Toxicological Sciences
Toxicological Sciences
5 years ago

Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver.

Elcombe CR, Pouché L, Zell A, Ellinger-Ziegelbauer H, Fekete A, Dumotier B, Stiehl DP, MacLeod AK, Wolf CR, Dubost V, Römer M, Moggs JG, Moreno R, Terranova R, Westphal M, Henderson CJ, Schwarz M, Glogovac M, Vitobello A, Huang JTJ, Moulin P
Derisking xenobiotic-induced nongenotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster noncoding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional ,and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced nongenotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28541575

DOI: PubMed:28541575

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