EVALUATION OF ARSENIC-INDUCED OXIDATIVE DNA DAMAGE AND ELUCIDATION OF MECHANISM OF ARSENIC CARCINOGENESIS
| Project/Area Number |
15310041
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation/Chemicals
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| Research Institution | Osaka City University |
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Principal Investigator |
WANIBUCHI Hideki Osaka City University, MEDICAL SCHOOL ; DEPT. PATHOLOGY, PROFESSOR (90220970)
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| Co-Investigator(Kenkyū-buntansha) |
WEI Min OSAKA CITY UNIVERSITY MEDICAL SCHOOL, DEPT. PATHOLOGY, ASSISTANT (70336783)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2005: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2004: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2003: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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Report
(4 results)
Research Products
(54 results)
