Science Inventory

MicroRNA Biomarkers of Liver and Metabolic Toxicities Associated with Environmental Exposures to Dioxin-like Pollutants

Citation:

Cave, M., C. Pinkston, S. Rai, B. Wahlang, M. Pavuk, K. Head, L. Jophlin, L. Birnbaum, AND B. Chorley. MicroRNA Biomarkers of Liver and Metabolic Toxicities Associated with Environmental Exposures to Dioxin-like Pollutants. AASLD The Liver Meeting, Anaheim, CA, November 12 - 15, 2021. https://doi.org/10.23645/epacomptox.24881571

Impact/Purpose:

The abstract describes a follow-up study in which miRNA measurements were performed in samples archived from a residential cohort that were exposed to polychlorinated biphenyl (PCB) and dioxin-like pollutants (e.g., non-ortho PCBs, PCDDs and PCDFs). The purpose of the study is to develop blood-based miRNA biomarkers of liver disease mediated by these exposures, as well as correlation with other clinical biomarkers of metabolic perturbation, oxidative stress and inflammation. MicroRNAs were also correlated with exposure biomarkers. The overall purpose is to further develop blood miRNAs as accessible and holistic biomarkers of adverse health outcomes.

Description:

Background: Associations between environmental polychlorinated biphenyl (PCB) exposures and liver/metabolic diseases and epigenetic marks have previously been reported in the Anniston Community Health Survey (ACHS-I). Exposures to dioxin-like pollutants (e.g., non-ortho PCBs, PCDDs and PCDFs) have reproducibly been associated with metabolic disruption and NAFLD in animal models. Here we determine relationships between dioxins and circulating liver biomarkers in the follow-up ACHS-II cohort. Methods: Serum dioxins (n=20); K18 (n=2); liver enzymes (n=7) and routine chemistries; microRNAs associated with hepatotoxicity (miRs, n=68); and cytokines were determined in 345 adult ACHS-II participants. The exposure biomarkers analyzed included total dioxin toxic equivalency (TEQ) and the individual TEQs for PCBs, PCDDs, or PCDFs. Associations were determined by log-transformed linear adjusted models using R software. Results: The mean age and BMI were 62.9±13.1 years and 31.7±8.1 kg/m2. Women (48.7%) and African Americans (51.3%) were included. There was a 60.0% prevalence of K18-catogorized liver disease associated with increased liver enzymes, miR-122-5p and miR-192-5p. Relationships between liver tests were determined by complete linkage analysis. The liver toxicity miRs clustered into four groups: Group 1 (G1, n=9); Group 2 (G2, n=4); Group 3 (G3, n=11); and Group 4 (G4, n=11). G2 also contained the liver enzyme and K18 biomarkers. Total dioxin TEQ was inversely associated with G1 (miR-29a-3p) and G2 (albumin, total protein and miR-185-5p) biomarkers. Albumin was inversely associated with all four TEQs. Secondary exposure biomarkers were also significantly associated with other miRs: PCB TEQ (miR-29a-3p); PCDD TEQ (2 from G3); and PCDF TEQ (2 from G1, 1 from G2, and 1 from G4). miR-29a-3p was associated with serum endotoxin, HOMA-IR, VLDL, HDL, and adiponectin. miR-185-5p was associated with LDL, TNFα, and PAI-1. Conclusion: The observed high prevalence of liver disease associated with miR-122-5p and miR-192-5p validated key findings from ACHS-I. Those results were extended in new directions by the inclusion of liver enzymes and dioxin biomarkers. Circulating miRs provided non-overlapping information with routine liver biochemistries. Environmental dioxin exposures were primarily associated with biomarkers of disrupted hepatic metabolism rather than cell death. We postulate that miRs could mediate both dioxin-induced metabolic toxicity and adaptation.