Effect of Antioxidants on Sperm Genetic Damage

  • Yves MenezoEmail author
  • Don Evenson
  • Marc Cohen
  • Brian Dale
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 791)


According to worldwide statistics, between one in four and one in five couples have fertility problems. These problems are equally distributed between males and females. Modern lifestyle has obviously increased these problems: endocrine-disrupting chemicals, such as plastic polymer catalysts, alkylphenols, phthalates and so on, and cosmetic additives seem to be strongly involved in this fertility problem. Many of these compounds increase oxidative stress (OS) and thus impair spermatogenesis. The oocyte has only a finite capacity, decreasing with maternal age, to repair sperm-borne decays. To decrease this DNA repair burden, reducing the sperm DNA damages linked to OS is tempting. Antioxidant vitamins are often given haphazardly; they are not very efficient and potentially detrimental. A detailed analysis of the sperm nucleus is mandatory (DNA fragmentation or lack of nuclear condensation) prior to any treatment. Here we discuss new concepts in OS and the corresponding therapeutic approaches.


Oxidative stress Gametes DNA damages Fertility Antioxidants Homocysteine 


  1. Agarwal A, Nallella KP, Allamaneni SS et al (2004) Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod Biomed Online 8:616–627PubMedCrossRefGoogle Scholar
  2. Aitken RJ, De Iuliis GN, Finnie JM et al (2010) Analysis of the relationships between oxidative stress, DNA damage and sperm vitality in a patient population: development of diagnostic criteria. Hum Reprod 25:2415–2426PubMedCrossRefGoogle Scholar
  3. Almbro M, Dowling DK, Simmons LW (2011) Effects of vitamin E and beta-carotene on sperm competitiveness. Ecol Lett 14:891–895PubMedCrossRefGoogle Scholar
  4. Ambruosi B, Uranio MF, Sardanelli AM et al (2011) In vitro acute exposure to DEHP affects oocyte meiotic maturation, energy and oxidative stress parameters in a large animal model. PLoS One 6:e27452PubMedCrossRefGoogle Scholar
  5. Badouard C, Menezo Y, Panteix G et al (2008) Determination of new types of DNA lesions in human sperm. Zygote 16:9–13PubMedCrossRefGoogle Scholar
  6. Belloc S, Benkhalifa M, Junca AM et al (2009) Paternal age and sperm DNA decay: discrepancy between chromomycin and aniline blue staining. Reprod Biomed Online 19:264–269PubMedCrossRefGoogle Scholar
  7. Benedetti S, Tagliamonte MC, Catalani S et al (2012) Differences in blood and semen oxidative status in fertile and infertile men, and their relationship with sperm quality. Reprod Biomed Online 25:300–306PubMedCrossRefGoogle Scholar
  8. Bleau G, Lemarbre J, Faucher G et al (1984) Semen selenium and human fertility. Fertil Steril 42:890–894PubMedGoogle Scholar
  9. Bøhn SK, Myhrstad MC, Thoresen M et al (2010) Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers. BMC Med 8:54–69PubMedCrossRefGoogle Scholar
  10. Boxmeer JC, Smit M, Utomo E et al (2009) Low folate in seminal plasma is associated with increased sperm DNA damage. Fertil Steril 92:548–561PubMedCrossRefGoogle Scholar
  11. Brack M, Brack O, Menezo Y et al (2013) Distinct profiles of systemic biomarkers of oxidative stress in chronic human pathologies: Cardiovascular, psychiatric, neurodegenerative, rheumatic, infectious, neoplasmic and endocrinological diseases. Adv BioSci Biotech 4:331–339Google Scholar
  12. Bungum M, Humaidan P, Axmon A et al (2007) Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod 22:174–179PubMedCrossRefGoogle Scholar
  13. Bungum M, Bungum L, Giwercman A (2011) Sperm chromatin structure assay (SCSA): a tool in diagnosis and treatment of infertility. Asian J Androl 13:69–75PubMedCrossRefGoogle Scholar
  14. Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), National Health and Nutrition Examination Survey Questionnaire. Hyattsville, MD 2001–2002. Available from: (cited 1 May 2007)
