Gestational cholestasis induced intrauterine growth restriction through triggering IRE1α‐mediated apoptosis of placental trophoblast cells

Abstract

Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17α‐Ethynylestradiol (E2) on gestational day 13 (GD13)–GD17. Some pregnant mice were intraperitoneally injected with 4μ8C on GD13–GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)‐treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase‐3 and Bax were increased, while placental Bcl2 level was decreased in mice with gestational cholestasis and in DCA‐treated trophoblast cells. Further analysis found that placental IRE1α pathway was activated in mice with gestational cholestasis and in DCA‐treated trophoblast cells. Interestingly, 4μ8C, an IRE1α RNase inhibitor, significantly inhibited caspase‐3 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4μ8C rescued gestational cholestasis‐induced placental insufficiency and IUGR. Furthermore, a case–control study demonstrated that placental IRE1α and caspase‐3 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1α‐mediated apoptosis of placental trophoblast cells.

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species‐mediated activation of placental GCN2/eIF2α pathway

“…Western blot was performed as previously described 14 . Briefly, mouse placentas or cells were lysed in RIPA lysis buffer.…”

“…Western blot was performed as previously described. 14 Briefly, mouse placentas or cells were lysed in RIPA lysis buffer. The BCA Kit (Thermo Fisher) was used to measure the protein concentrations.…”

“…Indeed, CA‐induced cholestasis as animal models for ICP has been well established in rodents 11,12 . Several reports in rodent models found that 17α‐ethynylestradiol (E2)‐induced gestational cholestasis resulted in a decrease in fetal weight and crown‐rump length, and an increase in the incidence of fetal growth restriction (FGR) or intrauterine growth restriction (IUGR) 13,14 . However, few reports have been carried out to study the roles of CA‐induced FGR in rodent models.…”

“…11,12 Several reports in rodent models found that 17α-ethynylestradiol (E2)-induced gestational cholestasis resulted in a decrease in fetal weight and crown-rump length, and an increase in the incidence of fetal growth restriction (FGR) or intrauterine growth restriction (IUGR). 13,14 However, few reports have been carried out to study the roles of CAinduced FGR in rodent models. FGR is defined as the failure of the fetus to reach its expected growth potential.…”