Journal
TOXICOLOGICAL SCIENCES
Volume 164, Issue 1, Pages 39-49Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfy076
Keywords
PCB; toxicant-associated steatohepatitis; TASH; NASH; endocrine disrupting chemicals; metabolism disrupting chemicals
Categories
Funding
- National Institutes of Health [R01ES021375, R35ES028373, F30ES025099, P42ES023716]
- Institutional Development Award [P20GM113226, P50AA024337]
- Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry [200-2013-M-57311]
- James Graham Brown Cancer Center
- Wendell Cherry Chair in Clinical Trial Research
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R35ES028373, P42ES023716, R01ES021375, F30ES025099] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM113226] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [P50AA024337] Funding Source: NIH RePORTER
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Endocrine and metabolism disrupting chemicals (EDCs/MDCs) have been associated with environmental liver diseases including toxicant-associated steatohepatitis (TASH). TASH has previously been characterized by hepatocellular necrosis, disrupted intermediary metabolism, and liver inflammation. Polychlorinated biphenyls (PCBs) are environmental EDCs/MDCs associated with the genesis and progression of steatohepatitis in animal models and human liver injury in epidemiology studies. The cross-sectional Anniston Community Health Survey (ACHS) investigates ortho-substituted PCB exposures and health effects near a former PCB manufacturing complex. The rates of obesity, diabetes, and dyslipidemia were previously determined to be high in ACHS. In this study, 738 ACHS participants were categorized by liver disease status using the serum cytokeratin 18 biomarker. Associations between PCB exposures and mechanistic biomarkers of intermediary metabolism, inflammation, and hepatocyte death were determined. The liver disease prevalence was high (60.2%), and 80.7% of these individuals were categorized as having TASH. Sex and race/ethnicity differences were noted. TASH was associated with increased exposures to specific PCB congeners, insulin resistance, dyslipidemia, proinflammatory cytokines, and liver necrosis. These findings are consistent with PCB-related steatohepatitis. RPCBs was inversely associated with insulin resistance/production, leptin, and hepatocyte apoptosis, while other adipocytokines were increased. This is possibly the largest environmental liver disease study applying mechanistic biomarkers ever performed and the most comprehensive analysis of PCBs and adipocytokines. It provides insight into the mechanisms of PCB-related endocrine and metabolic disruption in liver disease and diabetes. In the future, associations between additional exposures and liver disease biomarkers will be evaluated in the ACHS and follow-up ACHS-II studies.
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