  15. Cerda S, Weitzman SA (1997) Influence of oxygen radical injury on DNA methylation. Mutat Res 386:141–152PubMedCrossRefGoogle Scholar
  16. De Iuliis GN, Thomson LK, Mitchell LA et al (2009) DNA damage in human spermatozoa is highly correlated with the efficiency of chromatin remodeling and the formation of 8-hydroxy-2′-deoxyguanosine, a marker of oxidative stress. Biol Reprod 81:517–524PubMedCrossRefGoogle Scholar
  17. de Lamirande E, Gagnon C (1995) Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects. Hum Reprod 10(Suppl 1):15–21PubMedCrossRefGoogle Scholar
  18. Donnelly ET, McClure N, Lewis SE (1999) The effect of ascorbate and alpha-tocopherol supplementation in vitro on DNA integrity and hydrogen peroxide-induced DNA damage in human spermatozoa. Mutagenesis 14:505–512PubMedCrossRefGoogle Scholar
  19. Ebisch IM, Thomas CM, Peters WH et al (2007) The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update 13:163–174PubMedCrossRefGoogle Scholar
  20. Evenson DP, Darzynkiewicz Z, Melamed MR (1980) Relation of mammalian sperm chromatin heterogeneity to fertility. Science 210:1131–1133PubMedCrossRefGoogle Scholar
  21. Evenson DP, Larson KL, Jost LK (2002) Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J Androl 23:25–43PubMedGoogle Scholar
  22. Fernández-Gonzalez R, Moreira PN, Pérez-Crespo M et al (2008) Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol Reprod 78:761–772PubMedCrossRefGoogle Scholar
  23. Fraga CG, Motchnik PA, Shigenaga MK et al (1991) Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci USA 88:11003–11006PubMedCrossRefGoogle Scholar
  24. Franco R, Schoneveld O, Georgakilas AG et al (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266:6–11PubMedCrossRefGoogle Scholar
  25. García-Herrero S, Garrido N, Martínez-Conejero JA et al (2011) Differential transcriptomic profile in spermatozoa achieving pregnancy or not via ICSI. Reprod Biomed Online 22:25–36PubMedCrossRefGoogle Scholar
  26. Giustarini D, Dalle-Donne I, Colombo R (2008) Is ascorbate able to reduce disulfide bridges? A cautionary note. Nitric Oxide 19:252–258PubMedCrossRefGoogle Scholar
  27. Greco E, Romano S, Iacobelli M et al (2005) ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod 20:2590–2594PubMedCrossRefGoogle Scholar
  28. Hammadeh ME, al-Hasani S, Stieber M et al (1996) The effect of chromatin condensation (aniline blue staining) and morphology (strict criteria) of human spermatozoa on fertilization, cleavage and pregnancy rates in an intracytoplasmic sperm injection programme. Hum Reprod 11: 2468–2471PubMedCrossRefGoogle Scholar
  29. Hartwig A, Blessing H, Schwerdtle T et al (2003) Modulation of DNA repair processes by arsenic and selenium compounds. Toxicology 193:161–169PubMedCrossRefGoogle Scholar
  30. Hawkes WC, Alkan Z, Wong K (2009) Selenium supplementation does not affect testicular selenium status or semen quality in North American men. J Androl 30:525–533PubMedCrossRefGoogle Scholar
  31. Ho E (2004) Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem 15:572–578PubMedCrossRefGoogle Scholar
  32. Hoffman M (2011) Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses 77:1088–1093PubMedCrossRefGoogle Scholar
  33. Jaroudi S, Kakourou G, Cawood S et al (2009) Expression profiling of DNA repair genes in human oocytes and blastocysts using microarrays. Hum Reprod 24:2649–2655PubMedCrossRefGoogle Scholar
  34. Ji BT, Shu XO, Linet MS (1997) Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J Natl Cancer Inst 89:238–244PubMedCrossRefGoogle Scholar
  35. Junca AM, Gonzalez Marti B, Tosti E et al (2012) Sperm nucleus decondensation, hyaluronic acid (HA) binding and oocyte activation capacity: different markers of sperm immaturity? Case reports. J Assist Reprod Genet 29:353–355PubMedCrossRefGoogle Scholar
