EVALUATION OF ARSENIC-INDUCED OXIDATIVE DNA DAMAGE AND ELUCIDATION OF MECHANISM OF ARSENIC CARCINOGENESIS

砷引起的DNA氧化损伤的评估及砷致癌机制的阐明

• 批准号: 15310041
• 负责人: WANIBUCHI Hideki
• 金额: $ 9.34万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15310041/
• 关键词: Arsenic; Oxidative DNA damaee; Carcinogenesis; DMA; MMA; TMAO; Rat; cDNA microarrav; 酸化的DNA障害; 膀胱粘膜上皮; cDNAマイクロアレー法; OGG1遺伝子欠損マウス; 8-OHdG; 肺腫瘍; 膀胱上皮過形成

The purpose of the present studies is to investigate the role of oxidative stress in arsenic-induced carcinogenesis.In the study 1, MMA, DMA and TMAO significantly increased P450 total content and formation of hydroxyl radicals in rat livers. Significant elevations in 8-hydroxy-2-deoxyguanosine (8-OHdG) formation in DNA were found in livers treated with TMAO, and in the bladders treated with DMA. In addition, cell proliferation and apoptosis indices were significantly increased by TMAO in the liver and by DMA in the bladder of rats. Microarray analysis revealed that above events were accompanied by differential up-regulation of phase I and II metabolizing enzymes, oxidative response gene in the target organs.In the study 2, lung tumors were induced in Ogg1-knockout (Ogg1-/-) mice treated with DMAV for 72 weeks, and associated with increase in 8-OHdG levels and cell proliferation. No tumors were observed in wild type mice. These results indicate that DMAV exerts carcinogenicity in the lungs of Ogg1-/- knockout mice, with a possible role for persistent accumulation of DNA oxidative adducts.In the study 3, the findings that incidences and number of adenomas, and 8-OHdG formation level were significantly increased in male F344 rat livers treated with 200 ppm TMAO for 2 years compared to control, indicating that TMAO exerts liver tumorigenicity with possible mechanistic roles for oxidative DNA damage in rats. The results of 2-year bioassay of MMA showed MMA induced preneoplastic lesions in the liver and urinary bladder, but did not cause tumor development in male F344 rats.These findings indicate that oxidative DNA damage plays a critical role in arsenic carcinogenesis.

本研究旨在探讨氧化应激在砷致癌变中的作用。在研究1中，MMA、DMA和TMAO显著增加了大鼠肝脏中P450总含量和羟基自由基的形成。在TMAO处理的肝脏和DMA处理的膀胱中，DNA中8-羟基-2-脱氧鸟苷（8-OHdG）的形成显著升高。此外，TMAO对大鼠肝脏细胞增殖和细胞凋亡的影响显著，DMA对膀胱细胞凋亡的影响显著。微阵列分析显示，上述事件均伴随着靶器官I、II期代谢酶、氧化反应基因的差异上调。在研究2中，Ogg1-敲除（Ogg1-/-）小鼠经DMAV处理72周后，诱导出肺肿瘤，并伴有8-OHdG水平升高和细胞增殖。野生型小鼠未见肿瘤。这些结果表明，DMAV在Ogg1-/-敲除小鼠的肺部发挥致癌性，可能与DNA氧化加合物的持续积累有关。在研究3中，与对照组相比，200 ppm TMAO处理2年的雄性F344大鼠肝脏中腺瘤的发生率和数量以及8-OHdG形成水平显著增加，表明TMAO具有肝脏致瘤性，可能在大鼠DNA氧化损伤中发挥机制作用。2年的MMA生物测定结果显示，MMA在雄性F344大鼠的肝脏和膀胱中引起肿瘤前病变，但未引起肿瘤发展。这些发现表明DNA氧化损伤在砷致癌中起关键作用。

项目成果

Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 rats-asaociation with oxidative DNA damage and enhanced cell proliferation

三甲基胂氧化物对雄性 Fischer 344 大鼠的肝脏致瘤性——与氧化 DNA 损伤和增强细胞增殖的关系

• 发表时间: 2003
• 期刊: Journal of Toxicologic Science 28
• 作者: Shen;J.;Wanibuchi;H.;et. al.
• 通讯作者: et. al.

Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 ratsnsaociation with oxidative DNA damage and enhanced cell proliferation.

三甲基胂氧化物在雄性 Fischer 344 大鼠中的肝脏致瘤性与氧化性 DNA 损伤和增强的细胞增殖有关。

• 发表时间: 2003
• 期刊: Journal of Toxicologic Science 28
• 作者: Shen;J.;Wanibuchi;H.;et. al.
• 通讯作者: et. al.

Mechanism of MMA, DMA and TMAO carcinogenicity.

MMA、DMA 和 TMAO 致癌机制。

• 发表时间: 2004
• 作者: Wanibuchi;H.
• 通讯作者: H.

Dimethylarsinic acid carcinogenicity test in Mmh/OGG1 knockout mice.

Mmh/OGG1 敲除小鼠二甲基胂酸致癌性试验。

• 发表时间: 2003
• 作者: Kinoshita;A.;Wanibuchi;H.
• 通讯作者: H.

Shen, J., Wanibuchi, H., et al.: "Induction of glutathione S-transferase placental form positive foci in liver and epithelial hyperplasia in urinary bladder but no tumor development in male Fischer 344 rats treated with monomethylarsonic acid for 104 week

Shen, J., Wanibuchi, H. 等人：“用单甲基胂酸治疗 104 周的雄性 Fischer 344 大鼠中，诱导谷胱甘肽 S-转移酶胎盘在肝脏中形成阳性灶，并在膀胱中形成上皮增生，但没有肿瘤形成