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.

Comparison approach, Gene expression profiles, Mode of action, Mouse embryonic stem cells, Non-genotoxic carcinogens, Primary mouse hepatocytes, Safety assessment of chemicals
dx.doi.org/10.1007/s00204-014-1368-6, hdl.handle.net/1765/88511
Archives of Toxicology
Department of Molecular Genetics

Schaap, M, Wackers, F.J.T, Zwart, E, Huijskens, I, Jonker, M.J, Hendriks, G, … Luijten, M. (2015). A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens. Archives of Toxicology, 89(12), 2413–2427. doi:10.1007/s00204-014-1368-6