Department of Nutrition, Food Safety and Toxicology, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China.
West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
Environ Sci Pollut Res Int. 2022 Dec;29(56):85128-85142. doi: 10.1007/s11356-022-21605-z. Epub 2022 Jul 6.
The main goal of the study was to investigate the genotoxic response of N-ethyl-N-nitrosourea (ENU) and ethyl methanesulfonate (EMS) at low doses in a multi-endpoint genotoxicity assessment platform in rats and to derive potential thresholds and related metrics. Male Sprague-Dawley rats were treated by daily oral gavage for 28 consecutive days with ENU (0.25 ~ 8 mg/kg bw) and EMS (5 ~ 160 mg/kg bw), both with six closely spaced dose levels. Pig-a gene mutation assay, micronucleus test, and comet assay were performed in several timepoints. Then, the dose-response relationships were analyzed for possible points of departure (PoD) using the no observed genotoxic effect level and benchmark dose (BMD) protocols with different critical effect sizes (CES, 0.05, 0.1, 0.5, and 1SD). Overall, dose-dependent increases in all investigated endpoints were found for ENU and EMS. PoDs varied across genetic endpoints, timepoints, and statistical methods, and selecting an appropriate lower 95% confidence limit of BMD needs a comprehensive consideration of the mode of action of chemicals, the characteristics of tests, and the model fitting methods. Under the experimental conditions, the PoDs of ENU and EMS were 0.0036 mg/kg bw and 1.7 mg/kg bw, respectively.
本研究的主要目的是在大鼠多终点遗传毒性评估平台中，研究低剂量 N-乙基-N-亚硝脲（ENU）和乙基亚磺酸乙酯（EMS）的遗传毒性反应，并得出潜在的阈值和相关指标。雄性 Sprague-Dawley 大鼠通过每日口服灌胃 28 天，接受不同浓度的 ENU（0.25 至 8mg/kg bw）和 EMS（5 至 160mg/kg bw）处理，这两种物质都有六个紧密间隔的剂量水平。在多个时间点进行了 Pig-a 基因突变试验、微核试验和彗星试验。然后，使用无观察到遗传毒性效应水平和基准剂量（BMD）协议，以及不同关键效应大小（CES，0.05、0.1、0.5 和 1SD），分析了剂量-反应关系，以确定可能的起始点（PoD）。总体而言，ENU 和 EMS 引起了所有研究终点的剂量依赖性增加。PoD 因遗传终点、时间点和统计方法而异，选择适当的 BMD 置信下限 95%需要综合考虑化学物质的作用模式、测试特性和模型拟合方法。在实验条件下，ENU 和 EMS 的 PoD 分别为 0.0036mg/kg bw 和 1.7mg/kg bw。
