EUROTOX 2005 Proceedings of the 42nd Congress of the European Societies of Toxicology : Toxicology Letters, Volume 162, Issue 1

Genomic and proteomic approaches are widely explored to evaluate their usefulness for detecting early toxicological endpoints and mechanisms. In order to relate changes of transcriptional and translational profiles to conventional endpoints of toxicity, a common animal model of chemical hepatocarcinogenesis was used. N-Nitrosomorpholine (NNM) was administered to adult male Wistar rats for 7 weeks to induce hepatocarcinogenesis. Specimens of each treatment group (vehicle-control + NNM low and high dose) were killed at different time points between 1 day and 50 weeks after the start of the study and left liver lobes from five animals were sampled for simultaneous biochemical and histopathological processing. Gene expression was analysed using the Affymetrix rat genome chip U34A. Proteomic analysis was based on 2D-electrophoresis and mass spectrometry. Results demonstrated characteristic deregulations of genes and proteins by complementary use of transcriptomics and proteomics, which can be related to mechanisms of carcinogenicity. It was shown that comparably few genes were deregulated at both levels of expression and each approach contributes different parts of information, which can be used to analyse mechanistic toxicity of genotoxic carcinogens and to identify early biomarkers of carcinogenesis. By this approach, adverse long-term effects could be detected in short-term bioassays and, in consequence, the number of long-term animal studies can be reduced. New approaches focus on the identification of predictive molecular profiles for non-genotoxic carcinogens.