In vivo genotoxicity of EMS: Statistical assessment of the dose response curves
In vivo genotoxicity of EMS: Statistical assessment of the dose response curves
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DOI：
10.1016/j.toxlet.2009.03.008
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发表时间：
2009-11-12
影响因子：
3.5
通讯作者：
Wall, Michael
中科院分区：
文献类型：
--
作者：
Gocke, Elmar;Wall, Michael
在小鼠体内研究中，EMS诱导的微核和lacZ突变具有明显的亚线性剂量依赖性。正如本期其他地方报道的那样，在不同终点和分析的组织中观察到的NOEL剂量值在25 mg/kg/天至80 mg/kg/天之间。本研究表明，数据的统计评估为直接损伤DNA的诱变剂EMS在体内处理后的致突变和致裂效应遵循阈值剂量反应关系提供了坚实的支持。这些数据证实了在体外研究中获得的类似证据。我们得出的结论是，细胞完全有能力修复由EMS诱导的大量DNA乙基化，而不会经历突变频率升高。因此，通常用于DNA损伤基因毒素的随机线性风险评估模型可以被驳斥为EMS。虽然目前这一结论不能推广到其他基因毒素，但至少对于烷基化剂诱导的DNA损伤类型和谱与EMS相似，似乎表明了范式的变化。2009爱思唯尔爱尔兰有限公司版权所有。
EMS induced micronuclei and lacZ mutations in in vivo studies in mice with a clearly sublinear dose dependency. As reported elsewhere in this issue, NOEL dose values of between 25 mg/kg/day and 80 mg/kg/day were observed for the different endpoints and tissues analysed. Here we show that statistical assessment of the data provides solid support that the induction of mutagenic and clastogenic effects after in vivo treatment with the directly DNA damaging mutagen EMS adheres to a thresholded dose response relation. These data corroborate similar evidence obtained in in vitro studies. We conclude that cells are fully capable of repairing large amounts of DNA ethylations induced by EMS without experiencing elevated mutation frequencies. The stochastic, linear risk assessment model generally employed for DNA damaging genotoxins can therefore be refuted for EMS. While presently this conclusion cannot be generalized to other genotoxins a change of paradigm appears to be indicated at least for alkylating agents inducing a comparable type and spectrum of DNA lesions as EMS. (C) 2009 Elsevier Ireland Ltd. All rights reserved.