Oxidative stress and male reproductive biology
R. John Aitken A B and Mark A. Baker A
+ Author Affiliations
- Author Affiliations
A ARC Centre of Excellence in Biotechnology and Development and Reproductive Science Group, Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, Callaghan, NSW 2308, Australia.
B To whom correspondence should be addressed. email: jaitken@mail.newcastle.edu.au
Reproduction, Fertility and Development 16(5) 581-588 https://doi.org/10.1071/RD03089
Submitted: 13 October 2003 Accepted: 12 November 2003 Published: 22 July 2004
Abstract
Spermatozoa were the first cell type in which the cellular generation of reactive oxygen was demonstrated. This activity has now been confirmed in spermatozoa from all mammalian species examined including the rat, mouse, rabbit, horse, bull and human being. Under physiological circumstances, cellular redox activity is thought to drive the cAMP-mediated, tyrosine phosphorylation events associated with sperm capacitation. In addition to this biological role, human spermatozoa also appear to suffer from oxidative stress, with impacts on the normality of their function and the integrity of their nuclear and mitochondrial DNA. Recent studies have helped to clarify the molecular basis for the intense redox activity observed in defective human spermatozoa, the nature of the subcellular structures responsible for this activity and possible mechanisms by which oxidative stress impacts on these cells. Given the importance of oxidative damage in the male germ line to the origins of male infertility, early pregnancy loss and childhood disease, this area of sperm biochemistry deserves attention from all those interested in improved methods for the diagnosis, management and prevention of male-mediated reproductive failure.
References
Aitken, R. J. (1994). A free radical theory of male infertility. Reprod. Fertil. Dev. 6, 19–24.
| PubMed |
Aitken, R. J. (1999). The human spermatozoon: a cell in crisis? The Amoroso lecture. J. Reprod. Fertil. 115, 1–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , and Clarkson, J. S. (1987). Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa. J. Reprod. Fertil. 81, 459–469.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , and Fisher, H. (1994). Reactive oxygen species generation and human spermatozoa: the balance of benefit and risk Bioessays 16, 259–267.
| PubMed |
Aitken, R. J. , and Marshall Graves, J. A. (2002). The future of sex. Nature 415, 963.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , and Sawyer, D. W. (2003). The human spermatozoon: not waving but drowning. Adv. Exp. Med. Biol. 518, 85–99.
| PubMed |
Aitken, R. J. , Ross, A. , Hargreave, T. , Richardson, D. , and Best, F. (1984). Analysis of human sperm function following exposure to the ionophore A23187. Comparison of normospermic and oligozoospermic men. J. Androl. 5, 321–329.
| PubMed |
Aitken, R. J. , Sutton, M. , Warner, P. , and Richardson, D. W. (1985). Relationship between the movement characteristics of human spermatozoa and their ability to penetrate cervical mucus and zona-free hamster oocytes. J. Reprod. Fertil. 73, 441–449.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , Clarkson, J. S. , and Fishel, S. (1989a). Generation of reactive oxygen species, lipid peroxidation and human sperm function. Biol. Reprod. 41, 183–187.
| PubMed |
Aitken, R. J. , Clarkson, J. S. , Hargreave, T. B. , Irvine, D. S. , and Wu, F. C. W. (1989b). Analysis of the relationship between defective sperm function and the generation of reactive oxygen species in cases of oligozoospermia. J. Androl. 10, 214–220.
| PubMed |
Aitken, R. J. , Buckingham, D. , and Harkiss, D. (1993a). Use of a xanthine oxidase oxidant generating system to investigate the cytotoxic effects of reactive oxygen species on human spermatozoa. J. Reprod. Fertil. 97, 441–450.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , Harkiss, D. , and Buckingham, D. (1993b). Relationship between iron-catalysed lipid peroxidation potential and human sperm function. J. Reprod. Fertil. 98, 257–265.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , Harkiss, D. , and Buckingham, D. W. (1993c). Analysis of lipid peroxidation mechanisms in human spermatozoa. Mol. Reprod. Dev. 35, 302–315.
| PubMed |
Aitken, R. J. , Buckingham, D. , and Harkiss, D. (1994). Analysis of the extent to which sperm movement can predict the results of ionophore-enhanced functional assays of the acrosome reaction and sperm-oocyte fusion. Hum. Reprod. 9, 1867–1874.
