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<p>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)&#xa0;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 <i>z</i>-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 <i>Dehalobacterium</i> abundance, and decreased mRNA levels for genes encoding gut barrier and antimicrobial proteins (<i>Ocln</i>, <i>Reg3g</i>). 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Richa Singhal,
  • Zayna Qaissi,
  • Hao Zheng,
  • Yuan Hua,
  • Josiah E. Hardesty,
  • Eric C. Rouchka,
  • Michael L. Merchant,
  • Maiying Kong,
  • Banrida Wahlang

摘要

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.