Evidence of sexual dimorphism in the placental function with severe preeclampsia

Abstract

Preeclampsia (PE) affects 5-8% of pregnancies and is responsible for 18% of maternal deaths in the US, and for long-term complications in mother and child. PE is an inflammatory state and may influence placental function in a sex-specific manner. We determined if there is a sexual dimorphism in the placental inflammatory and apoptotic responses in preeclamptic pregnancies. Placentas were collected from normotensive and preeclamptic pregnancies with either male or female fetuses (MPE and FPE respectively) after c-section at term with no labor. Expression patterns of markers of inflammation measured by ELISA,as well as hypoxia, apoptosis and angiogenesis markers measured by Western blotting were determined in the placenta. Consistent with previous studies, an increase in inflammation, hypoxia, and apoptotic cell death was observed in PE compared to normotensive pregnancies. Levels of TNFα, IL-6 and IL-8,and HIF-1α were significantly greater, whereas the angiogenic marker VEGF was significantly reduced in MPE vs. FPE. Sexual dimorphism was also observed in the activation of cell death: the number of TUNEL-positive cells, and the expression pro-apoptotic markers PUMA and Bax being higher in MPE vs. FPE. We also found an increase in the levels of protein and DNA-binding activity of NFκB p65 in MPE vs. FPE. In summary, we show here that in preeclamptic pregnancies the placentas of males were associated with significantly higher expression of inflammatory, hypoxia and apoptotic molecules but reduced expression of a pro-angiogenic marker compared to placentas of female fetuses. We propose that the transcription factor NFκBp65 might, at least partially, be involved in sexual dimorphism during PE.

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…We found increased expression of inflammatory and apoptotic markers in placentas of male fetuses from preeclamptic pregnancies compared to female fetuses. 317 Similarly, we found differences in placental expression of miR210 and its mitochondrial target genes between male and female fetuses of lean, overweight and obese women which were mediated by differences in the transcription factor NFkB p50. 308 Our current data therefore indicate that in conditions such as GDM, PE and obesity inflammatory pathways are activated in the placenta in a sexually dimorphic manner to regulate production of reactive O 2 and nitrogen species leading to oxidative/nitrative stress and to mitochondrial dysfunction (Figure 10).…”

Anti-Mullerian hormone changes in pregnancy

“…The smaller decline in the AMH levels in women with a female fetus suggests that females have a stronger survival function when faced with an adverse placental environment. This finding is similar to the sexually dimorphic responses reported in other disease states (40,101,102,104). This ability to compensate for a possible progesterone deficit by maintaining or increasing ovarian function may account for the lower rates of spontaneous losses and PTBs in female pregnancies.…”

“…Fetuses of mothers treated with cortisol for asthma in pregnancy display sex-specific responses to maternal cortisol levels, with adaptations occurring exclusively in the female placentas that improve female fetal survival (101). Finally, placentas from pre-eclamptic mothers with male fetuses show sex-specific differences in expression of inflammatory, hypoxic and apoptotic markers (104). With all disease states, female placentas appear to be programmed for better adaptation when exposed to similar adverse environments (102) leading to improved survival in females.…”

Sexual Dimorphism in Umbilical Vein Blood Flow During the Second Half of Pregnancy: A Longitudinal Study

“…The placenta may respond and adapt differently to pathologic insults in a sex‐specific and gestational age–dependent manner. Sexual dimorphism in placental inflammatory, hypoxic, and apoptotic responses and angiogenesis has been observed in preeclamptic placentas, with male fetuses expressing higher levels of tumor necrosis factor α, interleukin 6, interleukin 8, hypoxia‐inducible factor 1α, and proapoptotic markers but lower vascular endothelial growth factor compared with female fetuses . Female fetuses born before 72 hours after antenatal betamethasone treatment have greater 11β‐hydroxysteroid dehydrogenase activity in the placenta and higher umbilical artery cortisol concentrations compared with male fetuses exposed to a similar treatment .…”