Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Fabp1, Srebf1, and Apoc3, while downregulated Acox1 and Cpt1a in rat liver. In addition, it was found that inorganic arsenite (iAsIII) was methylated to DMA, and the S-adenosylmethionine (SAM) level was decreased, which would contribute to the repression of H3K9me1/2 in rat liver after exposure. The in vitro studies revealed that SAM supplementation attenuated lipid accumulation by restoring H3K9me1/2 in HepG2 cells, which further confirmed our animal results. Therefore, it is suggested that As methylation depleted SAM, which inhibited H3K9me1/2 and activated Fabp1, Srebf1, and Apoc3 expressions, leading to NAFLD upon inorganic As exposure. Overall, these data shed new light on the role of SAM-mediated histone methylation in As-triggered NAFLD, which could be useful for the prevention and intervention of hepatotoxicity induced by environmental As exposure.
