TESTING CHEMICAL CARCINOGENICITY BY USING A TRANSCRIPTOMICS HEPARG-BASED MODEL?

Tatyana Y. Doktorova*, Reha Yildirimman, Liesbeth Ceelen, Mireia Vilardell, Tamara Vanhaecke, Mathieu Vinken, Gamze Ates, Anja Heymans, Hans Gmuender, Roque Bort, Raffaella Corvi, Pascal Phrakonkham, Ruoya Li, Nicolas Mouchet, Christophe Chesne, Joost van Delft, Jos Kleinjans, Jose Castell, Ralf Herwig, Vera Rogiers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances.
Original languageEnglish
Pages (from-to)623-637
JournalExcli Journal
Volume13
DOIs
Publication statusPublished - 2014

Keywords

  • genotoxic carcinogens
  • non-genotoxic carcinogens
  • gene expression profiling
  • pathways-based analysis
  • HepaRG cell line
  • liver-based in vitro models

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