Arnold Lora L, Suzuki Shugo, Yokohira Masanao, Kakiuchi-Kiyota Satoko, Pennington Karen L, Cohen Samuel M
Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Pathology and Microbiology and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Toxicol Pathol. 2014 Jul;42(5):855-62. doi: 10.1177/0192623313489778. Epub 2013 May 20.
Inorganic arsenic (arsenite and arsenate) at high exposures is a known human carcinogen, inducing tumors of the urinary bladder, skin, and lungs. In two experiments, we examined the urothelial proliferative effects of treatment with 173 ppm sodium arsenite (100 ppm arsenic) in the drinking water for 6 and 24 hr, and 3, 7, and 14 days in female F344 rats and 43.3 ppm sodium arsenite (25 ppm arsenic) in female C57BL/6 wild-type and arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice that are unable to methylate arsenicals. In the rat and both mouse genotypes, scanning electron microscopy showed cytotoxic urothelial changes as early as 6 hr after the start of arsenic exposure. The severity of As(III)-induced cytotoxic urothelial changes increased over time in the rat and in the As3mt KO mouse. Light microscopy showed an increase in urothelial hyperplasia in the rat. No significant increases in bromodeoxyuridine-labeling index were observed. The data support the hypothesis that the sequence of events in the mode of action for urothelial effects of orally administered inorganic arsenic in the rat and mouse involves superficial cytotoxicity with consequent regenerative increased cell proliferation similar to the findings associated with the administration of dimethylarsinic acid (DMA(V)) in rats.
高剂量接触无机砷（亚砷酸盐和砷酸盐）是一种已知的人类致癌物，可诱发膀胱癌、皮肤癌和肺癌。在两项实验中，我们研究了在雌性F344大鼠饮用水中添加173 ppm亚砷酸钠（100 ppm砷），分别处理6小时、24小时、3天、7天和14天，以及在雌性C57BL/6野生型和无法甲基化砷化合物的砷（+3氧化态）甲基转移酶基因敲除（As3mt KO）小鼠饮用水中添加43.3 ppm亚砷酸钠（25 ppm砷）后对尿路上皮的增殖作用。在大鼠以及两种小鼠基因型中，扫描电子显微镜显示，早在砷暴露开始后6小时就出现了细胞毒性的尿路上皮变化。在大鼠和As3mt KO小鼠中，As(III)诱导的细胞毒性尿路上皮变化的严重程度随时间增加。光学显微镜显示大鼠尿路上皮增生增加。未观察到溴脱氧尿苷标记指数有显著增加。这些数据支持以下假设：在大鼠和小鼠中，口服无机砷对尿路上皮产生影响的作用模式中的事件顺序涉及表面细胞毒性，随后是再生性细胞增殖增加，这与在大鼠中给予二甲基砷酸（DMA(V)）的相关发现相似。
