Abstract
In rodents, ochratoxin A (OTA) induces high incidences of renal adenomas/carcinomas. Since the results of conventional mutagenicity tests have caused controversy, the modes of action remains unknown. In the present study, we have noted the site specificity of OTA. We conducted the reporter gene mutation assay and global gene expression in the cortex (COR) and the outer medulla (OM) in the kidney of gpt delta rats carrying gpt and red/gam (Spi-) genes, given OTA at a carcinogenic dose. As a result, Spi- mutant frequencies (MFs), indicating an increase in deletion mutations, but not gpt MFs in the OM were significantly higher than in controls despite the absence of changes in the COR. In addition, to identify genes relating to OTA-induced carcinogenesis, comparison of gene expression changes between the COR and OM in response to OTA was performed. In the comprehensive analysis, up-regulated genes observed in only the OM were as follows: genes associated with DNA double strand break repair, cell cycle progression, G2/M arrest in response to DNA damage, and regulation by p53 or control of p53 function. The overall data suggest that OTA-induced deletion mutations might occur in the process of DNA double strand break repair. The observation of changes in several genes associated with DNA damage might imply that genotoxic mechanisms are involved in OTA-induced renal carcinogenesis.
