Lipid Peroxidation in Human Spermatozoa

  • Juan G. Alvarez
  • R. John Aitken
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Oxidation of lipids can be a blessing or a curse as far as spermatozoa are concerned. Beatitudes are conferred via the oxidative generation of oxysterols, which then drive sperm capacitation by promoting the removal of cholesterol from the sperm plasma membrane. Conversely, the anathema involves peroxidation of polyunsaturated fatty acids (PUFA) to generate lipid peroxides that have a detrimental effect on spermatozoa, disrupting DNA integrity and limiting their competence for fertilization. Spermatozoa actively detoxify and remove toxic lipid peroxides from the sperm plasma membrane, but once these defense mechanisms have been overwhelmed, lipid peroxidation spreads rapidly through the cell leading to membrane damage, leakage of ATP, and a rapid loss of sperm motility and viability. The excessive presence of unesterified PUFA may be instrumental in the genesis of oxidative stress through the ability of these amphiphiles to interfere with the mitochondrial electron transport chain and promote cellular generation of superoxide anion.


Lipid peroxidation Human spermatozoa Induction of sperm capacitation Unsaturated fatty acids Propagation of peroxidative damage 


  1. 1.
    MacLeod J. The role of oxygen in the metabolism and motility of human spermatozoa. Am J Physiol. 1943;138:512–8.Google Scholar
  2. 2.
    Tosic J, Walton A. Formation of hydrogen peroxide by spermatozoa and its inhibitory effect on respiration. Nature. 1946;158:485.PubMedCrossRefGoogle Scholar
  3. 3.
    Aitken RJ, Curry BJ. Redox regulation of human sperm function: from the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line. Antioxid Redox Signal. 2011;14:367–81.PubMedCrossRefGoogle Scholar
  4. 4.
    Alvarez JG, Storey BT. Role of glutathione peroxidase in protecting mammalian spermatozoa from loss of motility caused by spontaneous lipid peroxidation. Gamete Res. 1989;23:77–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Aitken RJ, Gordon E, Harkiss D, Twigg JP, Milne P, Jennings Z, Irvine DS. Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol Reprod. 1998;59:1037–46.PubMedCrossRefGoogle Scholar
  6. 6.
    Aitken RJ, Harkiss D, Knox W, Paterson M, Irvine DS. A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation. J Cell Sci. 1998;111:645–56.PubMedGoogle Scholar
  7. 7.
    Gharagozloo P, Aitken RJ. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. Hum Reprod. 2011;26:1628–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN. Smoking and low antioxidant levels increase oxidative damage to DNA. Mutat Res. 1996;351:199–203.PubMedCrossRefGoogle Scholar
  9. 9.
    de Lamirande E, Gagnon C, de Lamirande E, Gagnon C. Human sperm hyperactivation and capacitation as parts of an oxidative process. Free Radic Biol Med. 1993;14:157–66.PubMedCrossRefGoogle Scholar
  10. 10.
    Griveau JF, Renard P, Le Lannou D. An in vitro promoting role for hydrogen peroxide in human sperm capacitation. Int J Androl. 1994;17:300–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Bize I, Santander G, Cabello P, Driscoll D, Sharpe C. Hydrogen peroxide is involved in hamster sperm capacitation in vitro. Biol Reprod. 1991;44:389–403.CrossRefGoogle Scholar
  12. 12.
    Aitken RJ, Ryan AL, Baker MA, McLaughlin EA. Redox activity associated with the maturation and capacitation of mammalian spermatozoa. Free Radic Biol Med. 2004;36:994–1010.PubMedCrossRefGoogle Scholar
  13. 13.
    Rivlin J, Mendel J, Rubinstein S, Etkovitz N, Breitbart H. Role of hydrogen peroxide in sperm capacitation and acrosome reaction. Biol Reprod. 2004;70:518–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Ecroyd HW, Jones RC, Aitken RJ. Endogenous redox activity in mouse spermatozoa and its role in regulating the tyrosine phosphorylation events associated with sperm capacitation. Biol Reprod. 2003;69:347–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Lewis B, Aitken RJ. A redox-regulated tyrosine phosphorylation cascade in rat spermatozoa. J Androl. 2001;22:611–22.PubMedGoogle Scholar
  16. 16.
