As important members in steroids related signal pathways, bile acids are very important in regulating substance metabolism and immune homeostasis. However, bile acids are highly cytotoxic, and the excessive accumulation can induce several abnormalities such as cholestatic liver injury. It is known that the bile acid metabolism alters during pregnancy and mostly will not result in pathologies. However, the effect of dexamethasone exposure during pregnancy on bile acid metabolism is still unknown. In this study, pregnant Wistar rats were subcutaneously administered dexamethasone (0.2 mg/kg.d) or saline from gestation day 9 to 21, while virgin rats were given the same treatment for 13 days. We found that, physiological pregnancy or dexamethasone exposure during non-pregnancy did not affect maternal serum TBA level and liver function. Nevertheless, dexamethasone exposure during pregnancy increased serum TBA level and accompanied with liver injury. Furthermore, we discovered that the conservation of bile acid homeostasis under pregnancy or dexamethasone exposure was maintained through compensatory pathways. However, dexamethasone exposure during pregnancy tipped the balance of liver bile acid homeostasis by increasing classical synthesis and decreasing efflux and uptake. In addition, dexamethasone exposure during pregnancy also increased serum estrogen level and nuclear receptors mRNA expression levels. Finally, two-way ANOVA analysis showed that dexamethasone exposure during pregnancy could induce or facilitate maternal cholestasis and liver injury by up-regulating ERα and CYP7A1 expression. This study confirmed that dexamethasone exposure during pregnancy was related to maternal intrahepatic cholestasis of pregnancy and should be carefully monitored in clinical settings.

中文翻译：

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妊娠期地塞米松暴露对母体胆汁酸代谢的影响、潜在机制和相互作用

作为类固醇相关信号通路的重要成员，胆汁酸在调节物质代谢和免疫稳态方面非常重要。然而，胆汁酸具有很强的细胞毒性，过度积累会导致胆汁淤积性肝损伤等多种异常。众所周知，胆汁酸代谢在怀孕期间会发生变化，并且大部分不会导致病理。然而，妊娠期地塞米松暴露对胆汁酸代谢的影响尚不清楚。在这项研究中，怀孕的 Wistar 大鼠从妊娠第 9 天到第 21 天皮下注射地塞米松 (0.2 mg/kg.d) 或生理盐水，而处女大鼠则接受相同的治疗 13 天。我们发现，生理性妊娠或非妊娠期间地塞米松暴露不影响母体血清 TBA 水平和肝功能。尽管如此，孕期地塞米松暴露增加血清TBA水平并伴有肝损伤。此外，我们发现怀孕或地塞米松暴露下胆汁酸稳态的保护是通过补偿途径维持的。然而，怀孕期间暴露于地塞米松通过增加经典合成和减少外排和摄取来破坏肝胆汁酸稳态的平衡。此外，孕期地塞米松暴露也增加了血清雌激素水平和核受体mRNA表达水平。最后，双向方差分析表明，孕期地塞米松暴露可通过上调 ERα 和 CYP7A1 表达诱导或促进母体胆汁淤积和肝损伤。