24. Sexual dimorphism in the placenta

Abstract

There is a sexual dimorphism in pregnancy outcomes with male fetuses generally being at higher risk for adverse outcomes. The underlying physiologic mechanisms likely involve sexual dimorphism in placental function given the role of the placenta in directing both maternal metabolic and cardiovascular changes in gestation and fetal growth and development. Gene expression in the human placenta is sexually dimorphic and is affected by maternal inflammatory status, diet and fatty acids in a sex-dependent manner. We find increased markers of inflammation, hypoxia and apoptotic cell death in the placenta with preeclampsia compared to normotensive pregnancies but with sexual dimorphism as TNFa, Il-6, Il-8, HIF1a, apoptotic markers and DNA binding of the NFkB p65 transcription factor are significantly higher, but the angiogenic marker VEGF significantly lower, in male vs female preeclamptic placentas. Obesity and gestational diabetes are associated with increased placental inflammation and oxidative and nitrative stress, increased miR-210 expression and consequent decreased trophoblast respiration, altered autophagic responses and altered antioxidant defenses, however all of which occur in a sexually dimorphic manner. In trophoblast from a female, but not a male, placenta TNF stimulates the NFkBp50 pathway to increase miR210 expression which in turn depresses mitochondrial respiration. Interestingly miR210 expression is significantly higher in placenta from a female vs a male fetus across all birthweight centiles with the difference being greatest in placentas of large for gestational age fetuses. The mechanisms of sexual dimorphism in placenta with preeclampsia, obesity or GDM and the range of functional effects remain to be elucidated; however evidence links sex differences to gonadal steroids. Placental levels of aromatase, the rate-limiting enzyme converting androgens to estrogens, are higher in placentas of preeclamptic women with female vs male fetuses and aromatase can be downregulated by TNF α , hypoxia, insulin and leptin, factors which mirror placental conditions with maternal obesity.