Mainwaring Guy, Lim Fei Ling, Antrobus Kate, Swain Cindy, Clapp Mike, Kimber Ian, Orphanides George, Moggs Jonathan G
Syngenta CTL, Alderley Park, Cheshire SK10 4TJ, United Kingdom.
Toxicology. 2006 Aug 15;225(2-3):157-72. doi: 10.1016/j.tox.2006.05.017. Epub 2006 Jun 6.
We have used global gene expression profiling, combined with pathway analysis tools, to identify in rats the molecular events associated with paraquat toxicity in the lung. Early (2, 8 and 18h) gene expression changes induced following intraperitoneal (i.p.) exposure to paraquat were measured in the caudal lobe of lungs using Affymetrix rat genome GeneChips (31,042 probe sets). A single high dose of paraquat dichloride (20mg/kg) was used that has been shown previously to cause in rats extensive lung fibrosis after 10 days. Hierarchical clustering of 543 paraquat-responsive genes (false discovery rate<0.05) revealed that under these conditions of exposure paraquat induces a staged transcriptional response in the rat lung that precedes the appearance of lung damage. We report here that many of the transcriptional responses to paraquat were rapid (being maximal at 2h post-dose), and that the predominant molecular functions and biological processes associated with these genes include membrane transport, oxidative stress, lung development, epithelial cell differentiation and transforming growth factor beta (TGF-beta) signalling. These data provide novel insights into the molecular pathways that lead to toxicity after exposure of the rat lung to paraquat.
我们运用全基因组表达谱分析，并结合通路分析工具，来确定大鼠肺中与百草枯毒性相关的分子事件。利用Affymetrix大鼠基因组基因芯片（31,042个探针组），检测腹腔注射百草枯后早期（2、8和18小时）肺尾叶中诱导的基因表达变化。使用单一高剂量的二氯百草枯（20mg/kg），先前已证明该剂量会在10天后导致大鼠出现广泛的肺纤维化。对543个百草枯反应性基因（错误发现率<0.05）进行层次聚类分析，结果显示在这些暴露条件下，百草枯会在大鼠肺中诱导出一个在肺损伤出现之前的阶段性转录反应。我们在此报告，许多对百草枯的转录反应迅速（给药后2小时达到最大值），并且与这些基因相关的主要分子功能和生物学过程包括膜转运、氧化应激、肺发育、上皮细胞分化和转化生长因子β（TGF-β）信号传导。这些数据为大鼠肺暴露于百草枯后导致毒性的分子途径提供了新的见解。
