Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression.
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), G(2)/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.
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Daisuke
D
Hibi
Aki
A
Kijima
Ken
K
Kuroda
Yuta
Y
Suzuki
Yuji
Y
Ishii
Meilan
M
Jin
Masahiro
M
Nakajima
Yoshiko
Y
Sugita-Konishi
Tokuma
T
Yanai
Takehiko
T
Nohmi
Akiyoshi
A
Nishikawa
Takashi
T
Umemura
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects; D020869:Gene Expression Profiling; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009793:Ochratoxins / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction
D002273:Carcinogens; D009793:Ochratoxins; D012333:RNA, Messenger; C025589:ochratoxin A