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A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens

  • Genotoxicity and Carcinogenicity
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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.

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Acknowledgments

We thank Haziz Jadaar for his contribution to this study. Cyclosporin A was kindly provided by Novartis (Basel, Switzerland). This work was supported by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research [Grant Number 050-060-510] and the Dutch Technology Foundation STW [Grant Number 06935].

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands

    Mirjam M. Schaap, Paul F. K. Wackers, Edwin P. Zwart, Harry van Steeg & Mirjam Luijten

  2. Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands

    Mirjam M. Schaap, Giel Hendriks, Harry van Steeg & Mirjam Luijten

  3. MicroArray Department and Integrative Bioinformatics Unit, Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands

    Paul F. K. Wackers, Martijs J. Jonker & Timo M. Breit

  4. Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands

    Paul F. K. Wackers

  5. Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands

    Ilse Huijskens & Bob van de Water

  6. Netherlands Bioinformatics Centre, 6525 GA, Nijmegen, The Netherlands

    Martijs J. Jonker & Timo M. Breit

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  1. Mirjam M. Schaap
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  2. Paul F. K. Wackers
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Correspondence to Harry van Steeg.

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Schaap, M.M., Wackers, P.F.K., Zwart, E.P. et al. A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens. Arch Toxicol 89, 2413–2427 (2015). https://doi.org/10.1007/s00204-014-1368-6

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