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首页> 美国卫生研究院文献>Environmental Health Perspectives >Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies.
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Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies.

机译：亚砷酸盐致癌作用：一种源自遗传毒理学研究的动物模型。

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Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner.
机译：尽管流行病学证据表明饮用水中的无机砷与皮肤，肺癌和膀胱癌的风险增加之间存在关联，但尚无成功的砷致癌动物模型。这种缺乏阻碍了砷致癌机理的研究。以前，我们和其他人发现，不致突变的低浓度（<或= 5微米）的亚砷酸盐（可能是环境致癌物）可以增强其他试剂（包括紫外线辐射（UVR）和烷基化试剂）的致突变性。这种增强作用似乎是由于亚砷酸盐对DNA修复的抑制所致，而不是由于DNA修复酶的抑制所致。相反，低浓度的亚砷酸盐会破坏p53功能并上调细胞周期蛋白D1。未能找到砷致癌作用的动物模型，可能是由于砷本身不是致癌物，而是与遗传毒性伴侣一起充当增强剂（致癌物）。我们在无毛但具有免疫能力的Skh1小鼠中使用太阳UVR检验了这一假设。给予小鼠饮用水（或非饮用水）中的10 mg / L亚砷酸钠，每周接受3次1.7 KJ / m（2）的太阳UVR照射。如预期的那样，在对照小鼠或仅给予亚砷酸盐的小鼠的任何器官中均未出现肿瘤。与单独给予UVR的小鼠相比，接受亚砷酸盐照射的小鼠在26周后的皮肤肿瘤产量增加了2.4倍。肿瘤大部分是鳞状细胞癌，而在接受UVR和亚砷酸盐照射的小鼠中发生的肿瘤更大且更具侵袭性。这些结果与以下假设相吻合：砷通过抑制DNA修复和/或增强正向生长信号而与第二种（遗传毒性）试剂一起作为致癌物。含砷人口饮用水中的皮肤癌可能是由砷化合物增强紫外线辐射（或其他环境因素）诱发的致癌作用引起的。与饮用水中砷相关的肺癌和膀胱癌也可能需要致癌伴侣。

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