolic (D) flow velocity waveform profiles to calculate pulsatility (S – D/mean) and resistance (S – D/S) indices. Myocardial Glut-1, Glut-4, insulin signal transduction proteins involved in Glut-4 translocation, and glycogen content were measured. Compared to age-matched controls, HT 90-dGA fetal body weights and HT 135-dGA fetal weights and gross heart weights were lower. Heart weights as a percent of body weights were similar between C and HT sheep at 135 dGA. HT 135-dGA animals had (i) lower fetal arterial plasma glucose and insulin concentrations, (ii) lower arterial blood oxygen content and higher plasma lactate concentrations, (iii) higher myocardial Glut-4 plasma membrane (PM) protein and insulin receptor β protein (IRβ) concentrations, (iv) higher myocardial glycogen content, and (v) higher umbilical artery Doppler pulsatility and resistance indices. The HT ovine fetal myocardium adapts to reduced circulating glucose and insulin concentrations by increasing plasma membrane Glut-4 and IRβ protein concentrations. The increased myocardial Glut-4 PM and IRβ protein concentrations likely contribute to or increase the intracellular delivery of glucose and, together with the increased lactate concentrations, enhance glycogen synthesis, which allows for maintained myocardial growth commensurate with fetal body growth.
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2023
Publisher: American Physiological Society
Date: 02-2008
DOI: 10.1152/AJPENDO.00639.2007
Abstract: Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phospho enolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-γ coactivator-1α mRNA and phosphorylation of cAMP response element binding protein at Ser 133 were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4α, or CCAAT enhancer binding protein-β. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2020
DOI: 10.1038/S41523-020-0156-0
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues scoring outside the tumor boundary tumors with minimal assessable stroma including lymphocytes associated with other structures and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at itfalls .
Publisher: Humana Press
Date: 2006
DOI: 10.1385/1-59259-989-3:205
Abstract: This chapter presents experimental methods to measure in vivo uteroplacental nutrient substrate uptake, transfer to the fetus, and metabolism by the uteroplacental unit. The fundamental method involves application of the Fick principle, which requires determination of uterine and umbilical blood flow rates and measurement of nutrient substrate arterial and venous concentrations in the uterine and umbilical circulations. Surgical approaches to placing catheters into these circulations are described. Details are provided to illustrate key concepts for net rates of uteroplacental glucose and amino acid uptake, transfer to the fetus, and net uteroplacental uptake.
Publisher: Springer Science and Business Media LLC
Date: 04-2003
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000506939
Abstract: b i Background: /i /b We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for brain hypoxia and oxidative stress. b i Methods: /i /b Guinea pigs were fed ad libitum (control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1) was injected into pregnant sows. Fetuses were then necropsied and brain tissues were processed for HP-1 (hypoxia marker) and 4HNE, 8-OHdG, and 3-nitrotyrosine (oxidative stress markers) immunoreactivity (IR). b i Results: /i /b FGR-MNR fetal and brain weights were decreased 38 and 12%, respectively, with brain/fetal weights thereby increased 45% as a measure of brain sparing, and more so in males than females. FGR-MNR HP-1 IR was increased in most of the brain regions studied, and more so in males than females, while 4HNE and 8-OHdG IR were increased in select brain regions, but with no sex differences. b i Conclusions: /i /b Chronic hypoxia is likely to be an important signaling mechanism in the FGR brain, but with males showing more hypoxia than females. This may involve sex differences in adaptive decreases in growth and normalizing of oxygen, with implications for sex-specific alterations in brain development and risk for later neuropsychiatric disorder.
Publisher: Springer Science and Business Media LLC
Date: 2004
Publisher: Elsevier BV
Date: 02-2002
Publisher: Springer Science and Business Media LLC
Date: 15-10-2015
Publisher: Cambridge University Press
Date: 28-01-2010
Publisher: Elsevier BV
Date: 12-2006
Publisher: Cold Spring Harbor Laboratory
Date: 13-11-2020
DOI: 10.1101/2020.11.12.379891
Abstract: Intrauterine growth restriction (IUGR) and low birth weight (LBW) have been widely reported as an independent risk factor for hypercholesterolemia and increased hepatic cholesterol underlying liver dysfunction in adulthood. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. Hepatic cholesterol metabolism pathways were studied in uterine artery ablation-induced LBW and normal birth weight (NBW) male and female guinea pig offspring at postnatal day 150. Hepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that “Cholesterol metabolism” was an enriched pathway in LBW males but not females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. UPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination, in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. Low birth weight (LBW) is a risk factor for adult hypercholesterolemia and increased hepatic cholesterol. Uteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. UPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. These changes, at the current age studied, were sex-specific, only being observed in LBW males and not LBW females. These programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age.
