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Circulating microRNAs are associated with PCB exposures and liver disease in the Anniston Community Health Survey
Citation:
Cave, M., C. Pinkston, S. Rai, M. Pavuk, K. Head, B. Wahlang, AND B. Chorley. Circulating microRNAs are associated with PCB exposures and liver disease in the Anniston Community Health Survey. Society of Toxicology 2021 Virtual Annual Meeting, NA, Virtual, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.14470704
Impact/Purpose:
Poster presented to the Society of Toxicology 2021 Virtual Annual Meeting March 2021. Non-invasive biomarkers that are linked to mechanisms of chemical exposure and disease progression can be utilized for surveillance scenarios to identify susceptible subpopulations. Here, we explore the use non-coding RNAs in blood, specifically miRNAs, to identify liver disease in a residential cohort of high PCB exposures. This exploratory study will build a foundation of accessible molecular-based biomarkers that may be used to identify fatty liver disease development influenced by environmental pollutant exposure. Long-term, development of these biomarkers will assist risk assessors to determine the impact of pollutant exposures to human liver health.
Description:
PCB exposures have been associated with liver disease in cohort studies and steatohepatitis with liver necrosis in animal models. MicroRNAs (miRs) are non-coding RNAs that maintain cellular homeostasis, possibly in response to environmental exposures. This study tests the hypothesis that PCB-associated liver necrosis (suspected toxicant associated steatohepatitis) is associated with circulating miRs in an exposed human cohort. IRB approval was obtained for this analysis of 738 participants in the cross-sectional Anniston Community Health Survey (ACHS). Necrotic liver disease was defined by a combination of serum keratin 18 (K18) biomarkers as published (PMC6016643). Here, association studies were performed between highly-expressed serum hepatotoxicity miRs (n=35) and categorical liver disease (primary endpoint); continuous serum PCBs (n=35), cytokines (n=4), and HOMA-IR. Ingenuity Pathway Analysis (IPA) was performed.The necrotic liver disease category (n=359/738) was associated with 4 up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and 5 down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR197-3p, and miR-221-3p). 11 miRs were associated with 24 PCBs, most commonly congeners with (anti-)estrogenic activity. 22 miRs were associated with continuous K18. Most of the exposure-associated miRs were also associated with at least one hepatocyte death, pro-inflammatory cytokine and/or insulin resistance biomarker. miR-122-5p was the miR most significantly associated with each of the exposure and disease biomarkers. IPA demonstrated enrichment in liver toxicity functions related to inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis and hepatocellular carcinoma. P53 was central to the miR-associated networks. These results support the hepatotoxicity of PCBs in humans and previously reported high liver disease prevalence in ACHS. They provide insight into PCBs potential modes of action. The roles of estrogenic PCBs and miR-122-5p in environmental liver disease warrant further investigation. miR-derived ‘liquid liver biopsy’ appears to be a useful tool for environmental hepatology cohort studies. This abstract does not necessarily reflect EPA policy. Mention of trade names is not an endorsement or recommendation for use.
URLs/Downloads:
DOI: Circulating microRNAs are associated with PCB exposures and liver disease in the Anniston Community Health Survey