Dioxin-like and non-dioxin-like PCBs differentially regulate the hepatic proteome and modify diet-induced nonalcoholic fatty liver disease severity

• Published in: Medicinal chemistry research 2020-07, Vol.29 (7), p.1247-1263
• Main Authors: Jin, Jian, Wahlang, Banrida, Shi, Hongxue, Hardesty, Josiah E., Falkner, K. Cameron, Head, Kimberly Z., Srivastava, Sudhir, Merchant, Michael L., Rai, Shesh N., Cave, Matthew C., Prough, Russell A.
• Format: Article
• Language: English
• Subjects: Aromatic compounds; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Congeners; Cytoskeleton; Diet; Dioxins; Disruption; Epigenetics; Exposure; Fatty acids; Fatty liver; Fibrosis; Gene expression; Homeostasis; Inflammation; Inorganic Chemistry; Liver; Liver diseases; Medicinal Chemistry; Original Research; PCB; Persistent organic pollutants; Pharmacology/Toxicology; Pollutants; Polychlorinated biphenyls; Proteomes; Proteomics
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02581-w

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with metabolic disruption and nonalcoholic fatty liver disease (NAFLD). Based on their ability to activate the aryl hydrocarbon receptor (AhR), PCBs are subdivided into two classes: dioxin-like (DL) and non-dioxin-like (NDL) PCBs. Previously, we demonstrated that NDL PCBs compromised the liver to promote more severe diet-induced NAFLD. Here, the hepatic effects and potential mechanisms (by untargeted liver proteomics) of DL PCBs and NDL PCBs or co-exposure to both in diet-induced NAFLD are investigated. Male C57Bl/6 mice were fed a 42% fat diet and exposed to vehicle control; Aroclor1260 (20 mg/kg, NDL PCB mixture); PCB126 (20 μg/kg, DL PCB congener); or a mixture of Aroclor1260 (20 mg/kg) + PCB126 (20 μg/kg) for 12 weeks. Each exposure was associated with a distinct hepatic proteome. Phenotypic and proteomic analyses revealed increased hepatic inflammation and phosphoprotein signaling disruption by Aroclor1260. PCB126 decreased hepatic inflammation and fibrosis at the molecular level; while altering cytoskeletal remodeling, metal homeostasis, and intermediary/xenobiotic metabolism. PCB126 attenuated Aroclor1260-induced hepatic inflammation but increased hepatic free fatty acids in the co-exposure group. Aroclor1260 + PCB126 exposure was strongly associated with multiple epigenetic processes, and these could potentially explain the observed nonadditive effects of the exposures on the hepatic proteome. Taken together, the results demonstrated that PCB exposures differentially regulated the hepatic proteome and the histologic severity of diet-induced NAFLD. Future research is warranted to determine the AhR-dependence of the observed effects including metal homeostasis and the epigenetic regulation of gene expression.