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Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos.

ABSTRACT: Mutations in the gene encoding the cholesterol biosynthetic enzyme NSDHL are associated with the X-linked male-lethal bare patches (Bpa) mouse. Mutant male embryos for several Nsdhl alleles die in midgestation with placental insufficiency. We examined here a possible role of the maternal genotype in such placental pathology. Pre-pregnancy plasma cholesterol levels were similar between wild-type (WT) and Bpa(1H)/+ dams fed a standard, cholesterol-free diet. However, there was a marked decrease in cholesterol levels between embryonic day (E)8.5 and E10.5 for both genotypes. Further, there was a significant lag between E11.5 and E13.5 (P = 0.0011) in the recovery of levels in Bpa(1H)/+ dams to their pre-pregnancy values. To investigate possible effects of the maternal genotype on fetal placentation, we generated transgenic mice that expressed human NSDHL and rescued the male lethality of the Bpa(1H) null allele. We then compared placenta area at E10.5 in WT and Bpa(1H)/+ female embryos where the mutant X chromosome was transmitted from a heterozygous mother or a rescued mutant father. In mutant conceptuses, placental areas were approximately 50% less than WT. Surprisingly, expression of Nsdhl in trophoblast lineages of the placenta and yolk sac endoderm, which occurs only from the maternally inherited allele in a female embryo, had the largest effect on placental area (-0.681 mm(2); P < 0.0001). The maternal genotype had a smaller effect, independent of the fetal genotype (-0.283 mm(2); P = 0.024). These data demonstrate significant effects of the mother and fetal membranes on pregnancy outcome, with possible implications for cholesterol homeostasis during human pregnancy.

SUBMITTER: Cunningham D

PROVIDER: S-EPMC2796896 | biostudies-other | 2010 Jan

REPOSITORIES: biostudies-other

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Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos.

Cunningham David D Talabere Tiffany T Bir Natalie N Kennedy Matthew M McBride Kim L KL Herman Gail E GE

Human molecular genetics 20091030 2

Mutations in the gene encoding the cholesterol biosynthetic enzyme NSDHL are associated with the X-linked male-lethal bare patches (Bpa) mouse. Mutant male embryos for several Nsdhl alleles die in midgestation with placental insufficiency. We examined here a possible role of the maternal genotype in such placental pathology. Pre-pregnancy plasma cholesterol levels were similar between wild-type (WT) and Bpa(1H)/+ dams fed a standard, cholesterol-free diet. However, there was a marked decrease in ...[more]

PMID: 19880419

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Project description:BACKGROUND:During development, all amniotes (mammals, reptiles, and birds) form extraembryonic membranes, which regulate gas and water exchange, remove metabolic wastes, provide shock absorption, and transfer maternally derived nutrients. In viviparous (live-bearing) amniotes, both extraembryonic membranes and maternal uterine tissues contribute to the placenta, an endocrine organ that synthesizes, transports, and metabolizes hormones essential for development. Historically, endocrine properties of the placenta have been viewed as an innovation of placental amniotes. However, an endocrine role of extraembryonic membranes has not been investigated in oviparous (egg-laying) amniotes despite similarities in their basic structure, function, and shared evolutionary ancestry. In this study, we ask whether the oviparous chorioallantoic membrane (CAM) of chicken (Gallus gallus) has the capability to synthesize and receive signaling of progesterone, a major placental steroid hormone. METHODOLOGY/PRINCIPAL FINDINGS:We quantified mRNA expression of key steroidogenic enzymes involved in progesterone synthesis and found that 3beta-hydroxysteroid dehydrogenase, which converts pregnenolone to progesterone exhibited a 464 fold increase in the CAM from day 8 to day 18 of embryonic development (F(5, 68) = 89.282, p<0.0001). To further investigate progesterone synthesis, we performed explant culture and found that the CAM synthesizes progesterone in vitro in the presence of a steroid precursor. Finally, we quantified mRNA expression and performed protein immunolocalization of the progesterone receptor in the CAM. CONCLUSIONS/SIGNIFICANCE:Collectively, our data indicate that the chick CAM is steroidogenic and has the capability to both synthesize progesterone and receive progesterone signaling. These findings represent a paradigm shift in evolutionary reproductive biology by suggesting that endocrine activity of extraembryonic membranes is not a novel characteristic of placental amniotes. Rather, we hypothesize that these membranes may share an additional unifying characteristic, steroidogenesis, across amniotes at large.

