Stress-related gene expression in mice treated with inorganic arsenicals
Stress-related gene expression in mice treated with inorganic arsenicals
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DOI：
10.1093/toxsci/61.2.314
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发表时间：
2001-06-01
影响因子：
3.8
通讯作者：
Waalkes, MP
中科院分区：
文献类型：
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作者：
Liu, J;Kadiiska, MB;Waalkes, MP
砷是一种高度关注人类健康的环境化学物质。砷的急性毒性取决于其化学形态，接近局部高浓度砷是细胞死亡的机制之一。本研究旨在确定急性砷诱导的应激相关基因在体内的表达。小鼠分别注射亚砷酸钠[As(III)， 100 μ mol/kg]、砷酸钠[As(V)， 300 μ mol/kg]或生理盐水。为了检测应激相关基因的表达，我们在注射砷3小时后取出肝脏，提取RNA和蛋白质。Atlas小鼠应激/毒理学阵列显示，急性砷处理改变了应激、DNA损伤和代谢相关基因的表达。血红素加氧酶1 (HO-1)（砷诱导应激的标志）的表达增加了10倍，热休克蛋白60 （HSP60）、DNA损伤诱导蛋白GADD45和DNA切除修复蛋白ERCC1的表达也增加了10倍。砷处理导致某些细胞色素P450酶下调。多探针RNase保护实验显示砷处理后c-Jun/AP-1转录复合物活化。Western blot分析进一步证实，砷诱导的应激蛋白如HO-1、HSP70、HSP90、金属硫蛋白、金属反应转录因子MTF-1、核因子kappa B和c-Jun/AP-1的产生增加。caspase-1和细胞因子如肿瘤坏死因子- α (tnf - α)和巨噬细胞炎症蛋白-2的升高也很明显。总之，本研究描述了无机砷处理小鼠的基因表达模式，增加了我们对急性砷中毒及其毒性的理解。
Arsenic (As) is an environmental chemical of high concern for human health. Acute toxicity of arsenic is dependent on its chemical forms and proximity to high local arsenic concentrations is one of the mechanisms for cell death. This study was designed to define acute arsenic-induced stress-related gene expression in vivo. Mice were injected sc with either sodium arsenite [As(III), 100 mu mol/kg], sodium arsenate [As(V), 300 mu mol/kg], or saline. To examine stress-related gene expression, livers were removed 3 h after arsenic injection for RNA and protein extraction. The Atlas Mouse Stress/Toxicology array revealed that the expression of genes related to stress, DNA damage, and metabolism was altered by acute arsenic treatments. Expression of heme oxygenase 1 (HO-1), a hallmark for arsenic-induced stress, was increased 10-fold, along with increases in heat shock protein-60 (HSP60), DNA damage inducible protein GADD45, and the DNA excision repair protein ERCC1. Downregulation of certain cytochrome P450 enzymes occurred with arsenic treatment. Multiprobe RNase protection assay revealed the activation of the c-Jun/AP-1 transcription complex after arsenic treatments. Western blot analysis further confirmed the enhanced production of arsenic-induced stress proteins such as HO-1, HSP70, HSP90, metallothionein, the metal-responsive transcription factor MTF-1, nuclear factor kappa B and c-Jun/AP-1. Increases in caspase-1 and cytokines such as tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 were also evident. In summary, this study profiled the gene expression pattern in mice treated with inorganic arsenicals, which adds to our understanding of acute arsenic poisoning and toxicity.