    Brouwers JF, Boerke A, Silva PFN, Garcia-Gil N, van Gestel RA, Helms JB, van der Lest CHA, Gadella BM. Mass spectrometric detection of cholesterol oxidation in bovine sperm. Biol Reprod. 2011;85:128–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Davis BK. Influence of serum albumin on the fertilizing ability in vitro of rat spermatozoa. Proc Soc Exp Biol Med. 1976;151:240–3.PubMedGoogle Scholar
  18. 18.
    Ryan L, O’Callaghan YC, O’Brien NM. The role of the mitochondria in apoptosis induced by 7beta-hydroxycholesterol and cholesterol-5beta, 6beta-epoxide. Br J Nutr. 2005;94:519–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu H, Wang T, Huang K. Cholestane-3beta,5alpha,6 beta-triol-induced reactive oxygen ­species production promotes mitochondrial dysfunction in isolated mice liver mitochondria. Chem Biol Interact. 2009;179:81–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Laskar A, Yuan XM, Li W. Dimethyl sulfoxide prevents 7beta-hydroxycholesterol-induced apoptosis by preserving lysosomes and mitochondria. J Cardiovasc Pharmacol. 2010;56:263–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim DE, Youn YC, Kim YK, Hong KM, Lee CS. Glycyrrhizin prevents 7-ketocholesterol toxicity against differentiated PC12 cells by suppressing mitochondrial membrane permeability change. Neurochem Res. 2009;34:1433–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Aitken RJ. The capacitation-apoptosis highway: oxysterols and mammalian sperm function. Biol Reprod. 2011;85:9–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Jones R, Mann T, Sherins R. Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma. Fertil Steril. 1979;31:531–753.PubMedGoogle Scholar
  24. 24.
    Alvarez JG, Touchstone JC, Blasco L, Storey BT. Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity. J Androl. 1987;8:338–48.PubMedGoogle Scholar
  25. 25.
    Aitken RJ, Clarkson JS, Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod. 1989;41:183–97.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim YH, Haidl G, Schaefer M, Egner U, Herr JC. Compartmentalization of a unique ADP/ATP carrier protein SFEC (sperm flagellar energy carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human sperm flagellar principal piece. Dev Biol. 2007;302:463–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Alvarez JG, Storey BT. Role of superoxide dismutase in protecting rabbit spermatozoa from O2 toxicity due to lipid peroxidation. Biol Reprod. 1983;28:1129–36.PubMedCrossRefGoogle Scholar
  28. 28.
    Twigg J, Irvine DS, Houston P, Fulton N, Michael L, Aitken RJ. Iatrogenic DNA damage induced in human spermatozoa during sperm preparation: protective significance of seminal plasma. Mol Hum Reprod. 1998;4:439–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Aitken RJ, Clarkson JS. Significance of reactive oxygen species and antioxidants in defining the efficacy of sperm preparation techniques. J Androl. 1988;9:367–76.PubMedGoogle Scholar
  30. 30.
    O’Flaherty C, de Souza AR. Hydrogen peroxide modifies human sperm peroxiredoxins in a dose-dependent manner. Biol Reprod. 2011;84:238–47.PubMedCrossRefGoogle Scholar
  31. 31.
    van Overveld FW, Haenen GR, Rhemrev J, Vermeiden JP, Bast A. Tyrosine as important contributor to the antioxidant capacity of seminal plasma. Chem Biol Interact. 2000;127:151–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Rhemrev JP, van Overveld FW, Haenen GR, Teerlink T, Bast A, Vermeiden JP. Quantification of the nonenzymatic fast and slow TRAP in a post-addition assay in human seminal plasma and the antioxidant contributions of various seminal compounds. J Androl. 2000;21:913–20.PubMedGoogle Scholar
  33. 33.
    Hekman A, Rümke P. The antigens of human seminal plasma. With special reference to lactoferrin as a spermatozoa-coating antigen. Fertil Steril. 1969;20:312–23.PubMedGoogle Scholar
  34. 34.
    Holland MK, White IG. Heavy metals and human spermatozoa. III. The toxicity of copper ions for spermatozoa. Contraception. 1988;38:685–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Aitken RJ, Harkiss D, Buckingham DW. Analysis of lipid peroxidation mechanisms in human spermatozoa. Mol Reprod Dev. 1993;35:302–15.PubMedCrossRefGoogle Scholar
  36. 36.
