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

Authors

  • T. Y. Doktorova Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
  • Reha Yildirimman Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
  • Liesbeth Ceelen Pathlicon, 9940, Evergem, Belgium
  • Mireia Vilardell Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
  • Tamara Vanhaecke Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
  • Mathieu Vinken Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
  • Gamze Ates Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
  • Anja Heymans Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium
  • Hans Gmuender Genedata AG, 4053, Basel, Switzerland
  • Roque Bort Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain; University of Valencia, Faculty of Medicine, Department of Biochemistry and Molecular Biology, E-46009, Valencia, Spain
  • Raffaella Corvi European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy
  • Pascal Phrakonkham European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy
  • Ruoya Li Biopredic International, 35000, Rennes, France
  • Nicolas Mouchet Institut Génétique et Développement de Rennes, 6290, Rennes, France
  • Christophe Chesne Biopredic International, 35000, Rennes, France
  • Joost van Delft Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands
  • Jos Kleinjans Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands
  • Jose Castell Unit of Experimental Hepathology, University Hospital La Fe Valencia, Spain; University of Valencia, Faculty of Medicine, Department of Biochemistry and Molecular Biology, E-46009, Valencia, Spain
  • Ralf Herwig Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany
  • Vera Rogiers Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium

Keywords:

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

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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Published

2014-05-28

How to Cite

Doktorova, T. Y., Yildirimman, R., Ceelen, L., Vilardell, M., Vanhaecke, T., Vinken, M., … 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

Issue

Vol. 13 (2014)

Section

Original articles

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