Project description:Over the last thirty years, evidence has been accumulating that Hypertensive Disorders of Pregnancy (HDP) and, specifically, Preeclampsia (PE) produce not only long-term effects on the pregnant woman, but have also lasting consequences for the fetus. At the core of these consequences is the phenomenon known as defective deep placentation, being present in virtually every major obstetrical syndrome. The profound placental vascular lesions characteristic of this pathology can induce long-term adverse consequences for the pregnant woman's entire arterial system. In addition, placental growth restriction and function can, in turn, cause a decreased blood supply to the fetus, with long-lasting effects. Women with a history of HDP have an increased risk of Cardiovascular Diseases (CVD) compared with women with normal pregnancies. Specifically, these subjects are at a future higher risk of: Hypertension; Coronary artery disease; Heart failure; Peripheral vascular disease; Cerebrovascular accidents (Stroke); CVD-related mortality. Vascular pathology in pregnancy and CVD may share a common etiology and may have common risk factors, which are unmasked by the "stress" of pregnancy. It is also possible that the future occurrence of a CVD may be the consequence of endothelial dysfunction generated by pregnancy-induced hypertension that persists after delivery. Although biochemical and biophysical markers of PE abound, information on markers for a comparative evaluation in the various groups is still lacking. Long-term consequences for the fetus are an integral part of the theory of a fetal origin of a number of adult diseases, known as the Barker hypothesis. Indeed, intrauterine malnutrition and fetal growth restriction represent significant risk factors for the development of chronic hypertension, diabetes, stroke and death from coronary artery disease in adults. Other factors will also influence the development later in life of hypertension, coronary and myocardial disease; they include parental genetic disposition, epigenetic modifications, endothelial dysfunction, concurrent intrauterine exposures, and the lifestyle of the affected individual.

Project description:ObjectiveTo determine the placental pathologies and maternal factors associated with stillbirth at Kilimanjaro Christian Medical Centre, a tertiary referral hospital in Northern Tanzania.MethodsA 1:2 unmatched case-control study was carried out among deliveries over an 8-month period. Stillbirths were a case group and live births were the control group. Respective placentas of the newborns from both groups were histopathologically analyzed. Maternal information was collected via chart review. Mean and standard deviation were used to summarize the numerical variables while frequency and percentage were used to summarize categorical variables. Crude and adjusted logistic regressions were done to test the association between each variable and the risk of stillbirth.ResultsA total of 2305 women delivered during the study period. Their mean age was 30 ± 5.9 years. Of all deliveries, 2207 (95.8%) were live births while 98 (4.2%) were stillbirths. Of these, 96 stillbirths (cases) and 192 live births (controls) were enrolled. The average gestational age for the enrolled cases was 33.8 ±3.2 weeks while that of the controls was 36.3±3.6 weeks, (p-value 0.244). Of all stillbirths, nearly two thirds 61(63.5%) were males while the females were 35(36.5%). Of the stillbirth, 41were fresh stillbirths while 55 were macerated. The risk of stillbirth was significantly associated with lower maternal education [aOR (95% CI): 5.22(2.01-13.58)], history of stillbirth [aOR (95%CI): 3.17(1.20-8.36)], lower number of antenatal visits [aOR (95%CI): 6.68(2.71-16.48), pre/eclampsia [aOR (95%CI): 4.06(2.03-8.13)], and ante partum haemorrhage [OR (95%CI): 2.39(1.04-5.53)]. Placental pathology associated with stillbirth included utero-placental vascular pathology and acute chorioamnionitis.ConclusionsEducating the mothers on the importance of regular antenatal clinic attendance, monitoring and managing maternal conditions during antenatal periods should be emphasized. Placentas from stillbirths should be histo-pathologically evaluated to better understand the possible aetiology of stillbirths.

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Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos.

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Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos.

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