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.
摘要：
流行病学和动物实验研究表明，妊娠期胆汁淤积与宫内生长受限（IUGR）之间存在关联。这里,我们探讨了妊娠期胆汁淤积引起IUGR的机制。建立妊娠期胆汁淤积模型,妊娠小鼠在妊娠第13天（GD13）-GD17皮下注射17α-乙炔雌二醇（E2）。一些怀孕小鼠在GD13-GD17上腹膜内注射4μ8C。结果发现，妊娠胆汁淤积小鼠胎盘和脱氧胆酸（DCA）处理的人滋养层细胞系和原代小鼠滋养层细胞中滋养层细胞的凋亡升高。相应地,胎盘caspase-3和Bax水平升高，而妊娠胆汁淤积小鼠和DCA处理的滋养层细胞中胎盘Bcl2水平降低。进一步的分析发现，在妊娠胆汁淤积小鼠和DCA处理的滋养层细胞中，胎盘IRE1α途径被激活。有趣的是,4μ8C,一种IRE1αRNase抑制剂，在体内外显著抑制caspase-3活性和滋养细胞凋亡。重要的是,4μ8C挽救了妊娠胆汁淤积引起的胎盘功能不全和IUGR。此外，一项病例对照研究表明,在胆汁淤积病例中,胎盘IRE1α和caspase-3通路被激活.我们的结果提供了证据，表明妊娠期胆汁淤积会引起胎盘功能不全，IUGR可能是通过触发IRE1α介导的胎盘滋养层细胞凋亡。
