Subchronic low dose dioxin exposure disrupts hepatic and metabolic homeostasis in a sex- and diet-dependent manner

Persistent organic pollutants (POPs) such as “dioxins” have been associated with liver disease development. Population studies have highlighted sex-specific susceptibility to POP-induced liver damage, yet toxicological models looking at sex-specific toxic responses and the combined effects of dioxin mixtures remain insufficiently characterized. This study addresses a critical knowledge gap by investigating sex-dependent effects from exposure to a mixture of dioxin and dioxin-like compounds in the context of sex differences and dietary patterns. Male and female C57BL/6 J mice were fed either a low- (LFD) or high-fat diet (HFD) and administered a weekly dose of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD-10 ng/kg), 3,4,7,8-pentachlorodibenzofuran (PeCDF-80 ng/kg) and polychlorinated biphenyl 126 (PCB126-140 ng/kg) or vehicle control. After 12 weeks, the study was terminated and samples collected for downstream analyses. LFD-fed females exposed to the dioxin mixture displayed reduced liver weight but elevated hepatic triglycerides alongside elevated circulating alanine aminotransferase levels and upregulation of the hepatic fatty acid transport gene Cd36 . This observation was absent in diet-matched males. Instead, exposed LFD-fed males showed suppressed de novo lipogenic gene expression coupled with impaired glucose tolerance. Aryl hydrocarbon receptor (AHR) activation (↑ Cyp1a1 , Cyp1a2 ) was observed with exposure regardless of sex or diet, although HFD diminished AHR signaling, especially in males. Exposure also resulted in constitutive androstane receptor (CAR) activation (↑ Cyp2b10 , Cyp2c29 ), specifically in LFD-fed males. Notably, the dioxin mixture did not exacerbate HFD effects. Sex-specific toxicant responses were observed including dioxin-mediated steatotic liver phenotype in females and glucose perturbation in males, highlighting the negative impact of these chemicals on liver and metabolic outcomes even at low doses.