Pregnancy and lactation exposure to bisphenol S induces ferroptosis via disrupted hepatic lipid metabolism in offspring mice.

Introduction: Bisphenol S (BPS), a widely used environmental endocrine disruptor, induces multigenerational liver injury, though its underlying mechanisms remain unclear. Methods: In this study, pregnant mice were housed separately and randomly divided into control and BPS (0.2, 2, and 20 mg/L) group through drinking water exposure. We observed the pathological changes in the livers of the offspring mice and the indicators of liver lipid metabolism disorder. At the same time, we also measured the levels of liver peroxidation and ferroptosis. Additionally, we established a co-exposure situation of in vitro BPS and ferroptosis inhibitors (Fer-1), analyzed the expression of ferroptosis-related genes to evaluate the hepatotoxicity caused by BPS by disrupting liver lipid metabolism and inducing iron depletion. Results: In this study, we observed that BPS exposure induced liver injury and significantly impaired hepatic function in offspring, as indicated by elevated serum ALT and AST levels. Perinatal BPS exposure altered the expression of genes involved in fatty acid β- oxidation, synthesis, and absorption, and concurrently induced dyslipidemia characterized by elevated triglyceride, total cholesterol, and LDL-cholesterol levels and reduced HDL-cholesterol. We further established that BPS promotes ferroptosis in offspring mice, as evidenced by iron accumulation, mitochondrial damage, and oxidative damage. Mechanistically, BPS increased the expression of genes related to lipid peroxidation while suppressing those involved in the antioxidant system. Notably, Fer-1 cotreatment markedly alleviated both the lipid metabolism disorders and ferroptosis triggered by BPS. Discussion: this study provides evidence that perinatal BPS exposure leads to hepatic lipid metabolism dysfunction and ferroptosis activation in offspring mice, highlighting BPS as a potential hepatotoxicant.