Publisher: Elsevier BV
Date: 12-2006
Publisher: American Physiological Society
Date: 12-2004
DOI: 10.1152/AJPENDO.00259.2004
Abstract: Reductions in fetal plasma concentrations of certain amino acids and reduced amino acid transport in vesicle studies suggest impaired placental amino acid transport in human fetal growth restriction (FGR). In the present study, we tested the hypothesis of an impairment in amino acid transport in the ovine model of hyperthermia-induced FGR by determining transplacental and placental retention and total placental clearance of a branched-chain amino acid (BCAA) analog, the nonmetabolizable neutral amino acid aminocyclopentane-1-carboxylic acid (ACP), in singleton control (C) and FGR pregnancies at 135 days gestation age (dGA term 147 dGA). At study, based on the severity of the placental dysfunction, FGR fetuses were allocated to severe (sFGR, n = 6) and moderate FGR (mFGR, n = 4) groups. Fetal (C, 3,801.91 ± 156.83 mFGR, 2,911.33 ± 181.35 sFGR, 1,795.99 ± 238.85 g P 0.05) and placental weights (C, 414.38 ± 38.35 mFGR, 306.23 ± 32.41 sFGR, 165.64 ± 28.25 g P 0.05) were reduced. Transplacental and total placental clearances of ACP per 100 g placenta were significantly reduced in the sFGR but not in the mFGR group, whereas placental retention clearances were unaltered. These data indicate that both entry of ACP into the placenta and movement from the placenta into fetal circulation are impaired in severe ovine FGR and support the hypothesis of impaired placental BCAA transport in severe human FGR.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.AJOG.2004.05.088
Abstract: Our objective was to test the hypothesis that systemic blood pressure (BP) is increased above normal in intrauterine growth restricted (IUGR) fetal lambs with elevated umbilical artery (UmA) Doppler indices. Five pregnant ewes were exposed to hyperthermic conditions for 80 days beginning at 40 days' gestation (dGA) to induce IUGR. They were then placed in ambient conditions with 6 additional ewes that served as controls. Doppler indices were calculated from UmA Doppler flow velocity waveforms. At 128 dGA, fetal catheters were placed for measurement of umbilical blood flow (UBF) by an ethyl alcohol steady-state diffusion technique and for aortic BP measurements. At 132 dGA, fetal mean systemic BP and blood flow were determined. At necropsy the placental and fetal weights were recorded. UBF was normalized for fetal weight. Linear regression, F tests and t tests were performed as appropriate. P < .05 was considered significant. Compared with control pregnancies, the IUGR pregnancies showed: (1) reduced fetal and placental weights, (2) elevated systemic BP, (3) reduced UBF, (4) elevated UmA and aortic Doppler velocimetry indices, (5) increased resistance per 100 g placenta, and (6) decreased UmA oxygenation and increased lactic academia. The UmA Doppler index of resistance (systolic/diastolic ratio) correlated strongly with calculated resistance (R2 = 0.7). Doppler indices also correlated with systemic BP (R2 = 0.5). Ovine IUGR fetuses with high UmA Doppler indices have elevated systemic BPs. UmA Doppler indices of resistance correlate well with (1) fetal systemic BPs and (2) resistance as calculated by pressure/flow. This whole animal study shows that IUGR fetuses are hypertensive and that increased UmA Doppler resistance indices are consistent with a fetal-placental hypertensive state.
Publisher: Wiley
Date: 07-2003
Publisher: MDPI AG
Date: 03-10-2020
DOI: 10.3390/NU12103031
Abstract: The proportion of women of reproductive age who are overweight or obese is increasing globally. Gestational obesity is strongly associated in both human studies and animal models with early-onset development of adult-associated metabolic diseases including metabolic syndrome in the exposed offspring. However, animal model studies have suggested that gestational diet in obese pregnancies is an independent but underappreciated mediator of offspring risk for later life metabolic disease, and human diet consumption data have highlighted that many women do not follow nutritional guidelines prior to and during pregnancy. Thus, this review will highlight how maternal diet independent from maternal body composition impacts the risk for later-life metabolic disease in obesity-exposed offspring. A poor maternal diet, in combination with the obese metabolic state, are understood to facilitate pathological in utero programming, specifically through changes in lipid handling processes in the villous trophoblast layer of the placenta that promote an environment associated with the development of metabolic disease in the offspring. This review will additionally highlight how maternal obesity modulates villous trophoblast lipid processing functions including fatty acid transport, esterification and beta-oxidation. Further, this review will discuss how altering maternal gestational diet may ameliorate these functional changes in lipid metabolic processes in the obese placenta.
