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

Lucie Pouché , Antonio Vitobello, Michael Römer, Milica Glogovac, A. Kenneth MacLeod, Heidrun Ellinger-Ziegelbauer, Magdalena Westphal, Valérie Dubost, Daniel Philipp Stiehl, Bérengère Dumotier, Alexander Fekete, Pierre Moulin, Andreas Zell, Michael Schwarz, Rita Moreno , Jeffrey T. J. Huang, Cliff R. Elcombe, Colin J. Henderson, C. Roland Wolf, Jonathan G. MoggsRémi Terranova

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Abstract

Derisking xenobiotic-induced non-genotoxic 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 non-coding 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 non-genotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.
Original languageEnglish
Pages (from-to)367-378
Number of pages11
JournalToxicological Sciences
Volume158
Issue number2
Early online date25 May 2017
DOIs
Publication statusPublished - Aug 2017

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Keywords

  • Dlk1-Dio3 cluster
  • Non-coding RNAs
  • Constitutive Androstane Receptor (CAR)
  • Non-genotoxic Carcinogenesis (NGC)
  • Cancer risk assessment
  • Phenobarbital
  • Chlordane

Cite this

Pouché , L., Vitobello, A., Römer, M., Glogovac, M., MacLeod, A. K., Ellinger-Ziegelbauer, H., Westphal, M., Dubost, V., Stiehl, D. P., Dumotier, B., Fekete, A., Moulin, P., Zell, A., Schwarz, M., Moreno , R., Huang, J. T. J., Elcombe, C. R., Henderson, C. J., Wolf, C. R., ... Terranova, R. (2017). Xenobiotic CAR activators induce Dlk1-Dio3 locus non-coding RNA expression in mouse liver. Toxicological Sciences, 158(2), 367-378. https://doi.org/10.1093/toxsci/kfx104