Transgenerational hepatotoxicity induced by bisphenol B as a substitute for bisphenol A.

Accumulating evidence identifies bisphenol A (BPA) as an endocrine disruptor with demonstrated hepatotoxicity, driving the adoption of structural analogs like bisphenol B (BPB). Pregnancy constitutes a critical developmental window for endocrine disruptor-mediated hepatotoxicity in offspring. However, systematic toxicity evidence about BPB exposure-induced transgenerational hepatotoxicity in offspring remains scarce, and the regulatory mechanisms need to be further explored. To elucidate the gene markers and signaling pathways involved in the developmental origins of liver dysfunction induced by direct/maternal BPB exposure. In this study, we systematically analyzed the mechanism of hepatotoxicity and transgenerational effects of BPB by animal models (BPB, direct exposure and maternal exposure, 300 μg/kg bw (body weight)/day). Biochemical indicators and histopathological changes were examined, and bioinformatics analysis was used to explain the relationship between BPB exposure and the liver injuries. The results showed that direct BPB exposure induced subclinical hepatotoxicity with significant cholesterol reduction, circadian rhythm disruption, and Tmem87b/Fkbp1a-mediated chemoresistance. Maternal BPB exposure caused offspring hepatomegaly, transaminase elevation, drove oxidative stress and lipid metabolism imbalance through the Ppard-Slc23a2 dysregulation. Bioinformatics validation in human hepatocellular carcinoma (HCC) confirmed prognostic significance of Tmem87b/Fkbp1a/Ppard/Slc23a2. The study confirmed that BPB induces hepatotoxicity through circadian disruption and oxidative stress pathways, establishing these genes as dual biomarkers for early detection and therapeutic response prediction.