Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

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T. 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

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.

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How to Cite
Doktorova, T. Y., Yildirimman, R., Ceelen, L., Vilardell, M., Vanhaecke, T., Vinken, M., Ates, G., Heymans, A., Gmuender, H., Bort, R., Corvi, R., Phrakonkham, P., Li, R., Mouchet, N., Chesne, C., van Delft, J., Kleinjans, J., Castell, J., Herwig, R., & Rogiers, V. (2014). Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?. EXCLI Journal, 13, 623-637. Retrieved from https://www.excli.de/index.php/excli/article/view/727
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