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

• Published in: Archives of toxicology Vol. 89; no. 12; pp. 2413 - 2427
• Main Authors: Schaap, Mirjam M., Wackers, Paul F. K., Zwart, Edwin P., Huijskens, Ilse, Jonker, Martijs J., Hendriks, Giel, Breit, Timo M., van Steeg, Harry, van de Water, Bob, Luijten, Mirjam
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2015; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Carcinogens; Carcinogens - toxicity; Cellular biology; Down-Regulation - drug effects; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - pathology; Environmental Health; Gene expression; Gene Expression Profiling; Genomics; Genotoxicity and Carcinogenicity; Hepatocytes - drug effects; Hepatocytes - pathology; Male; Mice; Mice, Inbred C57BL; Mutagens - toxicity; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Toxicity; Toxicogenetics - methods; Up-Regulation - drug effects; Comparison approach; Primary mouse hepatocytes; Safety assessment of chemicals; Gene expression profiles; Non-genotoxic carcinogens; Mouse embryonic stem cells; Mode of action
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-014-1368-6

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.