Citation:

Cave, M., H. Clair, C. Pinkston, S. Rai, G. Carswell, G. Nelson, M. Pavuk, AND B. Chorley. Liquid Liver Biopsy is Consistent with Steatohepatitis in Polychlorinated Biphenyl Exposed Cohort with Suspected Toxicant Associated Steatohepatitis. Digestive Disease Week, Washington, DC, June 02 - 05, 2018.

Impact/Purpose:

This study is testing the utility of epigenetic-based biomarkers to identify individuals with liver disease associated with high PCB exposure. These epigenetic biomarkers (microRNA) are being measured in the serum that has been archived for approximately a decade. There is large amount of data available for these samples, therefore, we can correlate with these measurements that include liver toxicity biomarkers, inflammation, metabolic syndrome biomarkers and PCB levels (among others). To our knowledge, these microRNA data are the first ever generated in an environmental hepatology study. This type of data is important to Agency because these mechanism-based biomarkers can be utilized in screening paradigms, as well as used to identify subpopulations that may be susceptible or influenced by environmental chemical hazards (in this case liver disease).

Description:

Introduction. Polychlorinated biphenyl (PCB) exposures have been associated with toxicant associated steatohepatitis (TASH) in animal models and suspected TASH in epidemiological studies including the Anniston Community Health Survey (ACHS). MicroRNAs (miRs) are non-coding RNAs that maintain cellular homeostasis and potentially mediate responses to environmental exposures. A ‘liquid liver biopsy’ was performed by serum miR profiling in PCB-exposed ACHS participants. Materials and Methods. 152 ACHS participants (76 with and without suspected TASH) were evaluated. Suspected TASH was defined as serum cytokeratin 18 (CK18) M65>300 U/L and M30<200 U/L. “Not TASH” was defined as M65<300 U/L and M30<200 U/L. The groups were stratified by sex. 68 targeted hepatotoxicity miRs were profiled in serum (Fireplex miRNA multiplex assay, Abcam). Serum adipocytokines and HOMA-IR were measured. Adjusted Beta coefficients were determined to examine potential relationships between the miRs and suspected TASH, CK18, PCBs, adipocytokines, and HOMA-IR. Statistical significance was set at a p-value <0.05 with a false discovery rate of <0.15 for the main outcome variables. Ingenuity Pathway Analysis (IPA) was performed. Results: 8 miRs were associated with suspected TASH. 4 were upregulated (miRs -22, -122, -320, and -375) and 4 were downregulated (miRs -21, -92a, -223, and -410). 6 additional miRs were also associated with CK18 (3 upregulated and 3 downregulated), but not suspected TASH. Many of these miRs were previously associated with NASH. However, in some cases, the direction of the association differed. 2 miRs were associated with PCB exposures (let-7d and miR-181), including one which was also associated with increased CK18 M65 (let-7d). IPA demonstrated enrichment in pathways associated with liver steatosis, hyperplasia, decreased albumin, and HCC. Top IPA diseases and biofunctions included organismal injury and inflammatory response; while top significant networks included cell cycle/embryonic development/cell death and survival. Of the 8 miRs associated with suspected TASH, 4 miRs were also associated with adipocytokines including IL-6, IL-8, PAI-1, adiponectin and resistin; while 3 miRs were also associated with HOMA-IR. These associations help validate the inflammatory response biofunction detected by IPA. Conclusions: ‘Liquid liver biopsy’ in subjects with suspected PCB-related TASH was indeed consistent with steatohepatitis. Specifically, alterations in pathways related to steatosis, injury/death, inflammation, liver function, and hepatocarcinogenesis were detected. The results require histologic validation as well as confirmation in other cohorts. Likewise, more data are required on the potential mechanistic role of environmentally regulated miRs, such as let-7d, in hepatotoxicity and steatohepatitis. This abstract does not necessarily reflect US EPA policy.

Record Details: