title: Site-specific in vivo mutagenicity in the kidney of gpt delta rats given a carcinogenic dose of ochratoxin A.
abstract: Ochratoxin A (OTA) can induce renal tumors that originate from the S3 segment of the proximal tubules in rodents, but the results of conventional mutagenicity tests have caused controversy regarding the role of genotoxic mechanisms in the carcinogenesis. Human exposure to OTA from various foods is unavoidable. Therefore, an understanding of OTA-induced renal carcinogenesis is necessary for accurate estimates of the human risk hazard. In the present study, a 13-week exposure of gpt delta rats to OTA at a carcinogenic dose induced karyomegaly and apoptosis at the outer stripe of the outer medulla (OM) of the kidney but failed to affect the reporter gene mutations in DNA extracted from whole kidneys. This site specificity resulting from the kinetics of specific transporters might be responsible for the negative outcome of in vivo mutagenicity. The kidney was then macroscopically divided, based on anatomical characteristics, into the cortex, the OM, and the inner medulla, each of which was histopathologically confirmed. Spi⁻ mutant frequencies (MFs) but not gpt MFs in the OM after a 4-week exposure to OTA were significantly higher than in controls despite the absence of cortical changes. There were also no changes in 8-hydroxydeoxyguanosine levels in kidney DNA. These results strongly suggest the involvement of a genotoxic mechanism, with the exception of oxidative DNA damage in OTA-induced renal carcinogenesis. In addition, the reporter gene mutation assay using DNA from target sites could be a more powerful tool to investigate in vivo genotoxicities.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hibi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Meilan
authors.initials: M
authors.lastname: Jin
authors.forename: Maiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sugita-Konishi
authors.forename: Tokuma
authors.initials: T
authors.lastname: Yanai
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Umemura
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods; D009793:Ochratoxins / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A