Bisphenol S Exposure and MASLD: A Mechanistic Study in Mice

BACKGROUND: Bisphenol S (BPS) is a substitute for bisphenol A in various commercial products and is increasingly used globally due to restrictions on bisphenol A usage. Consequently, there are increasing public health concerns that substantial effects mediated by synthetic chemicals may impact human health. Recently, epidemiology studies reported associations between bisphenol exposure and nonalcoholic fatty liver disease [metabolic dysfunction-associated steatotic liver disease (MASLD)]. However, the causal relationship and the molecular mechanisms affecting hepatocellular functions are still unknown. OBJECTIVES: Our study aimed to understand the molecular mechanism by which BPS exposure caused hepatic lipid deposition. METHODS: C57BL/6J mice were exposed to BPS for 3 months, and its effects were assessed by histology. RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with high-throughout sequencing (ATAC-seq), and cleavage under targets and tagmentation (CUT&Tag) were used to investigate mechanistic details. ATF3 liver-specific knockout mice and cells were used to validate its functions in BPS-induced hepatotoxicity. RESULTS: significantly attenuates BPS-induced hepatic lipid accumulation via the regulation of chromatin accessibility and gene expression. Besides, inhibiting JunB also eliminates BPS-induced Atf3 upregulation and lipid accumulation. CONCLUSION: Our study reveals a novel mechanism, through which BPS upregulates JunB and Atf3 to impair hepatic lipid metabolism, and provides new insights into the hepatotoxicity of BPS. https://doi.org/10.1289/EHP17057.