ORCID Profile
0000-0002-5071-3805
Current Organisation
University of Oxford
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Publisher: Canadian Science Publishing
Date: 04-2018
Abstract: In western countries, alcohol consumption is widespread in women of reproductive age, and in binge quantities. These countries also continue to have high incidences of unplanned pregnancies, with women often reported to cease drinking after discovering their pregnancy. This suggests the early embryo may be highly exposed to the detrimental effects of alcohol during the periconception period. The periconception and pre-implantation windows, which include maturation of the oocyte, fertilisation, and morphogenesis of the pre-implantation embryo, are particularly sensitive times of development. Within the oviduct and uterus, the embryo is exposed to a unique nutritional environment to facilitate its development and establish de-novo expression of the genome through epigenetic reprogramming. Alcohol has wide-ranging effects on cellular stress, as well as hormonal, and nutrient signalling pathways, which may affect the development and metabolism of the early embryo. In this review, we summarise the adverse developmental outcomes of early exposure to alcohol (prior to implantation in animal models) and discuss the potential mechanisms for these outcomes that may occur within the protected oviductal and uterine environment. One interesting candidate is reduced retinoic acid synthesis, as it is implicated in the control of epigenetic reprogramming and cell lineage commitment, processes that have adverse consequences for the formation of the placenta, and subsequently, fetal programming.
Publisher: Cold Spring Harbor Laboratory
Date: 03-08-2020
DOI: 10.1101/2020.08.03.230615
Abstract: Congenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births 1 . Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases 2 . Many of the remaining cases of CHD are caused by in utero exposure to environmental factors 3 . Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic 4 , and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.PLACENTA.2016.08.080
Abstract: Maternal alcohol consumption is common prior to pregnancy recognition and in the rat results in altered placental development and fetal growth restriction. To assess the effect of ethanol (EtOH) exposure on the differentiation of trophoblast stem (TS) cells, mouse TS lines were differentiated in vitro for 6 days in 0%, 0.2% or 1% EtOH. This reduced both trophoblast survival and expression of labyrinth and junctional zone trophoblast subtype-specific genes. This suggests that fetal growth restriction and altered placental development associated with maternal alcohol consumption in the periconceptional period could be mediated in part by direct effects on trophoblast development.
Publisher: American Physiological Society
Date: 10-2018
DOI: 10.1152/AJPENDO.00251.2017
Abstract: The effects of maternal alcohol consumption around the time of conception on offspring are largely unknown and difficult to determine in a human population. This study utilized a rodent model to examine if periconceptional alcohol (PC:EtOH) consumption, alone or in combination with a postnatal high-fat diet (HFD), resulted in obesity and liver dysfunction. Sprague-Dawley rats were fed a control or an ethanol-containing [12.5% (vol/vol) EtOH] liquid diet from 4 days before mating until 4 days of gestation ( n = 12/group). A subset of offspring was fed a HFD between 3 and 8 mo of age. In males, PC:EtOH and HFD increased total body fat mass ( P PC:EtOH 0.05, P HFD 0.0001) in females, only HFD increased fat mass ( P HFD 0.0001). PC:EtOH increased microvesicular liver steatosis in male, but not female, offspring. Plasma triglycerides, HDL, and cholesterol were increased in PC:EtOH-exposed males ( P PC:EtOH 0.05), and LDL, cholesterol, and leptin (Lep) were increased in PC:EtOH-exposed females ( P PC:EtOH 0.05). mRNA levels of Tnf-α and Lep in visceral adipose tissue were increased by PC:EtOH in both sexes ( P PC:EtOH 0.05), and Il-6 mRNA was increased in males ( P PC:EtOH 0.05). These findings were associated with reduced expression of microRNA-26a, a known regulator of IL-6 and TNF-α. Alcohol exposure around conception increases obesity risk, alters plasma lipid and leptin profiles, and induces liver steatosis in a sex-specific manner. These programmed phenotypes were similar to those caused by a postnatal HFD, particularly in male offspring. These results have implications for the health of offspring whose mothers consumed alcohol around the time of conception.