Publisher: MDPI AG
Date: 14-06-2023
DOI: 10.20944/PREPRINTS202306.1022.V1
Abstract: Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs), palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in β-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advise and implementing dietary interventions that maintain appropriate placental function by limiting excessive exposure to saturated NEFAs such as PA, will continue to be crucial in the clinical management of at-risk obese and GDM pregnancies.
Publisher: Bioscientifica
Date: 06-2008
DOI: 10.1530/REP-06-0294E
Publisher: Elsevier BV
Date: 12-2005
Publisher: The Royal Society
Date: 08-2021
Abstract: Migratory birds experience bouts of muscle growth and depletion as they prepare for, and undertake prolonged flight. Our studies of migratory bird muscle physiology in vitro led to the discovery that sanderling ( Calidris alba ) muscle satellite cells proliferate more rapidly than other normal cell lines. Here we determined the proliferation rate of muscle satellite cells isolated from five migratory species (sanderling ruff, Calidris pugnax western sandpiper, Calidris mauri yellow-rumped warbler, Setophaga coronata Swainson's thrush, Catharus ustulatus ) from two families (shorebirds and songbirds) and with different migratory strategies. Ruff and sanderling satellite cells exhibited rapid proliferation, with population doubling times of 9.3 ± 1.3 and 11.4 ± 2 h, whereas the remaining species' cell doubling times were greater than or equal to 24 h. The results indicate that the rapid proliferation of satellite cells is not associated with total migration distance but may be related to flight bout duration and interact with lifespan.
Publisher: Elsevier BV
Date: 05-2023
Publisher: SAGE Publications
Date: 2003
DOI: 10.1177/153537020322800114
Abstract: Glucocorticoids near term are known to upregulate many important enzyme systems prior to birth. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that catalyzes both the reversible conversion of ammonium nitrogen into organic nitrogen (glutamate production) and the oxidative deamination of glutamate resulting in 2-oxoglutarate. The activity of this enzyme is considered to be of major importance in the development of catabolic conditions leading to gluconeogenesis prior to birth. Ovine hepatic GDH mRNA expression and activity were determined in near-term (130 days of gestation, term 147 ± 4 days) control and acutely dexamethasone-treated (0.07 mg –1 hr –1 for 26 hr) fetuses. Dexamethasone infusion had no effect on placental or fetal liver weights. Dexamethasone infusion for 26 hr significantly increased hepatic GDH mRNA expression. This increased GDH mRNA expression was accompanied by an increase in hepatic mitochondrial GDH activity, from 30.0 ± 7.4 to 58.2 ± 8.1 U GDH/U CS (citrate synthase), and there was a significant correlation between GDH mRNA expression and GDH activity. The generated ovine GDH sequence displayed significant similarity with published human, rat, and murine GDH sequence. These data are consistent with the in vivo studies that have shown a redirection of glutamine carbon away from net hepatic glutamate release and into the citric acid cycle through the forward reaction catalyzed by GDH, i.e., glutamate to oxoglutarate.
Publisher: Wiley
Date: 17-02-2016
DOI: 10.1113/JP271777
Publisher: Elsevier BV
Date: 04-2002
Publisher: Bioscientifica
Date: 2021
DOI: 10.1530/REP-19-0433
Abstract: Placental villous trophoblast mitochondrial respiratory function is critical for a successful pregnancy and environmental influences such as maternal obesity have been associated with respiratory impairment at term. More recently, a gestational high fat diet independent of maternal body composition, has been highlighted as a potential independent regulator of placental mitochondrial metabolism. The current study aimed to characterize the direct impact of a prolonged and isolated exposure to the dietary fatty acids Palmitate (PA) and Oleate (OA) upon placental cell mitochondrial respiratory function. BeWo cytotrophoblast (CT) and syncytiotrophoblast (SCT) cells were treated for 72 h with 100 µM PA, OA or PA+OA (P/O). Live-cell metabolic function was analyzed via the Seahorse XF Mito and Glycolysis Stress tests. Immunoblots and spectrophotometric activity assays were utilized to examine the protein expression and function of electron transport chain (ETC) complexes and key mitochondrial regulatory enzymes. Syncytialization of BeWo cells resulted reduced respiratory activity in conjunction with altered complex I and II activity and decreased pyruvate dehydrogenase (PDH) protein expression and activity. PA and P/O treatments were associated with increased basal and maximal respiratory activities in BeWo CT cells without alterations in protein expression or activity of in idual ETC complexes and mitochondrial substrate regulators. The metabolic suppression in BeWo SCTs was consistent with that previously observed in primary human trophoblast cell cultures, while the observed increases in respiratory activity in PA-treated BeWo CTs may be indicative of an early timepoint of specific dietary saturated fat-mediated placental cell mitochondrial dysfunction.
