Exposure to a persistent organic pollutant mixture resulted in sex-specific steatotic liver disease: Role of the liver-endocrine axis.

Exposures to persistent organic pollutants (POPs) have been associated with steatotic liver disease (SLD), but how these chemicals impact women's liver health is underexplored. Our goal was to determine the sex-specific impact of POPs on SLD and identify underlying sex-specific mechanisms. Male and female C57BL/6 mice were fed either a low-fat control diet (CD) or western diet (WD) and exposed to the vehicle control or a POP mixture of chlordane (20 mg/kg) and PCB 126 (20 μg/kg) over 12 weeks. Another group of intact or ovariectomized (OVX) female mice were exposed to the same POP mixture/vehicle control for 2 weeks. Compared to their diet- and sex-matched controls, WD-fed females exposed to the POP mixture exhibited steatosis, confirmed by H&E staining and quantification of hepatic triglycerides/cholesterol, and decreased physical activity (assessed using metabolic chambers). These observations were absent in males. Mechanistically, POPs activated hepatic xenobiotic receptors, namely the arylhydrocarbon receptor and constitutive androstane receptor (CAR), measured by Cyp1a1/Cyp1a2 and Cyp2b10 induction respectively. However, more robust CAR activation was observed in CD-fed females. This group also showed decreased liver gene expression of estrogen sulfotransferase (Sult1e1), a key enzyme in estrogen metabolism. Further, POPs induced hepatomegaly and resistance to glucose clearance only in intact, but not OVX females, suggesting that altered estrogen signaling by POPs played a mechanistical role in driving hepatic POP-mediated toxicity in females. Female mice exposed to the POP mixture were more susceptible to toxicant-associated SLD. Our findings emphasized the significance of examining biological sex in assessing environmental liver disease risk.