  36. Kanďár R, Drábková P, Hampl R (2011) The determination of ascorbic acid and uric acid in human seminal plasma using an HPLC with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci 879:2834–2839PubMedCrossRefGoogle Scholar
  37. Kao SH, Chao HT, Chen HW et al (2008) Increase of oxidative stress in human sperm with lower motility. Fertil Steril 89:1183–1190PubMedCrossRefGoogle Scholar
  38. Keefe DL, Liu L (2009) Telomeres and reproductive aging. Reprod Fertil Dev 21:10–14PubMedCrossRefGoogle Scholar
  39. Krausz C (2011) Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab 25:271–278PubMedCrossRefGoogle Scholar
  40. Lewis SE, Sterling ES, Young IS et al (1997) Comparison of individual antioxidants of sperm and seminal plasma in fertile and infertile men. Fertil Steril 67:142–147PubMedCrossRefGoogle Scholar
  41. Li P, Zhong Y, Jiang X et al (2012) Seminal plasma metals concentration with respect to semen quality. Biol Trace Elem Res 48:1–6CrossRefGoogle Scholar
  42. Liu ZX, Artmann C (2009) Relative bioavailability comparison of different coenzyme Q10 formulations with a novel delivery system. Altern Ther Health Med 15:42–46PubMedGoogle Scholar
  43. Lopes S, Jurisicova A, Casper RF (1998) Gamete-specific DNA fragmentation in unfertilized human oocytes after intracytoplasmic sperm injection. Hum Reprod 13:703–708PubMedCrossRefGoogle Scholar
  44. Mancini A, Balercia G (2011) Coenzyme Q(10) in male infertility: physiopathology and therapy. Biofactors 37:374–380PubMedCrossRefGoogle Scholar
  45. Menezo Y Jr, Russo G, Tosti E et al (2007a) Expression profile of genes coding for DNA repair in human oocytes using pangenomic microarrays, with a special focus on ROS linked decays. J Assist Reprod Genet 24:513–520PubMedCrossRefGoogle Scholar
  46. Menezo Y, Hazout A, Panteix G et al (2007b) Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect. Reprod Biomed Online 14:418–421PubMedCrossRefGoogle Scholar
  47. Menezo Y, Dale B, Cohen M (2010) DNA damage and repair in human oocytes and embryos: a review. Zygote 18:357–365PubMedCrossRefGoogle Scholar
  48. Menezo Y, Mares P, Cohen M et al (2011) Autism, imprinting and epigenetic disorders: a metabolic syndrome linked to anomalies in homocysteine recycling starting in early life? J Assist Reprod Genet 28:1143–1145PubMedCrossRefGoogle Scholar
  49. Menezo Y, Entezami F, Lichtblau I et al (2012) Oxidative stress and fertility: incorrect assumptions and ineffective solutions? Zygote 12:1–11CrossRefGoogle Scholar
  50. Montjean D, Menezo Y, Benkhalifa M et al (2010) Malonaldehyde formation and DNA fragmentation: two independent sperm decays linked to reactive oxygen species. Zygote 18:265–268PubMedCrossRefGoogle Scholar
  51. Montjean D, Belloc S, Benkhalifa M et al (2012) Sperm vacuoles are linked to capacitation and acrosomal status. Hum Reprod 27:2927–2932PubMedCrossRefGoogle Scholar
  52. Moretti E, Mazzi L, Terzuoli G et al (2012) Effect of quercetin, rutin, naringenin and epicatechin on lipid peroxidation induced in human sperm. Reprod Toxicol 34:651–657PubMedCrossRefGoogle Scholar
  53. Moskaug JØ, Carlsen H, Myhrstad MC et al (2005) Polyphenols and glutathione synthesis regulation. Am J Clin Nutr 81:277S–283SPubMedGoogle Scholar
  54. Muratori M, Tamburrino L, Tocci V et al (2010) Small variations in crucial steps of TUNEL assay coupled to flow cytometry greatly affect measures of sperm DNA fragmentation. J Androl 31:336–345PubMedCrossRefGoogle Scholar
  55. Oger I, Da Cruz C, Panteix G et al (2003) Evaluating human sperm DNA integrity: relationship between 8-hydroxydeoxyguanosine quantification and the sperm chromatin structure assay. Zygote 11:367–371PubMedCrossRefGoogle Scholar
  56. Omu AE, Al-Azemi MK, Kehinde EO et al (2008) Indications of the mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract 17:108–116PubMedCrossRefGoogle Scholar
  57. ORC Macro and the World Health Organization (2004) Sexual and reproductive health Infecundity, infertility, and childlessness in developing countries. Comparative reports No. 9, Demographic and Health Surveys (DHS) 74pGoogle Scholar
