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Early microRNA responses in rodent liver mediated by furan exposure establish dose thresholds for later adverse outcomes
Citation:
Nelson, G., G. Carswell, C. Swartz, L. Recio, C. Yauk, AND B. Chorley. Early microRNA responses in rodent liver mediated by furan exposure establish dose thresholds for later adverse outcomes. TOXICOLOGY LETTERS. Elsevier Science Ltd, New York, NY, 384:105-114, (2023). https://doi.org/10.1016/j.toxlet.2023.07.015
Impact/Purpose:
This case study demonstrates the utility of measuring small, non-coding RNA (specifically microRNA) in short-term (3 weeks) exposure mouse studies to serve as biomarkers of longer-term adverse outcome in the liver, here liver cancer. These biomarkers can augment mRNA measurements to define chemical thresholds of adversity and pinpoint the mode-of-action by which the chemical is mediating the outcome. By using a reference exposure (here, the mouse liver tumorigen, furan), we can apply these biomarkers to future studies and chemicals in which the mode-of-aciotn is not known. MicroRNAs were both more sensitive and informative than the mRNA measurments in this study, highlighting the utility these epigenetic biomarkers to build better novel approach methodologies (NAMs) for chemical hazards identification.
Description:
To reduce reliance on long-term in vivo studies, short-term data linking early molecular-based measurement to later adverse health effects is needed. Although transcriptional-based benchmark dose (BMDT) 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 (BMDmiR) were compared to the referent transcriptional (BMDT) and apical (BMDA) 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.
URLs/Downloads:
DOI: Early microRNA responses in rodent liver mediated by furan exposure establish dose thresholds for later adverse outcomes
https://pubmed.ncbi.nlm.nih.gov/37517673/