Publisher: Elsevier BV
Date: 04-2005
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.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.PLACENTA.2006.06.007
Abstract: Severe fetal growth restriction (FGR) is often associated with hypoxia. We studied FGR hypoxia in an experimental model which is produced by exposing pregnant ewes to a hyperthermic environment. The study utilized simultaneous measurements of several relevant factors, e.g., uterine and umbilical blood flows and O(2) uptakes. Sixteen ewes were ided equally into control (C) and hyperthermic (HT) groups. Hyperthermia (40 degrees C for 12h/35 degrees C for 12h approximately 35% relative humidity, RH) was maintained for 80 days commencing at approximately 38 days gestational age (dGA term 147+/-3 days). All ewes were then placed in a control environment ( approximately 21 degrees C, 24h approximately 30% RH) and studied at approximately 134 dGA. Mean HT placental and fetal weights were 39% and 45% of C, respectively (p<0.0001), umbilical O(2) uptake/kg fetus was 76% of C (p<0.01) and umbilical venous PO(2) was reduced (20.2 vs. 29.7 Torr, p<0.001). Contrary to the hypothesis that FGR hypoxia is due to maternal placental hypoperfusion, uterine flow was not reduced in relation to O(2) uptake. The uterine-umbilical venous PO(2) difference was enlarged (38 vs. 23 Torr, p<0.0001). This difference is the expression of a balance between developmental changes in placental structure and oxidative metabolism, which have opposite effects in terms of fetal oxygenation. We postulate that FGR hypoxia results from disproportionate underdevelopment of those changes which allow for a progressive increase in umbilical O(2) uptake.
Publisher: Elsevier BV
Date: 2004
Publisher: Cambridge University Press (CUP)
Date: 10-01-2014
DOI: 10.1017/S2040174413000524
Abstract: Intrauterine growth restriction (IUGR) is an important risk factor for development of hypertension, diabetes and the metabolic syndrome. Maternal low protein (LP) intake during rat pregnancy leads to IUGR in male and female offspring, although females may be resistant to the development of effect. Current evidence suggests that changes in the renin-angiotensin system (RAS) in utero contribute to this programmed hypertension, via sex-specific mechanisms. The previously orphaned G-protein coupled receptor (GPR91) was identified as a central player in the development of hypertension in adult mice, through a RAS-dependent pathway. However, whether the GPR91 pathway contributes to fetal programming is unknown. Furthermore, the nature of involvement of downstream modulators of the RAS including Gqα/11α and GαS has not been investigated in IUGR-LP rats. Therefore, we postulated that renal GPR91, in conjunction with RAS, is differentially impacted in a sex-specific manner from LP-induced IUGR rats. Pregnant Wistar rats were fed control (C, 20% protein) or LP (8% protein) diet until embryonic day 19 (E19) or postnatal d21. At E19, GPR91 protein and mRNA were increased in both male and female LP kidneys ( P .05), whereas renin and angiotensin converting enzyme (ACE) were only increased in males ( P =0.06 and P .05, respectively). On d21, AT 1 R and Gqα/11α were increased in LP males, while in LP females, AT 2 R protein was elevated and renin expression was decreased ( P .05). This study demonstrates that in IUGR-LP rats, up regulation of GPR91 in fetal kidney is mirrored by increased ACE and renin in males. These in utero alterations, when combined with postnatal increases in AT 1 R-Gqα/11α specifically in male offspring, may predispose to the development of hypertension.
Publisher: Elsevier
Date: 2004
Publisher: Cambridge University Press
Date: 04-05-2006
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