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

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

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  • 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
  • Jonathan G. Moggs
  • Rémi Terranova (Lead / Corresponding author)

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Original languageEnglish
Pages (from-to)367-378
Number of pages11
JournalToxicological Sciences
Issue number2
Early online date25 May 2017
StatePublished - Aug 2017


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.



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