Lin Zhang, Shengnan Liu, Fei Wang, Yingli Song, Qingshan Sun, Wei Sheng, Shuhua Xi, Guifan Sun
Department of Occupational and Environmental Health, Liaoning Provincial Key Lab of Arsenic Biological Effect and Poisoning, School of Public Health, China Medical University, No. 92 Bei Er Road, Heping District, Shenyang, 110001, China.
J Appl Toxicol. 2015 Feb;35(2):133-41. doi: 10.1002/jat.3001. Epub 2014 May 15.
Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats.
二甲基胂酸（DMA(V)）是无机砷的主要尿代谢产物，是成年大鼠的膀胱致癌物和膀胱肿瘤促进剂。尿路上皮细胞增殖增加被认为是DMA(V)诱导的膀胱癌发生过程中较早出现的表型。本研究通过透射电子显微镜（TEM）、qRT-PCR、免疫组织化学染色和ELISA方法，检测了暴露于DMA(V) 10周的大鼠膀胱上皮细胞的超微结构变化、增殖因子的表达以及炎性细胞因子的分泌。结果表明，饮用水中给予DMA(V)可导致大鼠尿路上皮细胞毒性和超微结构变化。膀胱尿路上皮中PCNA、细胞周期蛋白D1和COX-2的mRNA表达及免疫反应性升高。此外，200 ppm DMA(V)处理可增加大鼠尿液中转化生长因子-β1（TGF-β1）的分泌，并降低肿瘤坏死因子-α（TNF）-α水平。这些数据表明，慢性炎症、膀胱上皮病变和增殖可能是DMA(V)处理大鼠慢性毒性作用的基本过程。
