Reduced fertility in female mice lacking copper-zinc superoxide dismutase
Reduced fertility in female mice lacking copper-zinc superoxide dismutase
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DOI：
10.1074/jbc.273.13.7765
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发表时间：
1998-03-27
影响因子：
4.8
通讯作者：
Hutz, RJ
中科院分区：
文献类型：
--
作者：
Ho, YS;Gargano, M;Hutz, RJ
铜锌超氧化物歧化酶（CuZn-SOD）被认为在抗氧化防御的第一线中起主要作用，其催化超氧阴离子自由基歧化以形成过氧化氢和分子氧。最近的研究表明，该基因的错义突变显然通过功能获得机制导致了约20%的家族性肌萎缩侧索硬化症。为了进一步确定这种酶的生理作用，使用基因靶向技术产生了这种酶缺陷的小鼠模型。缺乏这种酶的小鼠显然是健康的，对高氧的敏感性没有增加，但是，它们对百草枯毒性表现出明显的敏感性。最令人惊讶的是，与野生型和杂合基因敲除小鼠相比，雌性纯合基因敲除小鼠显示出显著降低的生育力。进一步的研究表明，尽管这些小鼠正常排卵和受孕，但它们表现出显著增加的胚胎致死率。这些数据首次表明氧自由基在导致哺乳动物雌性生殖异常中的作用。
Copper-zinc superoxide dismutase (CuZn-SOD) is believed to play a major role in the first line of antioxidant defense by catalyzing the dismutation of superoxide anion radicals to form hydrogen peroxide and molecular oxygen. Recent studies have shown that missense mutations in this gene contribute, evidently through a gain-of-function mechanism, to about 20% of familial amyotrophic lateral sclerosis. To define further the physiologic role of this enzyme, a model of mice deficient in this enzyme was generated using gene targeting technology. Mice lacking this enzyme were apparently healthy and displayed no increased sensitivity to hyperoxia, However, they exhibited a pronounced susceptibility to paraquat toxicity. Most surprisingly, female homozygous knock out mice showed a markedly reduced fertility compared with that of wild-type and heterozygous knock-out mice, Further studies revealed that although these mice ovulated and conceived normally, they exhibited a marked increase in embryonic lethality. These data, for the first time, suggest a role of oxygen free radicals in causing abnormality of female reproduction in mammals.