Abstract
Chlordane is an organochlorine pesticide (OCP) that is environmentally persistent. Although exposures to OCPs including chlordane have been associated with elevated liver enzymes, current knowledge on OCPs' contribution to toxicant-associated steatotic liver disease (TASLD) and underlying sex-specific metabolic/endocrine disruption are still widely limited. Therefore, the objective of this study was to investigate the sex-dependent effects of chlordane in the context of TASLD. Age-matched male and female C57BL/6 mice were exposed to chlordane (20 mg/kg, one-time oral gavage) for two weeks. Female mice generally exhibited lower bodyfat content but more steatosis and hepatic lipid levels, consistent with increased hepatic mRNA levels of genes involved in lipid synthesis and uptake. Surprisingly, chlordane-exposed females demonstrated lower hepatic cholesterol levels. With regards to metabolic disruption, chlordane exposure decreased expression of genes involved in glycogen and glucose metabolism (Pklr, Gck), while chlordane-exposed females also exhibited decreased gene expression of HNF4A, an important regulator of liver identity and function. In terms of endocrine endpoints, chlordane augmented plasma testosterone levels in males. Furthermore, chlordane activated hepatic xenobiotic receptors, including the constitutive androstane receptor, in a sex-dependent manner. Overall, chlordane exposure led to altered hepatic energy metabolism, and potential chlordane-sex interactions regulated metabolic/endocrine disruption and receptor activation outcomes.