Investigation of Nrf2, AhR and ATF4 activation in toxicogenomic databases

Elias Zgheib, Alice Limonciel, Xiaoqi Jiang, Anja Wilmes, Steven Wink, Bob Van De Water, Annette Kopp-Schneider, Frederic Y. Bois*, Paul Jennings

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.

Original languageEnglish
Article number429
Pages (from-to)1-17
Number of pages17
JournalFrontiers in Genetics
Volume9
Issue numberOctober
DOIs
Publication statusPublished - 2 Oct 2018

Keywords

  • AhR
  • ATF4
  • Nrf2
  • Oxidative stress
  • Toxicity pathways
  • Toxicogenomic
  • Transcriptomics

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