Instem, Columbus, OH 43215, USA.
Center for Environmental Measurement and Modeling, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Mutat Res. 2023 Jul-Dec;827:111838. doi: 10.1016/j.mrfmmm.2023.111838. Epub 2023 Sep 30.
As part of an analysis performed under the auspices of the International Workshop on Genotoxicity Testing (IWGT) in 2017, we and others showed that Salmonella frameshift strain TA98 and base-substitution strain TA100 together + /- S9 detected 93% of the mutagens detected by all the bacterial strains recommended by OECD TG471 (Williams et al., Mutation Res. 848:503081, 2019). We have extended this analysis by identifying the numbers and chemical classes of chemicals detected by these two strains either alone or in combination, including the role of S9. Using the Leadscope 2021 SAR Genetox database containing > 21,900 compounds, our dataset containing 7170 compounds tested in both TA98 and TA100. Together, TA98 and TA100 detected 94% (3733/3981) of the mutagens detected using all the TG471-recommended bacterial strains; 39% were mutagenic in one or both strains. TA100 detected 77% of all of these mutagens and TA98 70%. Considering the overlap of detection by both strains, 12% of these mutagens were detected only by TA98 and 19% only by TA100. In the absence of S9, sensitivity dropped by 31% for TA98 and 29% for TA100. Overall, 32% of the mutagens required S9 for detection by either strain; 9% were detected only without S9. Using the 2021 Leadscope Genetox Expert Alerts, TA100 detected 18 mutagenic alerting chemical classes with better sensitivity than TA98, whereas TA98 detected 10 classes better than TA100. TA100 detected more chemical classes than did TA98, especially hydrazines, azides, various di- and tri-halides, various nitrosamines, epoxides, aziridines, difurans, and half-mustards; TA98 especially detected polycyclic primary amines, various aromatic amines, polycyclic aromatic hydrocarbons, triazines, and dibenzo-furans. Model compounds with these structures induce primarily G to T mutations in TA100 and/or a hotspot GC deletion in TA98. Both TA98 and TA100 + /- S9 are needed for adequate mutagenicity screening with the Salmonella (Ames) assay.
作为 2017 年国际遗传毒性检测工作坊（IWGT）分析的一部分，我们和其他人证明，沙门氏菌移码菌株 TA98 和碱基替换菌株 TA100 与 S9 一起使用，可检测到 OECD TG471 推荐的所有细菌菌株中 93%的诱变剂（Williams 等人，Mutation Res. 848:503081, 2019）。我们通过确定这两种菌株单独或联合检测到的化学品数量和化学类别，包括 S9 的作用，扩展了这一分析。使用包含>21,900 种化合物的 Leadscope 2021 SAR Genetox 数据库，我们的数据集中包含在 TA98 和 TA100 中测试的 7170 种化合物。TA98 和 TA100 一起检测到了使用所有 TG471 推荐的细菌菌株检测到的 94%（3733/3981）诱变剂；39%在一种或两种菌株中具有诱变活性。TA100 检测到了所有这些诱变剂的 77%，而 TA98 检测到了 70%。考虑到两种菌株的检测重叠，其中 12%的诱变剂仅被 TA98 检测到，19%的诱变剂仅被 TA100 检测到。在没有 S9 的情况下，TA98 的敏感性下降了 31%，TA100 的敏感性下降了 29%。总体而言，32%的诱变剂需要 S9 才能被任一种菌株检测到；9%的诱变剂仅在没有 S9 的情况下被检测到。使用 2021 年 Leadscope Genetox Expert Alerts，TA100 检测到 18 种具有更好敏感性的诱变警报化学类别，优于 TA98，而 TA98 检测到 10 种优于 TA100。TA100 检测到的化学类别比 TA98 多，特别是肼、叠氮化物、各种二卤代物和三卤代物、各种亚硝胺、环氧化物、氮丙啶、二呋喃和半马氏碱；TA98 特别检测到多环伯胺、各种芳香胺、多环芳烃、三嗪和二苯并呋喃。具有这些结构的模型化合物主要在 TA100 中诱导 G 到 T 突变和/或 TA98 中的热点 GC 缺失。沙门氏菌（Ames）试验需要 TA98 和 TA100 与 S9 一起使用才能进行充分的致突变性筛选。
