Bisphenol S Exposure and MASLD: A Mechanistic Study in Mice.

Area of Science:

• Environmental Health Sciences
• Toxicology
• Molecular Biology

Background:

• Bisphenol S (BPS) is a common substitute for Bisphenol A, raising public health concerns.
• Epidemiological studies suggest a link between bisphenol exposure and metabolic dysfunction-associated steatotic liver disease (MASLD).
• The molecular mechanisms underlying BPS-induced liver dysfunction remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Bisphenol S (BPS) exposure leads to hepatic lipid deposition.
• To investigate the role of ATF3 in BPS-induced hepatotoxicity.

Main Methods:

• Mice were exposed to BPS for 3 months, with assessments including histology, RNA sequencing (RNA-seq), ATAC-seq, and CUT&Tag.
• ATF3 liver-specific knockout mice and cells were utilized to validate findings.
• JunB inhibition was also investigated for its effect on BPS-induced toxicity.

Main Results:

• Chronic BPS exposure in mice resulted in significant liver lipid deposition, dyslipidemia, and MASLD predisposition.
• BPS exposure reprogrammed the liver's transcriptional network and chromatin accessibility, with enrichment for the ATF3 binding motif.
• ATF3 knockout significantly attenuated BPS-induced hepatic lipid accumulation by regulating chromatin accessibility and gene expression.
• Inhibition of JunB also prevented BPS-induced ATF3 upregulation and lipid accumulation.

Conclusions:

• BPS exposure impairs hepatic lipid metabolism through the upregulation of JunB and ATF3.
• This study uncovers a novel molecular mechanism contributing to BPS-induced hepatotoxicity.
• The findings provide critical insights into the health risks associated with BPS exposure.