Bisphenol S exposure and MASLD: a mechanistic study in mice

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 non-alcoholic fatty liver disease (MASLD). However, the causal relationship and the molecular mechanisms affecting hepatocellular functions are still unknown. Our study aimed to understand the molecular mechanism by which BPS exposure caused hepatic lipid deposition. C57BL/6J mice were exposed to BPS for three 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 knock out mice and cells were used to validate its functions in BPS induced hepatotoxicity. Here, mice that were chronically exposed to BPS showed significant lipid deposition in liver and dyslipidemia, and were predisposed to MASLD, accompanied with reprogrammed liver transcriptional network and chromatin accessibility that were enriched for Atf3 binding motif. Comparing to the control group, we identified numerous differential Atf3 binding sites associated with signaling pathways integral to lipid catabolism and synthesis in BPS exposure group, resulting in a drastic surge in lipid accumulation. Moreover, knocking out Atf3 in vitro and in vivo significantly attenuates BPS-induced hepatic lipid accumulation via the regulation of chromatin accessibility and gene expression. Besides, inhibiting the JunB also eliminates the BPS-induced Atf3 upregulation and lipid accumulation. 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.