Mechanism-Based Evaluation System for Hepato- and Nephrotoxicity or Carcinogenicity Using Omics Technology

We have been developing a carcinogenicity prediction system based on gene expression profiles focusing on omics technology to enable mechanism-based evaluations of toxicity to reduce the numbers of animals and toxicological endpoints required by animal studies. Here, we report the development of a mechanism-based evaluation system focused on chemically induced hepato- and nephrotoxicity or hepatic and renal carcinogenicity using a gene expression analysis with a DNA microarray. As a case study, the mode-of-action (MoA)/adverse outcome pathway (AOP) was constructed from the gene expression profiles and histopathological findings of carbon tetrachloride and cisplatin for hepatotoxicity and nephrotoxicity, respectively. Consequently, we developed an advanced toxicity evaluation system for hepato- and nephrotoxicity or hepatic and renal carcinogenicity based on the toxicity mechanisms. We also developed a new prediction system named “CARCINOscreen®” for evaluating the carcinogenic potentials of chemicals using the gene expression profiles of liver and kidney tissues from rats after a 28-day repeated administration. The prediction system could predict the carcinogenicity potential of a training chemical set including carcinogens and non-carcinogens with an accuracy of more than 90%. The marker genes established in this study are promising for the development of new effective in vitro testing methods in the future.