Publisher: Cold Spring Harbor Laboratory
Date: 06-05-2021
DOI: 10.1101/2021.05.06.442902
Abstract: Placental vascular gene networks in mammals have been largely unexplored due to a lack of well validated molecular markers to identify them. This is required to study how they form in development, and how they are impacted by embryonic or maternal defects, which in-turn adversely affects the forming heart and vasculature. Such defects are known to be a consequence of maternal iron deficiency (ID), the most common nutrient deficiency world-wide. Here we employed marker analysis to characterise the arterial/arteriole and venous/venule endothelial cells (ECs) during normal placental development, and in the context of maternal ID. We reveal for the first time that placental ECs are unique compared with their embryonic counterparts. In the developing embryo, arterial ECs express Neuropilin1 ( Nrp1 ), Delta-like ligand 4 ( Dll4 ) and Notch1 , while developing venous ECs express Neuropilin2 ( Nrp2 ), Apj (Aplnr) and Ephrinb4 (Ephb4) . However, in the E15.5 placenta, Nrp1 and Notch1 were restricted to arteries, but not continuing arteriole ECs. The arterial tree exclusively expressed Dll4. Nrp2 showed pan-EC expression at E15.5, while Ephb4 was not present at this stage. However, we found the placental venous vascular tree could be distinguished from the arterial tree by high versus low Endomucin (EMCN) and Apj (Aplnr) expression respectively. Using EMCN, we reveal that the placental arterial, but not venous, vascular tree is adversely impacted by maternal ID, with reduced area, total length and number of junctions of all vessels without affecting the EMCN high vessels. Defects to the embryonic cardiovascular system can therefore have a significant impact on blood flow delivery and expansion of the placental arterial tree.
Publisher: Frontiers Media SA
Date: 19-01-2022
DOI: 10.3389/FGENE.2021.806136
Abstract: The placental vasculature provides the developing embryo with a circulation to deliver nutrients and dispose of waste products. However, in the mouse, the vascular components of the chorio-allantoic placenta have been largely unexplored due to a lack of well-validated molecular markers. This is required to study how these blood vessels form in development and how they are impacted by embryonic or maternal defects. Here, we employed marker analysis to characterize the arterial/arteriole and venous/venule endothelial cells (ECs) during normal mouse placental development. We reveal that placental ECs are potentially unique compared with their embryonic counterparts. We assessed embryonic markers of arterial ECs, venous ECs, and their capillary counterparts—arteriole and venule ECs. Major findings were that the arterial tree exclusively expressed Dll4 , and venous vascular tree could be distinguished from the arterial tree by Endomucin (EMCN) expression levels. The relationship between the placenta and developing heart is particularly interesting. These two organs form at the same stages of embryogenesis and are well known to affect each other’s growth trajectories. However, although there are many mouse models of heart defects, these are not routinely assessed for placental defects. Using these new placental vascular markers, we reveal that mouse embryos from one model of heart defects, caused by maternal iron deficiency, also have defects in the formation of the placental arterial, but not the venous, vascular tree. Defects to the embryonic cardiovascular system can therefore have a significant impact on blood flow delivery and expansion of the placental arterial tree.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S41467-021-23660-5
Abstract: Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Publisher: The Company of Biologists
Date: 06-2019
DOI: 10.1242/DEV.172205
Abstract: The development of pathologies during pregnancy, including pre-ecl sia, hypertension and fetal growth restriction (FGR), often originates from poor functioning of the placenta. In vivo models of maternal stressors, such as nutrient deficiency, and placental insufficiency often focus on inadequate growth of the fetus and placenta in late gestation. These studies rarely investigate the origins of poor placental formation in early gestation, including those affecting the pre-implantation embryo and/or the uterine environment. The current study characterises the impact on blastocyst, uterine and placental outcomes in a rat model of periconceptional alcohol exposure, in which 12.5% ethanol is administered in a liquid diet from 4 days before until 4 days after conception. We show female-specific effects on trophoblast differentiation, embryo-uterine communication, and formation of the placental vasculature, resulting in markedly reduced placental volume at embryonic day 15. Both sexes exhibited reduced trophectoderm pluripotency and global hypermethylation, suggestive of inappropriate epigenetic reprogramming. Furthermore, evidence of reduced placental nutrient exchange and reduced pre-implantation maternal plasma choline levels offers significant mechanistic insight into the origins of FGR in this model.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2017
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.PLACENTA.2016.12.008
Abstract: Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the ergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental perturbations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-ecl sia and diabetes.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jacinta Kalisch-Smith.