PXR mediates maternal cholestatic liver injury and associated fetal dysplasia induced by antenatal dexamethasone exposure.

Previous studies have focused on advantages and disadvantages of antenatal dexamethasone therapy (ADT) on offspring development, but the effects on the mother have yet to be reported. In this study, the clinical cohort study found that ADT caused maternal susceptibility to cholestatic liver injury, which was manifested by elevated plasma total bile acid (TBA) levels, altered bile acid metabolic profiles and changed gut microbiota (mainly characterized by increased Bacteroides), accompanied by fetal dysplasia associated with high bile acids. Animal experiments confirmed that prenatal dexamethasone exposure (PDE) caused maternal cholestatic liver injury and associated fetal dysplasia, related to enhanced maternal hepatic bile acid synthesis and intestinal flora transformation. Furthermore, the in vitro experiments demonstrated that dexamethasone increased hepatocyte glucocorticoid receptor (GR) and estrogen receptor α (ERα) translocation into the nucleus, and then inhibited pregnane X receptor (PXR) by binding to its promoter region, which in turn increased cytochrome P4507A1 (CYP7A1) expression and TBA levels. Finally, the PXR agonist pregnenolone carbonitrile (PCN) effectively reversed PDE-induced maternal cholestatic liver injury and associated fetal dysplasia. The study systematically elucidated the liver-gut circulation mechanism of maternal cholestatic liver injury induced by ADT and confirmed potential drug intervention target-PXR, essential for guiding rational use of ADT and conducting early prevention and treatment research.