Abstract
To reduce reliance on long-term in vivo studies, short-term data linking early molecular-based measurements to later adverse health effects is needed. Although transcriptional-based benchmark dose (BMD(T)) modeling has been used to estimate potencies and stratify chemicals based on potential to induce later-life effects, dose-responsive epigenetic alterations have not been routinely considered. Here, we evaluated the utility of microRNA (miRNA) profiling in mouse liver and blood, as well as in mouse primary hepatocytes in vitro, to indicate mechanisms of liver perturbation due to short-term exposure of the known rodent liver hepatotoxicant and carcinogen, furan. Benchmark dose modeling of miRNA measurements (BMD(miR)) were compared to the referent transcriptional (BMD(T)) and apical (BMD(A)) estimates. These analyses indicate a robust dose response for 34 miRNAs to furan and involvement of p53-linked pathways in furan-mediated hepatotoxicity, supporting mRNA and apical measurements. Liver-sourced miRNAs were also altered in the blood and primary hepatocytes. Overall, these results indicate mechanistic involvement of miRNA in furan carcinogenicity and provide evidence of their potential utility as accessible biomarkers of exposure and disease.