Oxidative Stress in Developmental Origins of Disease: Teratogenesis, Neurodevelopmental Deficits, and Cancer
Oxidative Stress in Developmental Origins of Disease: Teratogenesis, Neurodevelopmental Deficits, and Cancer
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DOI：
10.1093/toxsci/kfn263
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发表时间：
2009-03-01
影响因子：
3.8
通讯作者：
Wong, Andrea W.
中科院分区：
文献类型：
--
作者：
Wells, Peter G.;McCallum, Gordon P.;Wong, Andrea W.
在发育中的胚胎和胎儿中，内源性或外源性增强的活性氧（ROS）（如羟基自由基）的形成可能会通过氧化损伤细胞脂质、蛋白质和DNA和/或改变信号转导而对发育产生不利影响。产后后果可能包括一系列出生缺陷（致畸）、产后功能缺陷和疾病。在动物模型中，子宫内暴露于沙利度胺、甲基苯丙胺、苯妥英、苯并[a]芘和电离辐射等药物的不良发育后果可以通过改变控制胚胎ROS平衡的途径来调节，包括将内源性底物和外源性物质生物激活为自由基中间体的酶、解毒ROS的抗氧化酶以及修复氧化DNA损伤的酶。通过 Ras、核因子 kappa B 和相关传感器的 ROS 介导的信号传导也可能有助于改变发育。自由基自旋捕获剂和抗氧化剂可以减少胚胎病，而谷胱甘肽消耗则可以增强胚胎病。在体内和/或胚胎培养中评估此类机制的进一步调节方法包括使用基因敲除小鼠、转基因敲入和酶活性改变的突变缺陷小鼠，以及反义寡核苷酸、抗氧化酶的蛋白质治疗、必需辅因子的饮食消耗和化学酶抑制剂。在少数情况下，预期的保护性措施反而增加了不良发育结果的风险，表明发育的复杂性以及在人类测试治疗策略时需要谨慎。更好地了解 ROS 对发育的影响可能为风险评估和减少不良产后后果提供见解。
In the developing embryo and fetus, endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS) like hydroxyl radicals may adversely alter development by oxidatively damaging cellular lipids, proteins and DNA, and/or by altering signal transduction. The postnatal consequences may include an array of birth defects (teratogenesis), postnatal functional deficits, and diseases. In animal models, the adverse developmental consequences of in utero exposure to agents like thalidomide, methamphetamine, phenytoin, benzo[a] pyrene, and ionizing radiation can be modulated by altering pathways that control the embryonic ROS balance, including enzymes that bioactivate endogenous substrates and xenobiotics to free radical intermediates, antioxidative enzymes that detoxify ROS, and enzymes that repair oxidative DNA damage. ROS-mediated signaling via Ras, nuclear factor kappa B and related transducers also may contribute to altered development. Embryopathies can be reduced by free radical spin trapping agents and antioxidants, and enhanced by glutathione depletion. Further modulatory approaches to evaluate such mechanisms in vivo and/or in embryo culture have included the use of knockout mice, transgenic knock-ins and mutant deficient mice with altered enzyme activities, as well as antisense oligonucleotides, protein therapy with antioxidative enzymes, dietary depletion of essential cofactors and chemical enzyme inhibitors. In a few cases, measures anticipated to be protective have conversely enhanced the risk of adverse developmental outcomes, indicating the complexity of development and need for caution in testing therapeutic strategies in humans. A better understanding of the developmental effects of ROS may provide insights for risk assessment and the reduction of adverse postnatal consequences.