Steroid hormone synthesis in pregnancy

Cadmium (Cd), commonly found in diet and drinking water, is known to be harmful to the human liver. Nevertheless, the effects and mechanisms of gestational Cd exposure on fetal liver development remain unclear. Here, we reported that gestational Cd (150 mg/L) exposure obviously downregulated the expression of critical proteins including PCNA, Ki67 and VEGF-A in proliferation and angiogenesis in fetal livers, and lowered the estradiol concentration in fetal livers and placentae. Maternal estradiol supplement alleviated aforesaid impairments in fetal livers. Our data showed that the levels of pivotal estrogen synthases, such as CYP17A1 and 17β-HSD, was markedly decreased in Cd-stimulated placentae but not fetal livers. Ground on ovariectomy (OVX), we found that maternal ovarian-derived estradiol had no major effects on Cd-impaired development in fetal liver. In addition, Cd exposure activated placental PERK signaling, and inhibited PERK activity could up-regulated the expressions of CYP17A1 and 17β-HSD in placental trophoblasts. Collectively, gestational Cd exposure inhibited placenta-derived estrogen synthesis via activating PERK signaling, and therefore impaired fetal liver development. This study suggests a protective role for placenta-derived estradiol in fetal liver dysplasia shaped by toxicants, and provides a theoretical basis for toxicants to impede fetal liver development by disrupting the placenta-fetal-liver axis.

The placenta is a remarkable organ. Its brief existence enables the mammalian fetus to survive and thrive within the otherwise inhospitable confines of the intrauterine environment. To accomplish this, the placenta plays a range of roles, from anchoring the conceptus and preventing its rejection by the maternal immune system to enabling the transport of nutrients and wastes between the mother and the embryo/fetus.

• •

  The placenta is the first organ to form in mammals and is required for establishment of a maternal–fetal vascular interface capable of supplying the bioenergetic needs of the developing conceptus.

• •

  Multiple placental cell types engage in highly varied functions, from attachment, invasion, and vascular remodeling to cell fusion, hormone production, and nutrient transport.

• •

  Multiple mechanisms allow transport of waste and nutrients across the placenta, including diffusion, transporter protein-mediated (facilitated diffusion and active transporters), and receptor-mediated mechanisms.

• •

  The placenta is not an inert transport interface. It consumes 40%–60% of the oxygen and glucose delivered to the uterus at term. Thus conditions that alter placental metabolism can indirectly affect nutrient transport to the fetus.

• •

  Maternal and fetal health alter placental function, which in turn influences fetal adaptations and contributes to in utero fetal programming.

• •

  Abnormal placentation and placental infections can lead to preeclampsia (PE), fetal growth retardation, or preterm birth, which can have lifelong bearing on health.

• •

  In the United States, iatrogenic delivery is responsible for almost half the births that occur between 28 and 37 weeks of gestation, primarily caused by placental pathologies such as PE or intrauterine growth restriction.

• •

  Efforts to standardize placental examination after delivery are in progress so that connections between specific placental problems and poor outcomes can be better defined. In parallel, new advanced imaging techniques and biomarkers for placental function are being developed.

Inflammatory responses in HIV (+) patients may be exacerbated due to reports of subclinical endotoxemia and existing immune dysregulation. As inflammation has been reported to mediate changes in the expression of transporters, this could be potentiated in pregnant HIV (+) women. Similar to humans, the HIV-Tg rat model develops immune dysregulation and chronic AIDS-like conditions. Our objective was to examine the expression of placental drug transporters in HIV-Tg rats in response to low-dose endotoxin.

Pregnant HIV-Tg rats or wild-type littermates (WT) were treated with low dose bacterial endotoxin 0.1 mg/kg (n = 8) or 0.25 mg/kg (n = 4–6) on GD18 and placentas were harvested 18 h later. Placental and hepatic expression of transporters and cytokines were examined using qRT-PCR and Western blotting.

As compared to WT, endotoxin administration increased the hepatic and placental expression of IL-6 and TNF-α to a greater extent in HIV-Tg rats (p < 0.05). The placental mRNA and protein expression of Abcb1a and Slco2b1 was significantly decreased in endotoxin-treated HIV-Tg but not WT rats and downregulation of Slco4a1 mRNA was more pronounced in the HIV-Tg group (p < 0.05). These changes significantly correlated with the placental expression of pro-inflammatory cytokines. Abcc3 mRNA expression was increased in the placenta of endotoxin treated WT rats only, while placental expression of Abcc1, Abcc2 and Abcc4 was not significantly affected in both WT and HIV rats. Endotoxin imposed a pronounced downregulation in the hepatic expression of Abcb1a, Abcc2, Abcc4, Abcg2, Slco1a1, Slco1b2 and Slc29a1 in both HIV-Tg and WT rats; however, Abcb1b expression was increased in HIV but not WT rats.

Our results indicate that low-dose endotoxin resulted in an augmented inflammatory response in HIV-Tg rats accompanied with significant changes in the placental expression of several drug transporters. Our data suggests that subclinical endotoxemia and other co-existing infections may alter the placental transfer of drugs in the HIV population.

• •

  The placenta is the first organ to form in mammals and is required for establishment of a maternal–fetal vascular interface capable of supplying the bioenergetic needs of the developing conceptus.

• •

  Multiple placental cell types engage in highly varied functions, from attachment, invasion, and vascular remodeling to cell fusion, hormone production, and nutrient transport.

• •

  Multiple mechanisms allow transport of waste and nutrients across the placenta, including diffusion, transporter protein-mediated (facilitated diffusion and active transporters), and receptor-mediated mechanisms.

• •

  The placenta is not an inert transport interface. It consumes 40%–60% of the oxygen and glucose delivered to the uterus at term. Thus conditions that alter placental metabolism can indirectly affect nutrient transport to the fetus.

• •

  Maternal and fetal health alter placental function, which in turn influences fetal adaptations and contributes to in utero fetal programming.

• •

  Abnormal placentation and placental infections can lead to preeclampsia (PE), fetal growth retardation, or preterm birth, which can have lifelong bearing on health.

• •

  In the United States, iatrogenic delivery is responsible for almost half the births that occur between 28 and 37 weeks of gestation, primarily caused by placental pathologies such as PE or intrauterine growth restriction.

• •

  Efforts to standardize placental examination after delivery are in progress so that connections between specific placental problems and poor outcomes can be better defined. In parallel, new advanced imaging techniques and biomarkers for placental function are being developed.