  58. Parmegiani L, Cognigni GE, Bernardi S et al (2010) “Physiologic ICSI”: hyaluronic acid (HA) favors selection of spermatozoa without DNA fragmentation and with normal nucleus, resulting in improvement of embryo quality. Fertil Steril 93:598–604PubMedCrossRefGoogle Scholar
  59. Patrizio P, Sakkas D (2009) From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril 91:1061–1066PubMedCrossRefGoogle Scholar
  60. Robinson L, Gallos ID, Conner SJ et al (2012) The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 27:2908–2917PubMedCrossRefGoogle Scholar
  61. Rodríguez S, Goyanes V, Segrelles E et al (2005) Critically short telomeres are associated with sperm DNA fragmentation. Fertil Steril 84:843–845PubMedCrossRefGoogle Scholar
  62. Song Y, Chung CS, Bruno RS et al (2009) Dietary zinc restriction and repletion affects DNA integrity in healthy men. Am J Clin Nutr 90:321–328PubMedCrossRefGoogle Scholar
  63. Sreekanth D, Arunasree MK, Roy KR et al (2007) Betanin a betacyanin pigment purified from fruits of Opuntia ficus-indica induces apoptosis in human chronic myeloid leukemia Cell line-K562. Phytomedicine 14:739–746PubMedCrossRefGoogle Scholar
  64. Tanaka A, Nagayoshi M, Tanaka I et al (2012) Human sperm head vacuoles are physiological structures formed during the sperm development and maturation process. Fertil Steril 98:315–320PubMedCrossRefGoogle Scholar
  65. Tesoriere L, Allegra M, Butera D (2004) Absorption, excretion, and distribution of dietary antioxidant betalains in LDLs: potential health effects of betalains in humans. Am J Clin Nutr 80:941–945PubMedGoogle Scholar
  66. Tunc O, Tremellen K (2009) Oxidative DNA damage impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet 26:537–544PubMedCrossRefGoogle Scholar
  67. Ursini F, Maiorino M, Roveri A (1997) Phospholipid hydroperoxide glutathione peroxidase (PHGPx): more than an antioxidant enzyme? Biomed Environ Sci 10:327–332PubMedGoogle Scholar
  68. Villalba JM, Parrado C, Santos-Gonzalez M et al (2010) Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations. Expert Opin Investig Drugs 19:535–554PubMedCrossRefGoogle Scholar
  69. Wachsman JT (1997) DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis. Mutat Res 375:1–8PubMedCrossRefGoogle Scholar
  70. WHO (2011) Guidelines for drinking-water quality., ISBN: 978 92 4 154815 1
  71. Wilding M, Coppola G, Fabozzi G et al (2012) Physiological IMSI (pIMSI) Improves results obtained with IMSI in patients with Idiopathic Infertility. Reprod Sys Sexual Disorders 3:1–5Google Scholar
  72. Wyrobek AJ, Eskenazi B, Young S et al (2006) Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc Natl Acad Sci USA 103:9601–9606PubMedCrossRefGoogle Scholar
  73. Zenzes MT (2000) Smoking and reproduction: gene damage to human gametes and embryos. Hum Reprod Update 6:122–123PubMedCrossRefGoogle Scholar
  74. Zenzes MT, Puy LA, Bielecki R (1998) Immunodetection of benzo[a]pyrene adducts in ovarian cells of women exposed to cigarette smoke. Mol Hum Reprod 4:159–165PubMedCrossRefGoogle Scholar
  75. Zhao R, Xiang N, Domann FE et al (2009) Effects of selenite and genistein on G2/M cell cycle arrest and apoptosis in human prostate cancer cells. Nutr Cancer 61:397–407PubMedCrossRefGoogle Scholar
  76. Zini A, Sigman M (2009) Are tests of sperm DNA damage clinically useful? Pros and cons. J Androl 30:219–229PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yves Menezo
    • 1
    • 2
    Email author
  • Don Evenson
    • 3
  • Marc Cohen
    • 4
  • Brian Dale
    • 1
    • 5
  1. 1.London Fertility AssociatesLondonUK
  2. 2.Laboratoire CLEMENTParisFrance
  3. 3.South Dakota State UniversityBrookingsUSA
  4. 4.Procrelys, Maison médicale Ambroise ParéLyonFrance
  5. 5.Centre for Assisted FertilizationNaplesItaly

Personalised recommendations