| PubMed |
Aitken, R. J. , Buckingham, D. W. , Brindle, J. , Gomez, E. , Baker, H. W. , and Irvine, D. S. (1995a). Analysis of sperm movement in relation to the oxidative stress created by leukocytes in washed sperm preparations and seminal plasma. Hum. Reprod. 10, 2061–2071.
| PubMed |
Aitken, R. J. , Paterson, M. , Fisher, H. , Buckingham, D. W. , and van Duin, M. (1995b). Redox regulation of tyrosine phosphorylation in human spermatozoa and its role in the control of human sperm function. J. Cell Sci. 108, 2017–2025.
| PubMed |
Aitken, R. J. , Buckingham, D. W. , Carreras, A. , and Irvine, D. S. (1996). Superoxide dismutase in human sperm suspensions: relationships with cellular composition, oxidative stress and sperm function. Free Rad. Biol. Med. 21, 495–504.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , Fisher, H. , Fulton, N. , Knox, W. , and Lewis, B. (1997). Reactive oxygen species generation by human spermatozoa is induced by exogenous NADPH and inhibited by the flavoprotein inhibitors diphenylene iodonium and quinacrine. Mol. Reprod. Dev. 47, 468–482.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Aitken, R. J. , Gordon, E. , Harkiss, D. , Twigg, J. P. , Milne, P. , Jennings, Z. , and Irvine, D. S. (1998a). Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol. Reprod. 59, 1037–1046.
| PubMed |
Aitken, R. J. , Harkiss, D. , Knox, W. , Paterson, M. , and Irvine, D. S. (1998b). A novel signal transduction cascade in capacitating human spermatozoa characterized by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation. J. Cell Sci. 111, 645–656.
| PubMed |
Aitken, R. J. , Baker, M. A. , and Sawyer, D. (2003a). Oxidative stress in the male germ line and its role in the aetiology of male infertility and genetic disease. Reprod. Biomed. Online 7, 65–70.
| PubMed |
Aitken, R. J. , Ryan, A. L. , Curry, B. J. , and Baker, M. A. (2003b). Multiple forms of redox activity in populations of human spermatozoa. Mol. Hum. Reprod. 9, 645–661.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Alvarez, J. G. , Touchstone, J. C. , Blasco, L. , and Storey, B. T. (1987). Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa J. Androl. 8, 338–348.
| PubMed |
Baker, M. A. , Krutskikh, A. , and Aitken, R. J. (2003). The biochemical entities involved in reactive oxygen species generation by human spermatozoa. Protoplasma 221, 145–151.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Banfi, B. , Molnar, G. , Maturana, A. , Steger, K. , Hegedus, B. , Demaurex, N. , and Krause, K. H. (2001). A Ca2+-activated NADPH oxidase in testes, spleen, and lymph nodes. J. Biol. Chem. 276, 37594–37601.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Bell, M. , Sikka, S. , Rajasekaran, M. , and Hellstrom, W. (1992). Time course of hydrogen peroxide induced changes in the lipid peroxidation of human sperm membranes. Adv. Contracept. Deliv. Syst. 8, 144–150.
| PubMed |
Bianchi, P. G. , Manicardi, G. C. , Bizzaro, D. , Bianchi, U. , and Sakkas, D. (1993). Effect of deoxyribonucleic acid protamination on fluorochrome staining and in situ nick-translation of murine and human mature spermatozoa. Biol. Reprod. 49, 1083–1088.
| PubMed |
Casano, R. , Orlando, C. , Serio, M. , and Forti, G. (1991). LDH and LDH-X activity in sperm from normospermic and oligozoospermic men. Int. J. Androl. 14, 257–263.
| PubMed |
Chapman, D. A. , Killian, G. J. , Gelerinter, E. , and Jarrett, M. T. (1985). Reduction of the spin-label TEMPONE by ubiquinol in the electron transport chain of intact rabbit spermatozoa. Biol. Reprod. 32, 884–893.
| PubMed |
Cummins, J. M. , Pember, S. M. , Jequier, A. M. , Yovich, J. L. , and Hartmann, P. E. (1991). A test of the human sperm acrosome reaction following ionophore challenge. Relationship to fertility and other seminal parameters. J. Androl. 12, 98–103.
| PubMed |
Cummins, J. M. , Jequier, A. M. , and Kan, R. (1994). Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress. Mol. Reprod. Dev. 37, 345–362.
| PubMed |
de Lamirande, E. , and Gagnon, C. (1992). Reactive oxygen species and human spermatozoa. II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. J. Androl. 13, 379–386.
| PubMed |
Engel, S. , Schreiner, T. , and Petzoldt, R. (1999). Lipid peroxidation in human spermatozoa and maintenance of progressive sperm motility. Andrologia 31, 17–22.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Ezra, Y. , and Schenker, J. G. (1995). Abortion rate in assisted reproduction – true increase? Early Pregnancy 1, 171–175.
| PubMed |
Fraga, C. G. , Motchnik, P. A. , Wyrobek, A. J. , Rempel, D. M. , and Ames, B. N. (1996). Smoking and low antioxidant levels increase oxidative damage to DNA. Mutat. Res. 351, 199–203.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Gaspari, L. , Chang, S. S. , Santella, R. M. , Garte, S. , Pedotti, P. , and Taioli, E. (2003). Polycyclic aromatic hydrocarbon-DNA adducts in human sperm as a marker of DNA damage and infertility. Mutat. Res. 535, 155–160.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Gomez, E. , Buckingham, D. W. , Brindle, J. , Lanzafame, F. , Irvine, D. S. , and Aitken, R. J. (1996). Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress and sperm function. J. Androl. 17, 276–287.
| PubMed |
Gomez, E. , Irvine, D. S. , and Aitken, R. J. (1998). Evaluation of a spectrophotometric assay for the measurement of malondialdehyde and 4-hydroxyalkenals in human spermatozoa: relationships with semen quality and sperm function. Int. J. Androl. 21, 81–94.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Halliwell, B., and Gutteridge, J. M. (2003).
Holland, M. K. , and Storey, B. T. (1981). Oxygen metabolism of mammalian spermatozoa. Generation of hydrogen peroxide by rabbit epididymal spermatozoa. Biochem. J. 198, 273–280.
| PubMed |
Horak, S. , Polanska, J. , and Widlak, P. (2003). Bulky DNA adducts in human sperm: relationship with fertility, semen quality, smoking, and environmental factors. Mutat. Res. 537, 53–65.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Hull, M. G. R. , Glazener, C. M. A. , Kelly, N. J. , Conway, D. I. , Foster, P. A. , Hunton, R. A. , Coulson, C. , Lambert, P. A. , Watt, E. M. , and Desai, K. M. (1985). Population study of causes, treatment and outcome of infertility. BMJ 291, 1693–1697.
| PubMed |
Huszar, G. , Vigue, L. , and Corrales, M. (1988). Sperm creatine phosphokinase quality in normospermic, variablespermic and oligospermic men. Biol. Reprod. 38, 1061–1066.
| PubMed |
Ichikawa, T. , Oeda, T. , Ohmori, H. , and Schill, W. B. (1999). Reactive oxygen species influence the acrosome reaction but not acrosin activity in human spermatozoa. Int. J. Androl. 22, 37–42.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Irvine, D. S. , Twigg, J. , Gordon, E. , Fulton, N. , Milne, P. , and Aitken, R. J. (2000). DNA integrity in human spermatozoa: relationship with semen quality. J. Androl. 21, 33–44.
| PubMed |
Ji, B. T. , Shu, X. O. , Linet, M. S. , Zheng, W. , Wacholder, S. , Gao, Y. T. , Ying, D. M. , and Jin, F. (1997). Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J. Nat. Cancer Inst. 89, 238–244.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Jones, R. , Mann, T. , and Sherins, R. (1979). Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma. Fertil. Steril. 31, 531–537.
| PubMed |
Keating, J. , Grundy, C. E. , Fivey, P. S. , Elliott, M. , and Robinson, J. (1997). Investigation of the association between the presence of cytoplasmic residues on the human sperm midpiece and defective sperm function. J. Reprod. Fertil. 110, 71–77.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Lapointe, S. , and Sirard, M. A. (1998). Catalase and oviductal fluid reverse the decreased motility of bovine sperm in culture medium containing specific amino acids. J. Androl. 19, 31–36.
| PubMed |
Leclerc, P. , de Lamirande, E. , and Gagnon, C. (1997). Regulation of protein-tyrosine phosphorylation and human sperm capacitation by reactive oxygen derivatives. Free Rad. Biol. Med. 22, 643–656.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Liu, D. Y. , and Baker, H. W. G. (1994). A new test for the assessment of sperm-zona pellucida penetration: relationship with results of other sperm tests and fertilization in vitro. Hum. Reprod. 9, 489–496.
| PubMed |
MacLeod, J. (1943). The role of oxygen in the metabolism and motility of human spermatozoa. Am. J. Physiol. 138, 512–518.
