Urothelial cytotoxicity and regeneration induced by dimethylarsinic acid in rats.
Urothelial cytotoxicity and regeneration induced by dimethylarsinic acid in rats.
复制标题
二甲基胂酸诱导大鼠尿路上皮细胞毒性和再生。
DOI：
10.1093/toxsci/59.1.68
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Arnold,LL
中科院分区：
文献类型：
--
作者：
Cohen,SM;Yamamoto,S;Cano,M;Arnold,LL
无机砷是一种已知的皮肤和呼吸道致癌物质。流行病学证据表明，它对膀胱和其他内脏器官也有致癌作用。缺乏动物模型限制了对砷致癌机制的理解。最近有报道，高剂量的有机砷，二甲基胂酸（DMA），增加膀胱肿瘤的大鼠时，在饮食或饮用水中给药2年，与女性比男性更敏感。我们以前表明，高剂量的DMA（40或100 ppm的饮食）喂养10周增加大鼠尿路上皮细胞增殖。DMA治疗还增加了肾钙化和尿钙浓度增加。在2项实验中，我们检查了雌性F344大鼠在饮食中使用100 ppm DMA处理2周和10周、6小时和24小时以及3天、7天和14天的尿路上皮增殖效应。早在治疗开始后6小时，通过SEM观察到尿路上皮细胞的细胞毒性变化。处理3天后检测到细胞坏死灶，处理7天后检测到尿路上皮广泛坏死。溴脱氧尿苷（BrdU）标记指数没有增加，直到7天的治疗后，这表明DMA的管理结果在细胞毒性与坏死，然后再生增生的膀胱上皮细胞。虽然大鼠提供了一个动物模型来研究DMA的尿路上皮影响，这一发现的相关性在人类无机砷致癌作用必须谨慎推断，由于高剂量的DMA必要的产生这些变化在大鼠和砷的代谢在啮齿动物，特别是大鼠，与人类相比。
Inorganic arsenic is a known human carcinogen of the skin and respiratory tract. Epidemiologic evidence indicates that it is also carcinogenic to the urinary bladder and other internal organs. Lack of an animal model has limited progress on understanding the mechanism of arsenic carcinogenesis. It was recently reported that high doses of an organic arsenical, dimethylarsinic acid (DMA), increased urinary bladder tumors in rats when administered in the diet or in the drinking water for 2 years, with the female being more sensitive than the male. We previously showed that high doses of DMA (40 or 100 ppm of the diet) fed for 10 weeks increased urothelial cell proliferation in the rat. Treatment with DMA also increased renal calcification and increased urinary calcium concentration. In 2 experiments, we examined the urothelial proliferative effects of treatment with 100 ppm DMA in the diet in female F344 rats for 2 and 10 weeks and for 6 and 24 h, and 3, 7, and 14 days. Cytotoxic changes in the urothelium were evident by SEM as early as 6 h after treatment was begun. Foci of cellular necrosis were detected after 3 days of treatment, followed by widespread necrosis of the urothelium after 7 days of treatment. The bromodeoxyuridine (BrdU) labeling index was not increased until after 7 days of treatment, suggesting that administration of DMA results in cytotoxicity with necrosis, followed by regenerative hyperplasia of the bladder epithelium. Although the rat provides an animal model to study the urothelial effects of DMA, the relevance of this finding to inorganic arsenic carcinogenesis in humans must be extrapolated cautiously, due to the high doses of DMA necessary to produce these changes in the rat and the differences in metabolism of arsenicals in rodents, especially rats, compared to humans.