Gene expression profiling to recognize specific features of (non-) genotoxic carcinogens

The current test strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Non-genotoxic carcinogens (NGTXC) are negative for genotoxicity and go undetected. Therefore, alternative tests to detect these chemicals are urgently needed. NGTXC act through different modes of action, which complicates the development of such assays. We have demonstrated recently in primary mouse hepatocytes that some, but certainly not all, NGTXC can be categorized according to their mode of action based on feature detection at a gene expression level (Schaap et al. 2012, PMID22710402). Identification of a wider range of chemicals probably requires multiple in vitro systems. In the current study we describe the added value of using mouse embryonic stem cells. In this study the focus is on NGTXC, but we also included genotoxic carcinogens and non-carcinogens. This approach enables us to assess the robustness of this method and to evaluate the system for recognizing features of chemicals in general, which is important for application in future risk assessment.

88

Schaap MM, Wackers PF, Zwart EP, Huijskens I, Jonker MJ, Hendriks G, Breit TM, van Steeg H, van de Water B, Luijten M