Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats.
Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats.
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DOI：
10.1093/toxsci/kfp133
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发表时间：
2009-09
期刊：
影响因子：
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通讯作者：
X. Pu;L. Kamendulis;J. Klaunig
中科院分区：
文献类型：
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作者：
X. Pu;L. Kamendulis;J. Klaunig
研究表明，氧化应激的诱导可能参与丙烯腈诱发大鼠脑肿瘤。本研究探讨了丙烯腈是否会诱导大鼠的氧化应激和DNA损伤，以及血液是否可以作为一个有效的替代品，在接触人群中由丙烯腈引起的氧化应激的生物监测。雄性Sprague-Dawley大鼠用0、3、30、100和200 ppm丙烯腈饮用水处理28天。一组大鼠还同时给予N-乙酰半胱氨酸（NAC）（饮食中0.3%）和丙烯腈（饮用水中200 ppm），以检查抗氧化剂补充剂是否对丙烯腈诱导的氧化应激具有保护作用。使用碱性彗星试验测量白色血细胞（WBC）和脑中的直接DNA链断裂。采用甲酰胺嘧啶DNA糖基化酶（fpg）改良彗星试验和高效液相色谱-电化学检测法评价WBC和脑中的氧化DNA损伤。在丙烯腈处理大鼠的脑和WBC中未观察到直接DNA链断裂显著增加。脑和白细胞DNA氧化损伤（fpg彗星和8 '羟基脱氧鸟苷）呈剂量依赖性增加。此外，在给予丙烯腈的大鼠中，活性氧（ROS）的血浆水平增加。饮食中补充NAC可防止丙烯腈诱导的脑和WBC中的氧化DNA损伤。在丙烯腈剂量> 30 ppm时，脑中GSH：GSSG比率轻微但显著降低。这些结果提供了额外的支持，丙烯腈诱导的星形细胞瘤的作用方式涉及氧化应激和损伤的诱导。观察到WBC和脑中的氧化性DNA损伤、血浆中的ROS形成与报告的肿瘤发生率之间存在显著相关性。由于脑中的氧化性DNA损伤与WBC中的氧化性损伤相关，因此这些结果表明，监测WBC DNA损伤可能是评估丙烯腈诱导的人类氧化应激的有用工具。
Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans.