Sex-dependent modulation of PCB-mediated toxicity from a proteomic and microbiome perspective

Polychlorinated biphenyls (PCBs) have been associated with sex-dependent liver disease outcomes. Current mechanisms only partially explain these sex differences and alternative mechanisms including gut-liver toxicity warrant investigation. This study aims to identify PCB-induced changes in the hepatic proteome and gut microbiome and determine their contributions to sex-specific PCB toxicity. Male and female C57BL/6J mice were exposed to Aroclor1260 (20 mg/kg) and PCB126 (20 μg/kg) via oral gavage. After two weeks, hepatic and intestinal tissues were collected for peptide measurements (LC/MS) and 16S sequencing respectively. Proteomic analysis revealed that biological sex largely drove differences seen in the hepatic proteome and dictated PCB liver responses. PCB-exposed females manifested higher abundance of aryl hydrocarbon receptor (AHR) targets including CD36 vs. PCB-exposed males. Computational analysis also demonstrated enhanced AHR and liver-X-receptor (LXR) activation (higher z-scores) in PCB-exposed females vs. males. With regards to gut microbiome, both exposure and sex impacted the composition of microbial communities. Intriguingly, only PCB-exposed males exhibited increased Dehalobacterium abundance, and decreased mRNA levels for genes encoding gut barrier and antimicrobial proteins (Ocln, Reg3g). Overall, PCB-exposed females exhibited an altered proteome relevant to AHR and LXR responses, while PCB-exposed males exhibited more distinct changes in gut microbiota coupled with altered ileal gene expression. The findings suggest that, in addition to biological sex, organ-organ interactions should be considered when predicting toxicity outcomes, particularly for persistent compounds such as PCBs that can impact multiple organs simultaneously yet have tissue-specific toxic effects.