title: Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?
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.
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: T Y
authors.initials: TY
authors.lastname: Doktorova
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany.
authors.forename: Reha
authors.initials: R
authors.lastname: Yildirimman
authors.affiliation: Pathlicon, 9940, Evergem, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Ceelen
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany.
authors.forename: Mireia
authors.initials: M
authors.lastname: Vilardell
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: Gamze
authors.initials: G
authors.lastname: Ates
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: Anja
authors.initials: A
authors.lastname: Heymans
authors.affiliation: Genedata AG, 4053, Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.affiliation: 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.
authors.forename: Roque
authors.initials: R
authors.lastname: Bort
authors.affiliation: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Corvi
authors.affiliation: European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), Systems Toxicology Unit, 21027, Ispra, Italy.
authors.forename: Pascal
authors.initials: P
authors.lastname: Phrakonkham
authors.affiliation: Biopredic International, 35000, Rennes, France.
authors.forename: Ruoya
authors.initials: R
authors.lastname: Li
authors.affiliation: Institut Génétique et Développement de Rennes, 6290, Rennes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mouchet
authors.affiliation: Biopredic International, 35000, Rennes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Chesne
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: van Delft
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6229 ER, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleinjans
authors.affiliation: 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.
authors.forename: Jose
authors.initials: J
authors.lastname: Castell
authors.affiliation: Max Planck Institute for Molecular Genetics, Department Vertebrate Genomics, D-14195 Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Herwig
authors.affiliation: Vrije Universiteit Brussel, Department of Toxicology, Center for Pharmaceutical Research, Brussels, Belgium.
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
keywords: HepaRG cell line; gene expression profiling; genotoxic carcinogens; liver-based in vitro models; non-genotoxic carcinogens; pathways-based analysis