In utero development represents a sensitive window for the induction of mutations. These mutations may subsequently expand clonally to populate entire organs or anatomical structures. Although not all adverse mutations will affect tissue structure or function, there is growing evidence that clonally expanded genetic mosaics contribute to various monogenic and complex diseases, including cancer. We posit that genetic mosaicism is an underestimated potential health problem that is not fully addressed in the current regulatory genotoxicity testing paradigm. Genotoxicity testing focuses exclusively on adult exposures and thus may not capture the complexity of genetic mosaicisms that contribute to human disease. Numerous studies have shown that conversion of genetic damage into mutations during early developmental exposures can result in much higher mutation burdens than equivalent exposures in adults in certain tissues. Therefore, we assert that analysis of genetic effects caused by in utero exposures should be considered in the current regulatory testing paradigm, which is possible by harmonization with current reproductive/developmental toxicology testing strategies. This is particularly important given the recent proposed paradigm change from simple hazard identification to quantitative mutagenicity assessment. Recent developments in sequencing technologies offer practical tools to detect mutations in any tissue or species. In addition to mutation frequency and spectrum, these technologies offer the opportunity to characterize the extent of genetic mosaicism following exposure to mutagens. Such integration of new methods with existing toxicology guideline studies offers the genetic toxicology community a way to modernize their testing paradigm and to improve risk assessment for vulnerable populations. Environ. Mol. Mutagen. 61:55-65, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

中文翻译：

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在子宫内暴露于导致基因镶嵌的基因毒性药物：在遗传毒理学测试中被忽略的易感性窗口？

在子宫内发育代表了诱导突变的敏感窗口。这些突变随后可克隆扩展以填充整个器官或解剖结构。尽管并非所有不良突变都会影响组织结构或功能，但越来越多的证据表明，克隆扩展的遗传花叶病会导致各种单基因和复杂疾病，包括癌症。我们认为，遗传镶嵌病是一个被低估的潜在健康问题，在当前的监管遗传毒性测试范例中并未完全解决。遗传毒性测试仅针对成年人的暴露，因此可能无法捕获导致人类疾病的遗传镶嵌复杂性。大量研究表明，在某些发育阶段，成年早期遗传暴露将遗传损伤转化为突变可能比成年人造成的突变负担高得多。因此，我们认为在当前的监管测试范式中应考虑对子宫内暴露引起的遗传效应进行分析，这可以通过与当前的生殖/发育毒理学测试策略相协调来实现。考虑到最近提出的从简单危害识别到定量诱变性评估的范式变化，这一点尤其重要。测序技术的最新发展为检测任何组织或物种中的突变提供了实用的工具。除了突变频率和频谱，这些技术提供了表征诱变剂后遗传镶嵌的程度的机会。这种将新方法与现有毒理学指南研究相结合的方法，为遗传毒理学界提供了一种现代化其检测范式并改善对易感人群的风险评估的方法。环境。大声笑 诱变剂。2020年61：55-65。©2019作者。Wiley Periodicals，Inc.代表环境诱变学会出版的《环境和分子诱变》。