Xenobiotic CAR Activators Induce Dlk1-Dio3 Locus Noncoding RNA Expression in Mouse Liver

• Published in: Toxicological sciences Vol. 158; no. 2; pp. 367 - 378
• Main Authors: Pouché, Lucie, Vitobello, Antonio, Römer, Michael, Glogovac, Milica, MacLeod, A Kenneth, Ellinger-Ziegelbauer, Heidrun, Westphal, Magdalena, Dubost, Valérie, Stiehl, Daniel Philipp, Dumotier, Bérengère, Fekete, Alexander, Moulin, Pierre, Zell, Andreas, Schwarz, Michael, Moreno, Rita, Huang, Jeffrey T J, Elcombe, Cliff R, Henderson, Colin J, Roland Wolf, C, Moggs, Jonathan G, Terranova, Rémi
• Format: Journal Article
• Language: English
• Published: United States 01-08-2017
• Subjects: Animals; Biomarkers - metabolism; Chlordan - toxicity; Gene Expression - drug effects; Intercellular Signaling Peptides and Proteins - genetics; Iodide Peroxidase - genetics; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Knockout; Phenobarbital - toxicity; Receptors, Cytoplasmic and Nuclear - agonists; RNA, Long Noncoding - genetics; Up-Regulation - drug effects; Xenobiotics - toxicity; phenobarbital; Dlk1-Dio3 cluster; cancer risk assessment; noncoding RNAs; nongenotoxic carcinogenesis (NGC); chlordane; constitutive androstane receptor (CAR)
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfx104

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.