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: Here, mice that were chronically exposed to BPS showed significant lipid deposition in the liver and dyslipidemia and were predisposed to MASLD, accompanied with a reprogrammed liver transcriptional network and chromatin accessibility that was enriched for the 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 the BPS exposure group, resulting in a drastic surge in lipid accumulation. Moreover, knocking out Atf3 and 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.