Role of glutathione peroxidase in protecting mammalian spermatozoa from loss of motility caused by spontaneous lipid peroxidation

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<jats:title>Abstract</jats:title><jats:p>Mouse and human spermatozoa, but not rabbit spermatozoa, have long been known to be sensitive to loss of motility induced by exogenous H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>. Recent work has shown that loss of sperm motility in these species correlates with the extent of spontaneous lipid peroxidation. In this study, the effect of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> on this reaction in sperm of the three species was investi gated. The rate of spontaneous lipid peroxidation in mouse and human sperm is markedly enhanced in the presence of 1‐5 mM H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>, while the rate in rabbit sperm is unaffected by H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>. The enhancement of lipid peroxidation, the rate of reaction of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> with the cells, the activity of sperm glutathione peroxidase, and the endogenous glutathione content are highest in mouse sperm, intermediate in human sperm, and very low in rabbit sperm. Inac tivation of glutathione peroxidase occurs in the presence of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> due to complete conver sion of endogenous glutathione to GSSG: No GSH is available as electron donor substrate to the peroxidase. Inactivation of glutathione peroxidase by the inhibitor mercaptosucci nate has the same effect on rate of lipid peroxidation and loss of motility in mouse and human sperm as does H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>. This implies that H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> by itself at 1‐5 mM is not intrinsically toxic to the cells. With merceptosuccinate, the endogenous glutathione is present as GSH in mouse and human sperm, indicating that the redox state of intracellular glutathione by itself plays little role in protecting the cell against spontaneous lipid peroxidation. Mouse and human sperm also have high rates of superoxide production. We conclude that the key intermediate in spontaneous lipid peroxidation is lipid hydroperoxide generated by a chain reaction initiated by and utilizing superoxide. Removal of this hydroperoxide by gluta thione peroxidase protects these sperm against peroxidation; inactivation of the peroxidase allows lipid hydroperoxide to increase and so increases the peroxidation rate. Rabbit sperm have low rates of superoxide reaction due to high activity of their superoxide dismutase; lack of endogenous glutathione and low peroxidase activity does not affect their rate or lipid peroxidation. As a result, these sperm are not affected by either H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> or mercapto‐succinate. These results lead us to postulate a mechanism for spontaneous lipid peroxida tion in mammalian sperm which involves reaction of lipid hydroperoxide and O<jats:sub>2</jats:sub> as the rate‐determining step.</jats:p>

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