Authors: Doktorova, Tatyana Y.
Yildirimman, Reha
Ceelen, Liesbeth
Vilardell, Mireia
Vanhaecke, Tamara
Vinken, Mathieu
Ates, Gamze
Heymans, Anja
Gmuender, Hans
Bort, Roque
Corvi, Raffaella
Phrakonkham, Pascal
Li, Ruoya
Mouchet, Nicolas
Chesne, Christophe
van Delft, Joost
Kleinjans, Jos
Castell, Jose
Herwig, Ralf
Rogiers, Vera
Title: Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?
Language (ISO): en
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.
Subject Headings: genotoxic carcinogens
non-genotoxic carcinogens
gene expression profiling
pathways-based analysis
HepaRG cell line
liver-based in vitro models
Issue Date: 2014-05-28
Appears in Collections:Original Articles

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