Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden and major contributor to chronic liver disease. Evidence suggests arsenic (As) and/or cadmium (Cd) exposure may influence MASLD development, yet effects of chronic low-dose metal mixtures on hepatic inflammation and immune responses remain unclear. Using the apolipoprotein E-knockout mouse model, we examined low-dose As and Cd exposure in male and female mice. We focused on hepatic steatosis and inflammation. Steatosis-related changes were assessed via lipid metabolism gene expression and PLIN2 levels. No significant changes were observed in males; however, females exposed to the metal mixture showed increased PLIN2 expression. In contrast, males exhibited an inflammatory phenotype following combined exposure. High-plex single-cell imaging (PhenoCycler) in male livers revealed increased Ki67+ hepatocytes, enhanced β-catenin signal, and elevated CD8+ T-cell infiltration, indicating enhanced proliferation and immune activation. These findings suggest sex-dependent responses to low-dose As and Cd, with females showing subtle steatotic changes and males a pronounced inflammatory signature. Collectively, combined metal exposure induces hepatic priming in both sexes; males show an increased inflammatory response with cellular proliferation in the absence of overt steatosis or fibrosis, whereas females demonstrate increased steatosis without inflammation or fibrosis.
Subramaniam et al. (Thu,) studied this question.