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Quantitative Dose-Response of Liver MicroRNA After Furan Exposure in Rodent Liver, Blood, and Cell Culture
Citation:
Nelson, G., G. Carswell, C. Swartz, L. Recio, AND B. Chorley. Quantitative Dose-Response of Liver MicroRNA After Furan Exposure in Rodent Liver, Blood, and Cell Culture. Society of Toxicology 2021 Virtual Annual meeting, NA, Virtual, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.18130661
Impact/Purpose:
Poster presented to the Society of Toxicology virtual annual meeting March 2021. Gene expression alterations in the liver due to environmental chemical exposure can indicate early, mechanistic, and dose-responsive measures of later adverse outcomes, such as cancer. Measuring these alterations in short-term in vivo and in vitro models may help reduce the cost, time, and uncertainty associated with assessing chemical hazard and risk. Recent studies in our lab have demonstrated that microRNAs (miRNAs) may similarly indicate chemical potency and mode-of-action associated with health outcomes of regulatory concern. Here, we examined the miRNA response to furan, a rodent hepatocarcinogen with a postulated mode of action of chronic cytotoxicity followed by regenerative proliferation. Overall, these results indicate mechanistic involvement of miRNA in furan carcinogenicity and provide evidence of their potential utility as accessible, dose-responsive biomarkers of chemical-mediated disease outcome.
Description:
Gene expression alterations in the liver due to environmental chemical exposure can indicate early, mechanistic, and dose-responsive measures of later adverse outcomes, such as cancer. Measuring these alterations in short-term in vivo and in vitro models may help reduce the cost, time, and uncertainty associated with assessing chemical hazard and risk. Recent studies in our lab have demonstrated that microRNAs (miRNAs) may similarly indicate chemical potency and mode-of-action associated with health outcomes of regulatory concern. Here, we examined the miRNA response to furan, a rodent hepatocarcinogen with a postulated mode of action of chronic cytotoxicity followed by regenerative proliferation. Previous gene expression measurements of short-term furan exposure in B6C3F1 mice were highly predictive of published cancer bioassay point of departure values. Using liver and blood samples from these same 3-week exposure studies to 0, 1, 2, 4 and 8 mg/kg body weight per day furan, we evaluated miRNA-based benchmark doses (BMDs) which were estimated based on small RNA sequencing and Nanostring nCounter miRGE Assay (miRNA and gene expression) measurements. In addition, we examined liver-sourced miRNAs in the blood and miRNA expression changes in furan-treated female B6C3F1 primary hepatocytes for comparison with in vivo results. In the mouse liver, miRNAs were significantly altered with carcinogenic doses of furan and were implicated in growth, proliferation, apoptosis, cell cycle regulation, and general cancer signaling networks. Many are shown in the literature to be altered with hepatocellular carcinoma. When mapped to altered mRNA, these miRNAs were linked to ATM and p53-mediated pathways. BMD analysis showed a robust dose response for 43 miRNA (BMD, 2.11) and 196 mRNA BMD, 3.01). These results suggest that miRNA are more sensitive biomarkers of furan exposure and hepatotoxicity than mRNA, and may be more reflective of the 2-year cancer endpoint (BMD, 2.3 – 2.6). Some of these dose-responsive miRNA were also altered in the blood (e.g., miR-676, miR-532, miR-34a, miR-183) and in primary hepatocytes (miR-34a). Overall, these results indicate mechanistic involvement of miRNA in furan carcinogenicity and provide evidence of their potential utility as accessible, dose-responsive biomarkers of chemical-mediated disease outcome.
URLs/Downloads:
DOI: Quantitative Dose-Response of Liver MicroRNA After Furan Exposure in Rodent Liver, Blood, and Cell Culture
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