Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM), Department of Pathology, Botucatu Medical School, UNESP-Univ Estadual Paulista, Botucatu, 18618-000 SP, Brazil.
Toxicol Sci. 2011 Aug;122(2):330-8. doi: 10.1093/toxsci/kfr108. Epub 2011 May 7.
Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. The present study evaluated the dose-dependent effects of mucosal alterations and transcriptional changes in the urinary bladder of rats exposed to diuron. Six-week-old male Wistar rats were treated with 0, 60, 125, 1250, and 2500 ppm of diuron in the diet for 20 weeks. Histologic examination showed urothelial hyperplasia present in rats treated with either 1250 or 2500 ppm of diuron but not 60 or 125 ppm. Comprehensive gene expression analyses of urothelial cell RNA were conducted using Affymetrix microarrays. The numbers of differentially expressed transcripts between each treatment group and control increased with diuron dose. Based on similar histology and gene expression responses, the treatment groups were regrouped into a high-dose (1250 and 2500 ppm) and low-dose group (60 and 125 ppm). These data suggest that persistent exposure to high dietary concentrations of diuron induces oxidative stress, increases cellular metabolism, and enhances cell death that is associated with sustained urothelial hyperplasia.
敌草隆（3-(3,4-二氯苯基）-1,1-二甲基脲）是一种取代脲类除草剂，在高膳食水平（2500ppm）下会导致大鼠膀胱尿路上皮肿瘤。然而，敌草隆的特定作用模式和引发的分子改变尚未阐明。本研究评估了暴露于敌草隆的大鼠膀胱黏膜改变和转录变化的剂量依赖性效应。6 周龄雄性 Wistar 大鼠用 0、60、125、1250 和 2500ppm 的敌草隆饲料处理 20 周。组织学检查显示，用 1250 或 2500ppm 的敌草隆处理的大鼠存在尿路上皮增生，但用 60 或 125ppm 的敌草隆处理的大鼠则没有。使用 Affymetrix 微阵列对尿路上皮细胞 RNA 进行了综合基因表达分析。每个处理组与对照组之间差异表达转录本的数量随着敌草隆剂量的增加而增加。基于相似的组织学和基因表达反应，将处理组重新分为高剂量（1250 和 2500ppm）和低剂量组（60 和 125ppm）。这些数据表明，持续暴露于高膳食浓度的敌草隆会诱导氧化应激，增加细胞代谢，并增强与持续尿路上皮增生相关的细胞死亡。