    Gomez E, Irvine DS, Aitken RJ. 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. 1998;21:81–94.PubMedCrossRefGoogle Scholar
  37. 37.
    Aitken RJ, Harkiss D, Buckingham D. Relationship between iron-catalysed lipid peroxidation potential and human sperm function. J Reprod Fertil. 1993;98:257–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Rhemrev JP, Vermeiden JP, Haenen GR, De Bruijne JJ, Rekers-Mombarg LT, Bast A. Progressively motile human spermatozoa are well protected against in vitro lipid peroxidation imposed by induced oxidative stress. Andrologia. 2001;33:151–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Alvarez JG, Storey BT. Differential incorporation of fatty acids into and peroxidative loss of fatty acids from phospholipids of human spermatozoa. Mol Reprod Dev. 1995;42:334–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Björnstedt M, Hamberg M, Kumar S, Xue J, Holmgren A. Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols. J Biol Chem. 1995;270:11761–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Twigg J, Fulton N, Gomez E, Irvine DS, Aitken RJ. Analysis of the impact of intracellular reactive oxygen species generation on the structural and functional integrity of human spermatozoa: lipid peroxidation, DNA fragmentation and effectiveness of antioxidants. Hum Reprod. 1998;13:1429–36.PubMedCrossRefGoogle Scholar
  42. 42.
    Aitken RJ, Wingate JK, De Iuliis GN, Koppers AJ, McLaughlin EA. Cis-unsaturated fatty acids stimulate reactive oxygen species generation and lipid peroxidation in human spermatozoa. J Clin Endocrinol Metab. 2006;91:4154–63.PubMedCrossRefGoogle Scholar
  43. 43.
    Ollero M, Gil-Guzman E, Lopez MC, Sharma RK, Agarwal A, Larson K, Evenson D, Thomas Jr AJ, Alvarez JG. Characterization of subsets of human spermatozoa at different stages of maturation: implications in the diagnosis and treatment of male infertility. Hum Reprod. 2001;16:1912–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Koppers AJ, Garg ML, Aitken RJ. Stimulation of mitochondrial reactive oxygen species ­production by unesterified, unsaturated fatty acids in defective human spermatozoa. Free Radic Biol Med. 2010;48:112–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Ollero M, Powers D, Alvarez JG. Variation of docosahexaenoic acid content in subsets of human spermatozoa at different stages of maturation: implications for sperm lipoperoxidative damage. Mol Reprod Dev. 2000;55:326–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Alvarez JG, Storey BT. Spontaneous lipid peroxidation in rabbit and mouse epididymal spermatozoa: dependence of rate on temperature and oxygen concentration. Biol Reprod. 1985;32:342–51.PubMedCrossRefGoogle Scholar
  47. 47.
    Alvarez JG, Storey BT. Spontaneous lipid peroxidation in rabbit epididymal spermatozoa. Biol Reprod. 1982;27:1102–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Holland MK, Alvarez JG, Storey BT. Production of superoxide dismutase and activity of superoxide dismutase in rabbit epididymal spermatozoa. Biol Reprod. 1982;27:1109–18.PubMedCrossRefGoogle Scholar
  49. 49.
    Alvarez JG, Holland MK, Storey BT. Spontaneous lipid peroxidation in rabbit spermatozoa: a useful model for the reaction of O2 metabolites with cells. In: Lubbers DW, Acker H, Leninger-Follert E, Goldstick TK, editors. Oxygen transport to tissue—V. New York: Plenum; 1984. p. 433–43.Google Scholar
  50. 50.
    Alvarez JG, Storey BT. Assessment of cell damage caused by spontaneuous lipid peroxidation in rabbit spermatozoa. Biol Reprod. 1984;30:323–32.PubMedCrossRefGoogle Scholar
  51. 51.
    Alvarez JG, Touchstone JC, Blasco L, Storey BT. Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity. J Androl. 1987;8:338–48.PubMedGoogle Scholar
  52. 52.
    Fraga CG, Motchnik PA, Shigenaga MK, Helbock HJ, Jacob RA, Ames BN. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci. 1991;88:11003–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Male InfertilityCentro Androgen, La CoruñaLa CoruñaSpain
  2. 2.Department of Biological SciencesUniversity of NewcastleCallaghanAustralia

Personalised recommendations