The Influence of a Human-Relevant Polychlorinated Biphenyl Mixture on the Liver in Male and Female Mice

Abstract

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with hepatic toxicity, yet the biological effects of exposure to complex, environmentally relevant PCB mixtures remain incompletely defined. This study evaluated hepatic accumulation and molecular responses to oral exposure to the HR-PCB Mixture, a human-relevant PCB mixture, in male and female C57BL/6J mice. Mice were exposed to 6 mg/kg bw/d HR-PCB Mixture for 7 weeks, followed by assessment of histopathology, PCB tissue burden, transcriptomics, and metabolomics. Liver PCB profiles were enriched in higher-chlorinated congeners relative to the administered mixture and were similar between males and females. Transcriptomic analyses indicated induction of cytochrome P450 enzymes, along with changes in lipid signaling, retinol metabolism, and pathways related to chemical carcinogenesis, without evidence of general toxicity. Targeted metabolomics identified limited hepatic metabolic changes, with females showing disruptions in lysine degradation and steroid biosynthesis. Integrated network analyses identified interactions between higher-chlorinated PCB congeners and gene networks reflecting detoxification and stress responses. Together, these findings suggest that hepatic accumulation of predominantly higher-chlorinated PCB congeners following exposure to the HR-PCB Mixture is associated with altered metabolic and detoxification pathways in the mouse liver.