title: A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.
abstract: Alternative methods to detect non-genotoxic carcinogens are urgently needed, as this class of carcinogens goes undetected in the current testing strategy for carcinogenicity under REACH. A complicating factor is that non-genotoxic carcinogens act through several distinctive modes of action, which makes prediction of their carcinogenic property difficult. We have recently demonstrated that gene expression profiling in primary mouse hepatocytes is a useful approach to categorize non-genotoxic carcinogens according to their modes of action. In the current study, we improved the methods used for analysis and added mouse embryonic stem cells as a second in vitro test system, because of their features complementary to hepatocytes. Our approach involved an unsupervised analysis based on the 30 most significantly up- and down-regulated genes per chemical. Mouse embryonic stem cells and primary mouse hepatocytes were exposed to a selected set of chemicals and subsequently subjected to gene expression profiling. We focused on non-genotoxic carcinogens, but also included genotoxic carcinogens and non-carcinogens to test the robustness of this approach. Application of the optimized comparison approach resulted in improved categorization of non-genotoxic carcinogens. Mouse embryonic stem cells were a useful addition, especially for genotoxic substances, but also for detection of non-genotoxic carcinogens that went undetected by primary hepatocytes. The approach presented here is an important step forward to categorize chemicals, especially those that are carcinogenic.
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.|Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: Schaap
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.|MicroArray Department and Integrative Bioinformatics Unit, Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands.|Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Paul F K
authors.initials: PF
authors.lastname: Wackers
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Zwart
authors.affiliation: Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Huijskens
authors.affiliation: MicroArray Department and Integrative Bioinformatics Unit, Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands.|Netherlands Bioinformatics Centre, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Martijs J
authors.initials: MJ
authors.lastname: Jonker
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Giel
authors.initials: G
authors.lastname: Hendriks
authors.affiliation: MicroArray Department and Integrative Bioinformatics Unit, Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands.|Netherlands Bioinformatics Centre, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Timo M
authors.initials: TM
authors.lastname: Breit
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands. harry.van.steeg@rivm.nl.|Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. harry.van.steeg@rivm.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.affiliation: Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.|Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000473:pathology; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D043922:Toxicogenetics / Q000379:methods*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002273:Carcinogens; D009153:Mutagens
keywords: Comparison approach; Gene expression profiles; Mode of action; Mouse embryonic stem cells; Non-genotoxic carcinogens; Primary mouse hepatocytes; Safety assessment of chemicals