Reduced Fertility in Female Mice Lacking Copper-Zinc Superoxide Dismutase

Abstract

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.

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

“…The SOD1-/-and WT mice were generated from 129SVJ × C57BL/6 mice [1]. All used mice were 8-10 weeks old and were fed a diet containing adequate levels of all required nutrients.…”

“…Keywords SOD1; Protein nitration; Acetaminophen; Peroxynitrite; Lipopolysaccharide; Mouse Although copper,zinc-superoxide dismutase (SOD1) has been widely considered a major intracellular antioxidant enzyme in mammals, its solely known function is to catalyze the conversion of superoxide anion into less active hydrogen peroxide. Indeed, SOD1 is protective against oxidative stress associated with acute paraquat toxicity, myocardial ischemia/reperfusion injury, and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration [1][2][3]. Mice deficient in SOD1 develop Address correspondence to: Xin Gen Lei, Department of Animal Science, Cornell University, Ithaca, NY 14853, Tel.…”

“…The extremely short biological half-life of peroxynitrite [32] and the lack of specific in vivo models have made such a test very difficult, if not impossible. The development of SOD1 knockout (SOD1-/-) mice [1] and the demonstration of several drugs such as APAP to induce protein nitration in tissues [24,25,33,34] provide us with an unprecedented opportunity to study the in vivo role of SOD1 in nitrotyrosine formation. Furthermore, the application of mass spectrometry allows identification of specific nitrated protein candidates in tissue homogenates and particular residues in selected proteins.…”

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

“…This suggests that elevated levels of ROS are not the actual cause of the disease because SOD activity is increased in the transgenic mice. Subsequently, SOD1 knockout mice have been generated by several groups [11][12][13]. Unexpectedly, SOD1 −/− mice grow normally but develop female infertility [12,13], cochlear hair cell loss [14] and vascular dysfunction [15].…”

“…Subsequently, SOD1 knockout mice have been generated by several groups [11][12][13]. Unexpectedly, SOD1 −/− mice grow normally but develop female infertility [12,13], cochlear hair cell loss [14] and vascular dysfunction [15]. This is in sharp contrast with SOD2 −/− mice that die of dilated cardiomyopathy during the neonatal stage [16].…”