Analysis of chemical structures and mutations detected by Salmonella TA98 and TA100

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2023-07-01 DOI:10.1016/j.mrfmmm.2023.111838

Kevin P. Cross , David M. DeMarini

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引用次数: 0

Abstract

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.

查看原文本刊更多论文

沙门氏菌TA98和TA100的化学结构和突变分析。

作为2017年在国际基因毒性测试研讨会（IWGT）主持下进行的分析的一部分，我们和其他人表明，沙门氏菌移码菌株TA98和碱基取代菌株TA100加起来+/-S9检测到经合组织TG471推荐的所有菌株检测到的93%的诱变剂（Williams等人，突变研究848:5030812019）。我们通过识别这两种菌株单独或联合检测到的化学物质的数量和化学类别，包括S9的作用，扩展了这一分析。使用包含>21900种化合物的Leadscope 2021 SAR Genetox数据库，我们的数据集包含在TA98和TA100中测试的7170种化合物。TA98和TA100总共检测到94%（3733/3981）的使用所有TG471推荐菌株检测到的诱变剂；39%的菌株在一个或两个菌株中具有诱变性。TA100检测到77%的这些诱变剂，TA98检测到70%。考虑到两种菌株的检测重叠，这些诱变剂中12%仅被TA98检测到，19%仅被TA100检测到。在没有S9的情况下，TA98和TA100的灵敏度分别下降了31%和29%。总的来说，32%的诱变剂需要S9才能被任一菌株检测；仅在没有S9的情况下检测到9%。使用2021 Leadscope Genetox专家警报，TA100检测到18种致突变警报化学类别，其灵敏度高于TA98，而TA98检测到10种类别高于TA100。TA100比TA98检测到更多的化学类别，特别是肼、叠氮化物、各种二卤化物和三卤化物、各种亚硝胺、环氧化物、氮丙啶、二呋喃和半芥末；TA98特别检测多环伯胺、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诱导TA100中的G至T突变和/或TA98中的热点GC缺失。TA98和TA100+/-S9都需要用沙门氏菌（Ames）试验进行足够的诱变性筛选。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.