Bhuller Yadvinder, Wells Peter G
Faculty of Pharmacy, and Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Toxicol Sci. 2006 Sep;93(1):156-63. doi: 10.1093/toxsci/kfl045. Epub 2006 Jun 21.
Ataxia-telangiectasia (A-T) is characterized by impaired recognition and repair of DNA damage and increased sensitivity to ionizing radiation (IR), cancer, and neurodegeneration. We previously showed pregnant knockout mice lacking the A-T gene product ataxia-telangiectasia mutated (Atm) are highly susceptible to the embryopathic effects of IR, which damages DNA, possibly via generation of reactive oxygen species (ROS). Here we show that Atm more broadly protects against both spontaneous and phenytoin-enhanced embryopathies. In the absence of drug exposure, cultured embryos from pregnant Atm knockout mice showed more embryopathies than wild-type littermates, with a gene dose-dependent decrease in susceptibility from -/- to +/- to +/+ embryos (p < 0.05). A similar but significantly enhanced gene dose-dependent pattern of embryopathic susceptibility was evident in Atm knockout embryos exposed to the ROS-initiating teratogen phenytoin (p < 0.05). These results provide the first evidence that Atm has a broad developmental importance beyond IR embryopathies, possibly by protecting the embryo from constitutive and xenobiotic-enhanced oxidative stress, with even heterozygotes showing increased risk. This developmental role of Atm further implicates DNA damage in ROS-mediated teratogenesis and DNA damage response and repair as risk factors for individual susceptibility.
共济失调毛细血管扩张症（A-T）的特征是DNA损伤的识别和修复受损，以及对电离辐射（IR）、癌症和神经退行性变的敏感性增加。我们之前发现，缺乏A-T基因产物共济失调毛细血管扩张症突变蛋白（Atm）的怀孕基因敲除小鼠对IR的胚胎病效应高度敏感，IR可能通过产生活性氧（ROS）来损伤DNA。在此我们表明，Atm更广泛地保护胚胎免受自发性和苯妥英增强的胚胎病影响。在无药物暴露的情况下，怀孕的Atm基因敲除小鼠所培养的胚胎比野生型同窝小鼠表现出更多的胚胎病，从-/-到+/-再到+/+胚胎，易感性呈基因剂量依赖性降低（p < 0.05）。在暴露于引发ROS的致畸剂苯妥英的Atm基因敲除胚胎中，也出现了类似但显著增强的胚胎病易感性基因剂量依赖性模式（p < 0.05）。这些结果首次证明，Atm在IR胚胎病之外具有广泛的发育重要性，可能是通过保护胚胎免受内源性和外源性增强的氧化应激影响，甚至杂合子也表现出风险增加。Atm的这一发育作用进一步表明，DNA损伤在ROS介导的致畸作用以及DNA损伤反应和修复中是个体易感性的风险因素。
