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Identifying sex differences arising from polychlorinated biphenyl exposures in toxicant-associated liver disease

Wahlang, Banrida, Jin, Jian, Hardesty, Josiah E., Head, Kimberly Z., Shi, Hongxue, Falkner, K. Cameron, Prough, Russell A., Klinge, Carolyn M., Cave, Matthew C.
Food and chemical toxicology 2019 v.129 pp. 64-76
animal models, aroclors, epidemiological studies, epidermal growth factor receptors, females, gender differences, gene expression, hepatotoxicity, hyperlipidemia, lipids, liver, liver diseases, males, mice, pollutants, thyroid hormones, toxicology
Exposures to persistent environmental pollutants like polychlorinated biphenyls (PCBs) has been associated with liver diseases such as toxicant-associated steatohepatitis (TASH). However, previously published PCB hepatotoxicity studies evaluated mostly male animal models. Moreover, epidemiologic studies on PCB-exposed cohorts evaluating sex differences are scarce. Therefore, the objective of this study was to examine hepato-toxicological responses of PCB exposures in the context of sex-dependent outcomes. Male and female C57Bl/6 mice were exposed to Aroclor 1260 (20 mg/kg), and PCB126 (20 μg/kg), by gavage for two weeks. Female mice appeared to be more sensitive to PCB-induced hepatotoxic effects as manifested by increased liver injury markers, namely, hepatic Serpine1 expression. Additionally, compared to their male counterparts, PCB-exposed females exhibited dysregulated hepatic gene expression favoring lipid accumulation rather than lipid breakdown; accompanied by dyslipidemia. Sex differences were also observed in the expression and activation of PCB targets such as the epidermal growth factor receptor (EGFR) while PCB-induced pancreatic toxicity was similar in both sexes. Importantly, PCB exposure appeared to cause pro-androgenic, anti-estrogenic along with sex-dependent thyroid hormone effects. The overall findings demonstrated that the observed PCB-mediated hepatotoxicity was sex-dependent; confirming the existence of sex differences in environmental exposure-induced markers of TASH and warrants further investigation.