Defining EMS and ENU dose-response relationships using the Pig-a mutation assay in rats
Defining EMS and ENU dose-response relationships using the Pig-a mutation assay in rats
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DOI：
10.1016/j.mrgentox.2011.06.005
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发表时间：
2011-10-09
影响因子：
1.9
通讯作者：
Schuler, Maik
中科院分区：
文献类型：
--
作者：
Dobo, Krista L.;Fiedler, Ronald D.;Schuler, Maik
近年来，积累的实验证据支持低剂量DNA反应性诱变剂存在亚线性剂量-反应关系。然而，使用现有工具创建必要的体内数据以进行更详细的剂量-反应建模可能并不总是可行的。当前工作的目的是评估猪-a基因突变测定的效用，以快速确定直接作用的基因毒物的剂量-反应关系。在低剂量直接作用烷基化剂甲烷磺酸乙酯（EMS）和乙基亚硝基脲（ENU）暴露28天后，对大鼠外周血突变的诱导进行了评估。利用基于28天研究的统计模型，EMS的突变诱导阈值估计为21.9 mg/kg，而对于更有效的ENU，阈值估计为0.88 mg/kg。比较急性和亚慢性给药的突变频率表明，加性剂量-反应关系不明显，进一步证实了两种化合物存在阈值剂量-反应关系的可能性。总之，本研究提供的证据表明，在评估直接作用诱变剂的剂量-反应关系时，Pig-a试验可能是其他体内突变试验的实际替代方案，并且使用分段给药的实验方法可用于证实负责观察亚线性剂量-反应关系的生物学机制。(C) 2011 Elsevier B.V.版权所有
In recent years, experimental evidence has accumulated that supports the existence of sublinear dose-response relationships at low doses of DNA reactive mutagens. However, creating the in vivo data necessary to allow for a more detailed dose-response modeling with the currently available tools might not always be practical. The purpose of the current work was to evaluate the utility of the Pig-a gene mutation assay to rapidly identify dose-response relationships for direct acting genotoxicants. The induction of mutations in the peripheral blood of rats was evaluated following 28 days of exposure down to low doses of the direct acting alkylating agents ethyl methane sulfonate (EMS) and ethylnitrosourea (ENU). Using statistical modeling based on the 28-day studies, a threshold for mutation induction for EMS was estimated to be 21.9 mg/kg, whereas for the more potent ENU, the threshold was estimated to be 0.88 mg/kg. Comparing mutation frequencies from acute and sub-chronic dosing indicated less than additive dose-response relationships, further confirming the possibility of a threshold dose-response relationship for both compounds. In conclusion, the work presented provides evidence that the Pig-a assay might be a practical alternative to other in vivo mutation assays when assessing dose-response relationships for direct acting mutagens and that an experimental approach using fractionated dosing could be used to substantiate a biological mechanism responsible for the observation of a sublinear dose-response relationship. (C) 2011 Elsevier B.V. All rights reserved.