Biol Reprod Keystone Symposia Conference on Frontiers in Reproductive Biology & Regulation of Fertility.
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BOR - Papers in Press, published online ahead of print June 9, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.028407
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BIOLOGY OF REPRODUCTION 71, 1309–1316 (2004)
DOI: 10.1095/biolreprod.104.028407
© 2004 by the Society for the Study of Reproduction, Inc.

Gamete Biology

Functional Significance of the Pentose Phosphate Pathway and Glutathione Reductase in the Antioxidant Defenses of Human Sperm1

A.C. Williams, and W.C.L. Ford2

University Division of Obstetrics & Gynaecology, St Michael's Hospital, Bristol BS2 8EG, United Kingdom

Glutathione peroxidase is one of the principal antioxidant defense enzymes in human spermatozoa, but it requires oxidized glutathione to be reduced by glutathione reductase using NADPH generated in the pentose phosphate pathway. We investigated whether flux through the pentose phosphate pathway would increase in response to oxidative stress and whether glutathione reductase was required to protect sperm from oxidative damage. Isotopic measurements of the pentose phosphate pathway and glycolytic flux, thiobarbituric acid assay of malondialdehyde for lipid peroxidation, and computer-assisted sperm analysis for sperm motility were assessed in a group of normal, healthy semen donors. Applying moderate oxidative stress to human spermatozoa by adding cumene hydroperoxide, H2O2, or xanthine plus xanthine oxidase or by promoting lipid peroxidation with ascorbate increased flux through the pentose phosphate pathway without changing the glycolytic rate. However, adding higher concentrations of oxidants inhibited both the pentose phosphate pathway and glycolytic flux. At concentrations of 50 µg/ml or greater, the glutathione reductase-inhibitor 1,3-bis-(2-chloroethyl) 1-nitrosourea decreased flux through the pentose phosphate pathway and blocked the response to cumene hydroperoxide. It also increased lipid peroxidation and impaired the survival of motility in sperm incubated under 95% O2. These data show that the pentose phosphate pathway in human spermatozoa can respond dynamically to oxidative stress and that inhibiting glutathione reductase impairs the ability of sperm to resist lipid peroxidation. We conclude that the glutathione peroxidase-glutathione reductase-pentose phosphate pathway system is functional and provides an effective antioxidant defense in normal human spermatozoa.

1 Supported by a grant from the Wellcome Trust.

2 Correspondence: W.C.L. Ford, University Division of Obstetrics & Gynaecology, St Michael's Hospital, Southwell Street, Bristol BS2 8EG, U.K. FAX: 44 117 9285290; chris.ford{at}bristol.ac.uk






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Copyright © 2004 by the Society for the Study of Reproduction.