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.