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

Author:
Wahlang, Banrida, Jin, Jian, Hardesty, Josiah E., Head, Kimberly Z., Shi, Hongxue, Falkner, K. Cameron, Prough, Russell A., Klinge, Carolyn M., Cave, Matthew C.
Source:
Food and chemical toxicology 2019 v.129 pp. 64-76
ISSN:
0278-6915
Subject:
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
Abstract:
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.
Agid:
6379732