Low dose exposure to dioxins alters hepatic energy metabolism and steatotic liver disease development in a sex-specific manner.

"Dioxins" are persistent organic pollutants (POPs) that are continuously present in the environment at appreciable levels and have been associated with increased risk of steatotic liver disease (SLD). However, current understanding of the role of sex and effects of mixtures of dioxins in SLD development is limited. Additionally, there exists debates on the levels of dioxins required to be considered dangerous as emphasis has shifted from high level exposure events to the steady state of lower-level exposures. We therefore investigated sex-dependent effects of low-level exposures to a mixture of dioxins: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and Polychlorinated biphenyl 126 (PCB126), in the context of SLD and associated metabolic dysfunction. Male and female C57BL/6J mice were fed a low-fat diet and weekly administered either vehicle control or TCDD (10 ng/kg), PeCDF (80 ng/kg) and PCB 126 (140 ng/kg) over a two-week period. Female mice generally demonstrated higher hepatic fat content compared to males. However, exposure to dioxins further elevated hepatic cholesterol levels in females, and this was accompanied by increased lipogenic gene expression (Acaca, Fasn) in the liver. In contrast, exposed males but not females displayed higher white adipose tissue weights. Furthermore, TCDD + PeCDF + PCB126 activated the AHR (hepatic Cyp1a1, Cyp1a2 induction); with Cyp1a1 induction observed only in exposed females. Notably, gene expression of hepatic albumin (Alb) was also reduced only in exposed females. Overall, exposure to the low dose dioxin mixture compromised hepatic homeostasis via metabolic perturbations, and hepatic dysregulation was more accelerated in female livers.