Quantitative Dose-Response Analysis of Ethyl Methanesulfonate Genotoxicity in Adult gpt-delta Transgenic Mice
Quantitative Dose-Response Analysis of Ethyl Methanesulfonate Genotoxicity in Adult gpt-delta Transgenic Mice
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DOI：
10.1002/em.21854
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发表时间：
2014-06-01
影响因子：
2.8
通讯作者：
Heflich, Robert H.
中科院分区：
文献类型：
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作者：
Cao, Xuefei;Mittelstaedt, Roberta A.;Heflich, Robert H.
诱变剂具有线性剂量反应的假设最近受到了挑战。特别是甲磺酸乙酯（EMS），一种 DNA 反应性诱变剂和致癌剂，对转基因 Muta (TM) 小鼠中的 LacZ 突变和 CD1 小鼠中的微核 (MN) 频率表现出亚线性或阈值剂量反应（Gocke E 和 Muller L [2009]：Mutat Res 678：101-107）。为了探索建立遗传毒性剂量反应的变量，我们使用基因突变测定来表征 EMS 的遗传毒性，预计其自发突变频率 (MF) 低于 Muta (TM) 小鼠。雄性 gpt-delta 转基因小鼠每天接受 5 至 100 mg/kg EMS 治疗，持续 28 天，并测量： (i) 肝脏、肺、骨髓、肾脏、小肠和脾脏中的 gpt MF； (ii) 外周血网织红细胞 (RET) 和总红细胞中的 Pig-a MF。还在外周血 RET 中测量了 MN 诱导。这些数据用于计算剂量反应的出发点 (PoD)，即。即，未观察到的基因毒性效应水平 (NOGEL)、阈值效应水平的置信下限 (Td-LCIs) 和 10% 基准响应率的置信下限 (BMDL(10)s)。根据已发表的 LacZ 突变和 CD1 MN 诱导的 EMS 剂量反应计算出类似的 PoD。媒介物对照 gpt 和 Pig-a MF 比已发布的媒介物对照 LacZ MF 低 13-40 倍。一般来说，gpt-delta 小鼠中的 EMS 基因毒性剂量反应的 PoD 低于根据 Muta (TM) 小鼠和 CD1 小鼠数据计算的 PoD。我们的结果表明，体内模型之间致突变性剂量反应的幅度和可能的形状有所不同，较低背景的基因突变测定通常检测到较低的 PoD。 (C) 2014 年 Wiley 期刊公司。
The assumption that mutagens have linear dose-responses recently has been challenged. In particular, ethyl methanesulfonate (EMS), a DNA-reactive mutagen and carcinogen, exhibited sublinear or thresholded dose-responses for LacZ mutation in transgenic Muta (TM) Mouse and for micronucleus (MN) frequency in CD1 mice (Gocke E and Muller L [2009]: Mutat Res 678: 101-107). In order to explore variables in establishing genotoxicity dose-responses, we characterized the genotoxicity of EMS using gene mutation assays anticipated to have lower spontaneous mutant frequencies (MFs) than Muta (TM) Mouse. Male gpt-delta transgenic mice were treated daily for 28 days with 5 to 100 mg/kg EMS, and measurements were made on: (i) gpt MFs in liver, lung, bone marrow, kidney, small intestine, and spleen; and (ii) Pig-a MFs in peripheral blood reticulocytes (RETs) and total red blood cells. MN induction also was measured in peripheral blood RETs. These data were used to calculate Points of Departure (PoDs) for the dose responses, i. e., no-observed-genotoxic-effect-levels (NOGELs), lower confidence limits of threshold effect levels (Td-LCIs), and lower confidence limits of 10% benchmark response rates (BMDL(10)s). Similar PoDs were calculated from the published EMS dose-responses for LacZ mutation and CD1 MN induction. Vehicle control gpt and Pig-a MFs were 13-40-fold lower than published vehicle control LacZ MFs. In general, the EMS genotoxicity dose-responses in gpt-delta mice had lower PoDs than those calculated from the Muta (TM) Mouse and CD1 mouse data. Our results indicate that the magnitude and possibly the shape of mutagenicity dose responses differ between in vivo models, with lower PoDs generally detected by gene mutation assays with lower backgrounds. (C) 2014 Wiley Periodicals, Inc.