Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats.

This study was designed to identify early-response genes of chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats. We conducted a 28-day repeated-dose test in male Crl:CD (SD) rats with 12 carcinogens and 10 non-carcinogens as the training dataset, and five carcinogens and five non-carcinogens as the validation dataset. Renal gene expression profiles were analyzed by using a microarray. Fifteen candidate genes were selected from the gene expression profiles of the training dataset as genes that showed specific expression in response to carcinogens. To assess the prediction performance of the candidate genes for renal carcinogenicity, a prediction formula was developed on the basis of the gene expression data. When this formula was applied to the training dataset to check its predictive performance, all of the carcinogens and non-carcinogens were predicted correctly; the prediction formula was then applied to the validation dataset, and five carcinogens and four non-carcinogens were correctly predicted. However, 4-Hydroxy-m-phenylenediammonium dichloride (AMIDOL), a known non-renal carcinogen, was judged as positive. Therefore, the accuracy of the prediction formula for renal carcinogenicity was 100% for the training dataset and 90% for the validation dataset. Among the predictive genes, Hamp and Ranbp1 are known to be important for cell growth and cell cycle regulation, which are important events in carcinogenesis. Given our current limited knowledge of the genes responsible for renal carcinogenesis, the identification of candidate genes of chemical-induced renal carcinogenicity by use of this gene expression-based prediction method represents a promising advance in renal carcinogen identification.