Serum microRNA biomarker identification in a residential cohort with elevated polychlorinated biphenyl exposures
Citation:
Chorley, B., G. Nelson, M. Angrish, M. Cave, M. Pavuk, C. Pinkston, AND G. Carswell. Serum microRNA biomarker identification in a residential cohort with elevated polychlorinated biphenyl exposures. SOT 56th Annual Meeting, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
This research addresses Goal 4 of the FY2014-2018 EPA Strategic Plan (to ensure the safety of chemicals) and a recent amendment to the Toxic Substances Control Act (TSCA) which mandates considerations of greater risk for adverse health effects because of exposure due to susceptible subpopulations. Specifically, we are evaluating epigenetic-based biomarkers that can demark the initiation and progression of fatty liver disease and help determine susceptibility to environmental chemicals. Fatty liver is estimated to affect 25-30% of the US population making it one of the most prevalent liver diseases. It is a characteristic of obesity, type II diabetes and metabolic syndrome, conditions which cross demographic lines but are frequently associated with socially and economically disadvantaged populations. While it has been recognized that diet and some therapeutic drugs cause fatty liver, the contribution of environmental chemicals has received little attention. By developing biomarkers to fatty liver, we can better understand how environmental chemicals cause fatty liver disease and identify subpopulations that may be susceptible to chemical exposure.
Description:
Exposure to liver toxicants can result in or exacerbate fatty liver disease. Recent evidence suggests that serum-derived microRNAs (miRs) may improve identification of chemical-induced fatty liver disease relative to traditional protein-based biomarkers alone. Historical serum samples from a residential cohort exposed to polychlorinated biphenyls (PCBs) levels approximately 2-3 fold higher than the average U.S. population were used to identify microRNA biomarkers of PCB exposure. To select a subset of the 738 sample cohort uniformly exposed high levels of PCBs, cytokeratin 18 M65 fragments (CK18 M65), a biomarker of necrotic hepatocytes and an indirect indicator of toxicant-induced steatohepatitis, was measured. 76 samples with levels greater than 300 U/L were designated as the high CK18 M65 group and 76 samples with levels less than 300 U/L were designated as the low CK18 M65 group. To determine whether miR profiling could be used to further stratify cohort samples, a suite of 68 miRs were assessed for differential gene expression patterns. While miR-21-5p expression was decreased and miR-320a was increased in the high CK18 M65 cohort, correlation of miR-21-5p or miR-320a expression to the continuous range of CK18 M65 measurements was not significant. Interestingly, miR-122-5p, a well-established indicator of hepatocyte toxicity, was markedly differentially expressed across samples. Study samples were therefore stratified based on miR-122-5p expression. In samples with miR-122-5p levels elevated twice the standard deviation of the mean, 79% also exhibited CK18 M65 measurements > 300 U/L. This suggests that elevated miR-122-5p might serve as an indicator of more extensive liver injury. Taken together, while selected serum miRs did not correlate with the toxicant-induced steatohepatitis biomarker CK18 M65, they may indicate other facets of fatty liver disease and severity. The abstract does not necessarily reflect the views and the policies of the Agency.