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首页> 外文期刊>The Journal of toxicological sciences >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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Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression

机译：ochratoxinα-诱导的遗传毒性的分子机制：全局基因表达分析表明DNA双链断裂和细胞周期进展的诱导

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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.
机译：Ochratoxin A（OTA）是一种主要影响啮齿动物中近端小管的S3区段的肾致癌物。在我们以前的研究中，我们报道了OTA在S3区段中特别地诱导报道基因突变，主要是缺失突变，在肾外髓质中，特别是在S3区段中。在本研究中，为了鉴定参与OTA诱导的遗传毒性的基因，我们对来自GPT Delta大鼠在致癌剂量的GPT Delta大鼠中进行了肾皮层（Cor）和OM的全局基因表达的比较分析。与DNA损伤和DNA损伤修复相关的基因，以及细胞周期调节在OM中明确地改变。有趣的是，在OM中解毒的基因具有DNA双链断裂（DSB）修复（RAD18，Brip1和BrCC3），细胞周期进展（Cyce1，CCNA2和CCNB1），G 2 < /亚> / m响应DNA损伤（CHEK1和WEE1）和P53相关因子（PHLDA3和CCNG1）的抑弹。使用实时RT-PCR在OM中观察到许多这些基因的mRNA水平的显着增加。然而，与氧化应激相关的基因表现出OM和COR中的改变基因的数量或功能的差异。这些结果表明OTA在靶位点诱导DSB和细胞周期进展。除氧化应激之外的这些事件可能会引发遗传毒性，导致OTA诱导的肾肿瘤性。

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