Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression

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  • Hibi Daisuke
    Division of Pathology, National Institute of Health Sciences
  • Kijima Aki
    Division of Pathology, National Institute of Health Sciences
  • Kuroda Ken
    Division of Pathology, National Institute of Health Sciences
  • Suzuki Yuta
    Division of Pathology, National Institute of Health Sciences
  • Ishii Yuji
    Division of Pathology, National Institute of Health Sciences
  • Jin Meilan
    Division of Pathology, National Institute of Health Sciences
  • Nakajima Masahiro
    Environmental Health Department, Nagoya City Public Health Institute
  • Sugita-Konishi Yoshiko
    Division of Microbiology, National Institute of Health Sciences
  • Yanai Tokuma
    Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Applied Biological Sciences,Gifu University
  • Nohmi Takehiko
    Division of Genetics and Mutagenesis, National Institute of Health Sciences
  • Nishikawa Akiyoshi
    Biological Safety Research Center, National Institute of Health Sciences
  • Umemura Takashi
    Division of Pathology, National Institute of Health Sciences

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Ochratoxin A (OTA) is a renal carcinogen primarily affecting the S3 segment of proximal tubules in rodents. In our previous study, we reported that OTA induces reporter gene mutations, primarily deletion mutations, in the renal outer medulla (OM), specifically in the S3 segment. In the present study, to identify genes involved in OTA-induced genotoxicity, we conducted a comparative analysis of global gene expression in the renal cortex (COR) and OM of kidneys from gpt delta rats administered OTA at a carcinogenic dose for 4 weeks. Genes associated with DNA damage and DNA damage repair, and cell cycle regulation were site-specifically changed in the OM. Interestingly, genes that were deregulated in the OM possessed molecular functions such as DNA double-strand break (DSB) repair (Rad18, Brip1, and Brcc3), cell cycle progression (Cyce1, Ccna2, and Ccnb1), G2/M arrest in response to DNA damage (Chek1 and Wee1), and p53-associated factors (Phlda3 and Ccng1). Significant increases in the mRNA levels of many of these genes were observed in the OM using real-time RT-PCR. However, genes related to oxidative stress exhibited no differences in either the number or function of altered genes in both the OM and COR. These results suggested that OTA induced DSB and cell cycle progression at the target site. These events other than oxidative stress could trigger genotoxicity leading to OTA-induced renal tumorigenicity.

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