STUDY OF EXPERIMENTAL PATHOLOGY CONCERNING TO CARCINOGENICITY OF ARSENIC BASED ON THE METABOLISM OF INORGANIC ARSENIC

基于无机砷代谢的砷致癌实验病理学研究

• 批准号: 10670215
• 负责人: WANIBUCHI Hideki
• 金额: $ 1.98万
• 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 (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670215/
• 关键词: 8-OHdG; ODC transgenic mice; carcinogenicity; arsenic; DMA; cell proliferation; bladder cancer; skin carcinogenesis; P53ノックアウトマウス; dimethylarsinic acid; monomethylarsonic acid; thrimethylarsine oxide; 細胞増殖; 80HdG; 無機ヒ素; dimethylarsinie acid

Although numerous epidemiological findings have indicated that arsenics are associated with increased incidences of lung, skin, liver, and bladder cancers, experimental data from animal models to support the hypothesis of carcinogenic effects are limited. Dimethylarsinic acid (DMA) is a major form of organic arsenic in the environment. In addition, it is a major metabolite of ingested inorganic arsenics in most animals. Male F344/DuCrj rats were administered 12.5, 50, or 200 ppm of DMA in the drinking water for 104 weeks, urinary bladder tumors were observed in 0 of 33,8 of 31, and 12 of 31 animals, respectively. No bladder tumors developed in the controls. These results indicate that DMA is carcinogenic for the rat urinary bladder. Promotion effect of DMA on skin carcinogenesis in K6/ODC transgenic mice were tested. DMA showed promoting effect on skin tumorigenesis in k6/ODC transgenic mice as well as TPA.DMA treatment in NBR rats revealed the elevation of 8-OHdG formation in the kidney . PCNA positive-cells were increased in the rats kidney tissue treated with DMA.Inorganic arsenics (arsenite and arsenate) are metabolized to monomethylarsonic acid (MMA), DMA, and trimethylarsine oxide (TMAO) in most mammals. Promoting effects of sodium arsenite and these related organic arsenics (MMA, DMA, TMAO) in a rat submultiorgan-carcinogenesis test were therefore investigated. With regard to bladder carcinogenesis, DMA most-strongly enhanced the tumor induction, followed in decreasing order by MMA and TMAO, whereas AsBe and NaAsIII did not. The enhancement of bladder carcinogenesis was correlated with production of one unknown urinary metabolite of arsenics. These results revealed that MMA and TMAO have carcinogenic potential, as well as DMA.

尽管许多流行病学发现表明砷与肺，皮肤，肝脏和膀胱癌的发病率增加有关，但来自动物模型的实验数据以支持致癌作用的假设是有限的。二甲基苯胺酸（DMA）是环境中有机砷的一种主要形式。此外，它是大多数动物中摄入的无机砷的主要代谢产物。雄性F344/DUCRJ大鼠在饮用水中施用12.5、50或200 ppm的DMA，持续104周，在31个33,8中的0个和31只动物中，观察到尿膀胱肿瘤分别分别观察到膀胱肿瘤。对照组中没有膀胱肿瘤。这些结果表明，DMA对于大鼠膀胱具有致癌性。测试了DMA对K6/ODC转基因小鼠皮肤致癌作用的促进作用。 DMA显示出对K6/ODC转基因小鼠的皮肤肿瘤发生的促进作用以及NBR大鼠的TPA治疗，显示肾脏中8-OHDG形成的升高。在大多数哺乳动物中，用DMA的大鼠肾脏组织中的PCNA阳性细胞增加了用DMA的大鼠肾脏组织。因此，研究了砷酸钠和这些相关的有机砷（MMA，DMA，TMAO）在大鼠近端 - 癌变测试中的作用。关于膀胱癌发生，DMA最严格地增强了肿瘤诱导，随后以MMA和TMAO的降低降低，而Asbe和Naasiii则没有。膀胱癌发生的增强与一种未知的尿砷代谢产生相关。这些结果表明，MMA和TMAO具有致癌潜力以及DMA。

项目成果

Wei, M., Wanibuchi, H., et al.: "Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats"Carcinogenesis. 20. 1873-1876 (1999)

Wei, M., Wanibuchi, H., 等人：“二甲基胂酸对雄性 F344 大鼠的膀胱致癌性”致癌作用。

Wei,M.,Wanibashi,H., et al.: "Urinary bladder carcinogenecity of dimethylarsinic acid in F344 rats."Carcinogenesis. 20. 1873-1876 (1999)

Wei，M.，Wanibashi，H.，等人：“二甲基胂酸对 F344 大鼠膀胱的致癌性。”致癌作用。

Li, W., Wanibuchi, H., et al.: "Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid an organic arsenic compound"Cancer Lett.. 134. 29-36 (1998)

Li，W.，Wanibuchi，H.，等人：“有机砷化合物二甲基胂酸促进 NCI-Black-Reiter 雄性大鼠膀胱癌发生”Cancer Lett.. 134. 29-36 (1998)

Yoshida,K.: "The urinary excretion of arsenic metabolites after a single oral administration of dimethylarsinic acid to rats." Environ Contam.Toxicol.32. 416-421 (1997)

Yoshida,K.：“大鼠单次口服二甲基胂酸后砷代谢物的尿排泄。”

Fukushima, S., Wanibuchi, H. et al.: "Urinary bladder cancer. In: Carcinogenicity. (eds.) Kitchin, K.T.,"Marcel Dekker, Inc.,. 895 (1999)

Fukushima, S., Wanibuchi, H. 等人：“膀胱癌。在：致癌性。（编辑）Kitchin, K.T.”Marcel Dekker, Inc.,。