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Early MicroRNA Alterations in Mouse Liver with Carcinogenic Phthalate DEHP Exposure Linked with Dose Response
Citation:
Carswell, G., G. Nelson, C. Wood, S. Hester, AND B. Chorley. Early MicroRNA Alterations in Mouse Liver with Carcinogenic Phthalate DEHP Exposure Linked with Dose Response. Toxicoepigenetics: The Interface of Epigenetics and Risk Assessment, Tysons, VA, November 02 - 04, 2016.
Impact/Purpose:
MicroRNA (miRs) are highly conserved short non-coding sequences which regulate cellular processes by transcriptional and post-transcriptional repression of targeted messenger RNAs. MiRs are highly responsive to cellular perturbation due to toxicant exposure and are being widely investigated as biomarkers of adverse outcomes. In this study we identify early miR alterations in response to a carcinogenic dose of the phthalate DEHP. These alterations are linked to known mRNA targets in established pathways for liver metabolism and stress responses, as well as a specific miR that shows an early dose dependent response at 7 days and is associated with liver hepatocarcinogenesis. These results may possibly identify candidate biomarkers of liver toxicity and PPAR alpha activation useful as a model in chemical screening for later life stage events.
Description:
MicroRNAs (miRs) are promising translatable biomarkers of adverse toxicological effects. However, miR dose responses and linkages with target pathways are not well defined. In this study we evaluated early miR alterations in mouse liver after exposure to di(2-ethylhexyl) phthalate (DEHP), a reference rodent liver carcinogen and PPAR alpha activator. Mice were exposed to DEHP in the diet for 7 d (0.75, 1.5, 3, and 6K ppm) and 28 d (6K ppm). Liver miR expression was determined by small RNA sequencing. DEHP treatment induced a modest miR response at 7 d (35 miRs altered at 6K dose) compared to a more robust response at 28 d (88 miRs altered at 6K), capturing 34% of the changes seen at 7 d. Notably, miR-182-5p increased with dose at 7 d and remained elevated at 28 d. Increased miR-182 has been linked to hepatocellular proliferation and cancer in humans and mice, along with other cancers and is regarded as an oncogene. MiR changes seen with high dose exposure at 7 d were expression paired to 768 mRNA targets previously shown to be altered with DEHP exposure in these samples. These mRNA were associated with transcriptional activators of liver metabolism and stress response functions, including PPARA, PPARG, NFE2L2, POR, and MED1. Top enriched canonical biological pathways were associated with lipid metabolism, energy production, and metabolic disease. These results identify early miR alterations to carcinogenic doses of DEHP in mice and candidate biomarkers of liver toxicity and PPAR alpha activation. The abstract does not necessarily reflect the views and the policies of the Agency.