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; 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.

本研究的目的是研究氧化应激在砷诱导的致癌作用中的作用。在研究1，MMA，DMA和TMAO中，大鼠肝自由基的P450总含量和形成P450。在用TMAO处理的肝脏以及用DMA处理的膀胱中发现了8-羟基-2-脱氧鸟苷（8-OHDG）的显着升高。此外，肝脏中TMAO和大鼠膀胱中的DMA显着增加了细胞增殖和凋亡指数。微阵列分析表明，上述事件伴随着I期和II期代谢酶的差异上调，靶器官中的氧化反应基因。在研究2中，在用DMAV治疗72周的OGG1-KNOCKOUT（OGG1-/ - ）小鼠中诱导了肺部肿瘤，并在8--升高中诱导了肺部肿瘤。在野生型小鼠中未观察到肿瘤。 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发挥肝肿瘤性，并在大鼠中氧化DNA损伤可能作用。 MMA的2年生物测定结果显示，MMA在肝脏和膀胱中诱导的肿瘤性病变，但并未引起男性F344大鼠的肿瘤发育。这些发现表明氧化性DNA损伤在砷癌发生中起关键作用。