Oxidative DNA damage in the in utero initiation of postnatal neurodevelopmental deficits by normal fetal and ethanol-enhanced oxidative stress in oxoguanine glycosylase 1 knockout mice
Oxidative DNA damage in the in utero initiation of postnatal neurodevelopmental deficits by normal fetal and ethanol-enhanced oxidative stress in oxoguanine glycosylase 1 knockout mice
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DOI：
10.1016/j.freeradbiomed.2014.09.026
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发表时间：
2015-01-01
影响因子：
7.4
通讯作者：
Wells, Peter G.
中科院分区：
文献类型：
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作者：
Miller-Pinsler, Lutfiya;Pinto, Daniel J.;Wells, Peter G.
对缺乏抗氧化酶的小鼠的研究表明，生理水平的活性氧（ROS）会对发育中的胚胎和胎儿产生不利影响。在本文中，缺乏氧化DNA损伤8-氧代-2 '-脱氧鸟苷（8-oxodGuo）修复的氧代鸟嘌呤糖基化酶1（ogg 1）敲除小鼠的DNA修复缺陷后代表现出增强的出生后神经发育缺陷，揭示了8-oxodGuo由胎脑中生理性ROS产生引发的致病潜力，并为ogg 1敲除小鼠的病理表型提供了第一个证据。此外，当暴露在子宫内的乙醇（EtOH），ogg 1基因敲除后代表现出较高水平的8-oxodGuo在胎脑和更严重的出生后神经发育缺陷比野生型同窝仔，这两者都被阻断预处理与自由基捕获剂苯基丁基硝酮。这些结果表明，ROS引发的DNA氧化，不同于改变信号转导，有助于子宫内EtOH暴露引起的神经发育缺陷，胎儿DNA修复是风险的决定因素。(C)2014 Elsevier Inc. All rights reserved.
Studies in mice with deficient antioxidative enzymes have shown that physiological levels of reactive oxygen species (ROS) can adversely affect the developing embryo and fetus. Herein, DNA repair-deficient progeny of oxoguanine glycosylase 1 (ogg1)-knockout mice lacking repair of the oxidative DNA lesion 8-oxo-2'-deoxyguanosine (8-oxodGuo) exhibited enhanced postnatal neurodevelopmental deficits, revealing the pathogenic potential of 8-oxodGuo initiated by physiological ROS production in fetal brain and providing the first evidence of a pathological phenotype for ogg1-knockout mice. Moreover, when exposed in utero to ethanol (EtOH), ogg1-knockout progeny exhibited higher levels of 8-oxodGuo in fetal brain and more severe postnatal neurodevelopmental deficits than wild-type littermates, both of which were blocked by pretreatment with the free radical trapping agent phenylbutylnitrone. These results suggest that ROS-initiated DNA oxidation, as distinct from altered signal transduction, contributes to neurodevelopmental deficits caused by in utero EtOH exposure, and fetal DNA repair is a determinant of risk. (C) 2014 Elsevier Inc. All rights reserved.