Science Inventory

MicroRNA Liver Toxicity Biomarkers Associated with Dioxin-Like Molecule Exposures in ACHS-II

Citation:

Cave, M., C. Pinkston, S. Rai, B. Wahlang, G. Carswell, M. Pavuk, L. Birnbaum, AND B. Chorley. MicroRNA Liver Toxicity Biomarkers Associated with Dioxin-Like Molecule Exposures in ACHS-II. Society of Toxicology 61st Annual Meeting and ToxExpo 2022, San Diego, CA, March 27 - 31, 2022. https://doi.org/10.23645/epacomptox.20344038

Impact/Purpose:

Poster presented to the 61st Annual Meeting of the Society of Toxicology (SOT) March 2022. This study is a follow-up of a recently published work that demonstrated correlaiton of blood-based miRNA correlation to liver toxicity biomarkers in a residential cohort who have been exposed to high PCB levels. This follow-up study utilizes samples collected year later from the same purpose that have additional biomarker and chemical measurements. The findings stengthen the hypotehsis that blood miRNA serve as biomarkers of adverse outcomes in a human population. This further supports the use of epigenetic biomarkers that link to adverse outcomes of regulatory concern.

Description:

Associations between ortho- PCB exposures, NAFLD, and microRNAs (miRs) were previously reported in the Anniston Community Health Survey (ACHS-I). Here, we determine relationships between liver toxicity biomarkers, including miRs, and dioxin-like molecules (e.g., non-ortho PCBs, PCDDs and PCDFs) in the follow-up ACHS-II cohort. Serum liver enzymes; keratin 18 (K18); highly-expressed hepatoxicity miRs (n=30); and dioxin-like molecules (n=20) 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 SAS v9.4 and R. There was a 60.0% prevalence of K18-catogorized liver disease associated with increased liver enzymes and miRs-122-5p and -192-5p. Using complete linkage analysis, miRs and liver enzymes clustered into four groups (G): G1 (n=9 miRs), G2 (n=4), G3 (n=11), G4 (n=11). G2 miRs were associated with the liver enzyme and K18 biomarkers. By Ingenuity Pathway Analysis, miRs in the four groups were linked to various liver disease processes including: hepatic steatosis (G2), hepatitis (G4), cirrhosis (G4), liver hyperplasia (G1-G2), and hepatocellular carcinoma (G1-G3). Total dioxin TEQ was inversely associated with G1 (miR-29a-3p) and G2 (albumin, total protein and miR-185-5p) liver biomarkers. Albumin was inversely associated with all four TEQs. Individual PCB, PCDD, and PCDF TEQs were associated with additional miRs. The observed high prevalence of liver disease associated with miR-122-5p and miR-192-5p validated key findings recently published 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. We postulate that serum miRs could serve as accessible biomarkers of both dioxin-induced metabolic toxicity or adaptation. This abstract does not necessarily reflect EPA, ATSDR or NIH policy.