Morris, I. D. , Ilott, S. , Dixon, L. , and Brison, D. R. (2002). The spectrum of DNA damage in human sperm assessed by single cell gel electrophoresis (Comet assay) and its relationship to fertilization and embryo development. Hum. Reprod. 17, 990–998.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Oehninger, S. , Blackmore, P. , Mahony, M. , and Hodgen, G. (1995). Effects of hydrogen peroxide on human spermatozoa. J. Assist. Reprod. Genet. 12, 41–47.
| PubMed |
Richer, S. C. , and Ford, W. C. (2001). A critical investigation of NADPH oxidase activity in human spermatozoa. Mol. Hum. Reprod. 7, 237–244.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Saleh, R. A. , and Agarwal, A. (2002). Oxidative stress and male infertility: from research bench to clinical practice. J. Androl. 23, 737–752.
| PubMed |
Sawyer, D. E. , Mercer, B. G. , Wiklendt, A. M. , and Aitken, R. J. (2003). Quantitative analysis of gene-specific DNA damage in human spermatozoa. Mutat. Res. 529, 21–34.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Storey, B. T. (1997). Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa. Mol. Hum. Reprod. 3, 203–213.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Suleiman, S. A. , Elamin Ali, M. , Zaki, Z. M. S. , El-Malik, E. M. A. , and Nasr, M. A. (1996). Lipid peroxidation and human sperm motility: protective role of vitamin E. J. Androl. 17, 530–537.
| PubMed |
Tosic, J. , and Walton, A. (1946). Formation of hydrogen peroxide by spermatozoa and its inhibitory effect on respiration. Nature 158, 485.
Twigg, J. , Irvine, D. S. , and Aitken, R. J. (1998). Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection. Hum. Reprod. 13, 1429–1436.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Upreti, G. C. , Jensen, K. , Munday, R. , Duganzich, D. M. , Vishwanath, R. , and Smith, J. F. (1998). Studies on aromatic amino acid oxidase activity in ram spermatozoa: role of pyruvate as an antioxidant. Anim. Reprod. Sci. 51, 275–287.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Vernet, P. , Fulton, N. , Wallace, C. , and Aitken, R. J. (2001). Analysis of a plasma membrane redox system in rat epididymal spermatozoa. Biol. Reprod. 65, 1102–1113.
| PubMed |
Zabludovsky, N. , Eltes, F. , Geva, E. , Berkovitz, E. , Amit, A. , Barak, Y. , Har-Even, D. , and Bartoov, B. (1999). Relationship between human sperm lipid peroxidation, comprehensive quality parameters and IVF outcome. Andrologia 31, 91–98.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zalata, A. A. , Lammertijn, N. , Christophe, A. , and Comhaire, F. H. (1998). The correlates and alleged biochemical background of the resazurin reduction test in semen. Int. J. Androl. 21, 289–294.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zini, A. , O’Bryan, M. K. , Israel, L. , and Schlegel, P. N. (1998). Human sperm NADH and NADPH diaphorase cytochemistry: correlation with sperm motility. Urology 51, 464–468.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zini, A. , Buckspan, M. , Jamal, M. , and Jarvi, K. (1999). Effect of varicocelectomy on the abnormal retention of residual cytoplasm by human spermatozoa. Hum. Reprod. 14, 1791–1793.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zini, A. , Defreitas, G. , Freeman, M. , Hechter, S. , and Jarvi, K. (2000). Varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa. Fertil. Steril. 74, 461–464.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zini, A. , Bielecki, R. , Phang, D. , and Zenzes, M. T. (2001). Correlations between two markers of sperm DNA integrity, DNA denaturation and DNA fragmentation, in fertile and infertile men. Fertil. Steril. 75, 674–677.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Zouari, R. , De Almeida, M. , Rodrigues, D. , and Jouannet, P. (1993). Localization of antibodies on spermatozoa and sperm movement characteristics are good predictors of in vitro fertilization success in cases of male autoimmune infertility. Fertil. Steril. 59, 606–612.
| PubMed |
