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Arch Toxicol. 2015 Dec;89(12):2413-27. doi: 10.1007/s00204-014-1368-6. Epub 2014 Oct 2.

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

Author information

1
Center for Health Protection, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
2
Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
3
MicroArray Department and Integrative Bioinformatics Unit, Faculty of Science, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands.
4
Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands.
5
Division of Toxicology, Leiden Amsterdam Center for Drug Research, Leiden University, 2333 CC, Leiden, The Netherlands.
6
Netherlands Bioinformatics Centre, 6525 GA, Nijmegen, The Netherlands.
7
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.
8
Department of Toxicogenetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. harry.van.steeg@rivm.nl.

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.

KEYWORDS:

Comparison approach; Gene expression profiles; Mode of action; Mouse embryonic stem cells; Non-genotoxic carcinogens; Primary mouse hepatocytes; Safety assessment of chemicals

PMID:
25270620
DOI:
10.1007/s00204-014-1368-6
[Indexed for MEDLINE]

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