Oxidative DNA damage and repair in teratogenesis and neurodevelopmental deficits.
Oxidative DNA damage and repair in teratogenesis and neurodevelopmental deficits.
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DOI：
10.1002/bdrc.20177
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发表时间：
2010-06
期刊：
影响因子：
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通讯作者：
P. G. Wells;G. McCallum;Kyla Lam;J. Henderson;S. L. Ondovcik
中科院分区：
文献类型：
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作者：
P. G. Wells;G. McCallum;Kyla Lam;J. Henderson;S. L. Ondovcik
几种致畸物质，包括电离辐射和外源物质，如苯妥英、苯并[a]芘、沙利度胺和甲基苯丙胺，都可以引发活性氧物种(ROS)的形成，从而氧化损伤包括DNA在内的细胞大分子。氧化性DNA损伤，特别是最常见的8-氧鸟嘌呤损伤，可能会通过基因转录的改变而不是突变机制对发育产生不利影响。氧化性DNA损伤的贡献不排除其他启动机制的作用，如受体介导的过程或形成共价的异物-大分子加合物，对其他大分子靶标的损伤，如蛋白质和脂类，以及ROS的其他作用，如信号转导的改变。即使在没有致畸物质暴露的情况下，如果缺乏解毒ROS或修复DNA损伤的关键途径，内源性发育氧化应激也会产生胚胎病态后果。DNA损伤检测/修复信号通路中的关键蛋白，如p53和共济失调毛细血管扩张发生突变，以及DNA修复本身，如氧鸟嘌呤糖基酶1和Cockayne综合征B，经常但不总是可以保护胚胎免受ROS启动的畸形菌的影响。保护可能取决于不同的因素，如畸胎原的性质及其在胚胎中的浓度、发育阶段、物种、品系、性别、目标组织和细胞类型等因素。
Several teratogenic agents, including ionizing radiation and xenobiotics such as phenytoin, benzo[a]pyrene, thalidomide, and methamphetamine, can initiate the formation of reactive oxygen species (ROS) that oxidatively damage cellular macromolecules including DNA. Oxidative DNA damage, and particularly the most prevalent 8-oxoguanine lesion, may adversely affect development, likely via alterations in gene transcription rather than via a mutational mechanism. Contributions from oxidative DNA damage do not exclude roles for alternative mechanisms of initiation like receptor-mediated processes or the formation of covalent xenobiotic-macromolecular adducts, damage to other macromolecular targets like proteins and lipids, and other effects of ROS like altered signal transduction. Even in the absence of teratogen exposure, endogenous developmental oxidative stress can have embryopathic consequences in the absence of key pathways for detoxifying ROS or repairing DNA damage. Critical proteins in pathways for DNA damage detection/repair signaling, like p53 and ataxia telangiectasia mutated, and DNA repair itself, like oxoguanine glycosylase 1 and Cockayne syndrome B, can often, but not always, protect the embryo from ROS-initiating teratogens. Protection may be variably dependent upon such factors as the nature of the teratogen and its concentration within the embryo, the stage of development, the species, strain, gender, target tissue and cell type, among other factors.