Optimization of a toxicogenomics-based comparison approach to categorize chemicals based on their modes of action

The current test strategy for carcinogenicity consists initially of in vivo and in vitro genotoxicity tests. Non-genotoxic carcinogens do not directly induce DNA damage and, as such, go undetected under this test strategy. In a previous study we setup a comparison approach to categorize chemicals having similar modes of action, according to similarity in gene expression. In the current study we will investigate whether this comparison approach can be improved by omptimizing the concentration selection procedure and by testing a concentration range per chemical. Primary mouse hepatocytes were exposed to a concentration range of Cyclosporin A and Tacrololimus. Cytotoxicty was measured using two different tests. Based on these tests a concentration range was selected for gene expression profiling. The previously described comparison approach was applied and pathway and GSEA analyses were used to biologically confirm the results of the comparison approach.