AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations.
AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations.
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DOI：
10.1002/em.22479
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发表时间：
2022-03
影响因子：
2.8
通讯作者：
中科院分区：
文献类型：
--
作者：
健康与环境科学研究所（HESI）的遗传毒理学技术委员会（GTTC）正在开发不良结果途径（AOP），描述导致潜在遗传性基因组损伤的作用模式。目的是通过建立相关分子起始事件（MIE）和遗传毒理学监管终点之间关系的经验支持，加强遗传毒性评估中机制信息的使用。在此，我们提出了一个AOP网络，将氧化DNA损伤与两个不良结果（AO）联系起来：突变和染色体畸变。我们从文献中收集经验证据，以评价MIE和AO之间的关键事件关系，并使用改良的Bradford-Hill因果关系标准评估证据的权重。由于活性氧和自由基的普遍存在，氧化性DNA损伤在细胞中不断诱导和修复。然而，外源性暴露可能会通过各种机制增加损伤超过基线水平，并压倒DNA修复和内源性抗氧化能力。未修复的氧化性DNA碱基损伤可导致复制过程中的碱基置换，并且沿着修复中间体，也可导致DNA链断裂，如果未充分修复，DNA链断裂可导致突变和染色体畸变。该AOP网络确定了可以通过有针对性的研究来填补的知识空白，这些研究旨在更好地确定关键事件之间的定量关系，这些关系可以用于定量化学品安全评估。我们预计，这个AOP网络将为其他遗传毒性相关AOP提供构建模块，并有助于设计新的遗传毒性综合检测方法。
The Genetic Toxicology Technical Committee (GTTC) of the Health and Environmental Sciences Institute (HESI) is developing adverse outcome pathways (AOPs) that describe modes of action leading to potentially heritable genomic damage. The goal was to enhance the use of mechanistic information in genotoxicity assessment by building empirical support for the relationships between relevant molecular initiating events (MIEs) and regulatory endpoints in genetic toxicology. Herein, we present an AOP network that links oxidative DNA damage to two adverse outcomes (AOs): mutations and chromosomal aberrations. We collected empirical evidence from the literature to evaluate the key event relationships between the MIE and the AOs, and assessed the weight of evidence using the modified Bradford‐Hill criteria for causality. Oxidative DNA damage is constantly induced and repaired in cells given the ubiquitous presence of reactive oxygen species and free radicals. However, xenobiotic exposures may increase damage above baseline levels through a variety of mechanisms and overwhelm DNA repair and endogenous antioxidant capacity. Unrepaired oxidative DNA base damage can lead to base substitutions during replication and, along with repair intermediates, can also cause DNA strand breaks that can lead to mutations and chromosomal aberrations if not repaired adequately. This AOP network identifies knowledge gaps that could be filled by targeted studies designed to better define the quantitative relationships between key events, which could be leveraged for quantitative chemical safety assessment. We anticipate that this AOP network will provide the building blocks for additional genotoxicity‐associated AOPs and aid in designing novel integrated testing approaches for genotoxicity.
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