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Sperm DNA damage in male infertility: etiologies, assays, and outcomes

  • Ryan T. Schulte
  • Dana A. Ohl
  • Mark Sigman
  • Gary D. Smith
ANDROLOGY

Abstract

Male factor infertility is the sole cause of infertility in approximately 20% of infertile couples, with an additional 30% to 40% secondary to both male and female factors. Current means of evaluation of male factor infertility remains routine semen analysis including seminal volume, pH, sperm concentration, motility, and morphology. However, approximately 15% of patients with male factor infertility have a normal semen analysis and a definitive diagnosis of male infertility often cannot be made as a result of routine semen analysis. Attention has focused on the role of sperm nuclear DNA integrity in male factor infertility. Here we review the structure of human sperm chromatin, the etiology and mechanisms of sperm DNA damage, current tests available to assess sperm DNA integrity, and effect of sperm DNA integrity on reproductive outcomes.

Keywords

Etiologies Assays Sperm, DNA Damage 

References

  1. 1.
    Agarwal A, Allamaneni SS. Sperm DNA damage assessment: a test whose time has come. Fertil Steril. 2005;84:850–3.PubMedGoogle Scholar
  2. 2.
    Aitken RJ, Bowie H, Buckingham D, Harkiss D, Richardson DW, West KM. Sperm penetration into a hyaluronic acid polymer as a means of monitoring functional competence. J Androl. 1992;13:44–54.PubMedGoogle Scholar
  3. 3.
    Aitken RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction. 2001;122:497–506.PubMedGoogle Scholar
  4. 4.
    Alvarez C, Castilla JA, Martinez L, Ramirez JP, Vergara F, Gaforio JJ. Biological variation of seminal parameters in healthy subjects. Hum Reprod. 2003;18:2082–8.PubMedGoogle Scholar
  5. 5.
    Alvarez JG, Sharma RK, Ollero M, Saleh RA, Lopez MC, Thomas AJ Jr, et al. Increased DNA damage in sperm from leukocytospermic semen samples as determined by the sperm chromatin structure assay. Fertil Steril. 2002;78:319–29.PubMedGoogle Scholar
  6. 6.
    Amann RP. Can the fertility potential of a seminal sample be predicted accurately? J Androl. 1989;10:89–98.PubMedGoogle Scholar
  7. 7.
    Aravindan GR, Bjordahl J, Jost LK, Evenson DP. Susceptibility of human sperm to in situ DNA denaturation is strongly correlated with DNA strand breaks identified by single-cell electrophoresis. Exp Cell Res. 1997;236:231–7.PubMedGoogle Scholar
  8. 8.
    Arnon J, Meirow D, Lewis-Roness H, Ornoy A. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum Reprod Update. 2001;7:394–403.PubMedGoogle Scholar
  9. 9.
    Auger J, Mesbah M, Huber C, Dadoune JP. Aniline blue staining as a marker of sperm chromatin defects associated with different semen characteristics discriminates between proven fertile and suspected infertile men. Int J Androl. 1990;13:452–62.PubMedGoogle Scholar
  10. 10.
    Barroso G, Morshedi M, Oehninger S. Analysis of DNA fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa. Hum Reprod. 2000;15:1338–44.PubMedGoogle Scholar
  11. 11.
    Bench GS, Friz AM, Corzett MH, Morse DH, Balhorn R. DNA and total protamine masses in individual sperm from fertile mammalian subjects. Cytometry. 1996;23:263–71.PubMedGoogle Scholar
  12. 12.
    Benchaib M, Braun V, Lornage J, Hadj S, Salle B, Lejeune H, et al. Sperm DNA fragmentation decreases the pregnancy rate in an assisted reproductive technique. Hum Reprod. 2003;18:1023–8.PubMedGoogle Scholar
  13. 13.
    Benchaib M, Lornage J, Mazoyer C, Lejeune H, Salle B, Francois Guerin J. Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome. Fertil Steril. 2007;87:93–100.PubMedGoogle Scholar
  14. 14.
    Bonduelle M, Aytoz A, Van Assche E, Devroey P, Liebaers I, Van Steirteghem A. Incidence of chromosomal aberrations in children born after assisted reproduction through intracytoplasmic sperm injection. Hum Reprod. 1998;13:781–2.PubMedGoogle Scholar
  15. 15.
    Braude P, Bolton V, Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature. 1988;332:459–61.PubMedGoogle Scholar
  16. 16.
    Bungum M, Humaidan P, Axmon A, Spano M, Bungum L, Erenpreiss J, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007;22:174–9.PubMedGoogle Scholar
  17. 17.
    Bungum M, Humaidan P, Spano M, Jepson K, Bungum L, Giwercman A. The predictive value of sperm chromatin structure assay (SCSA) parameters for the outcome of intrauterine insemination, IVF and ICSI. Hum Reprod. 2004;19:1401–8.PubMedGoogle Scholar
  18. 18.
    Carrell DT, Liu L. Altered protamine 2 expression is uncommon in donors of known fertility, but common among men with poor fertilizing capacity, and may reflect other abnormalities of spermiogenesis. J Androl. 2001;22:604–10.PubMedGoogle Scholar
  19. 19.
    Centola G, Ginsburg K. Evaluation and treatment of the infertile male. Cambridge, United Kingdom: Cambridge University Press; 1996.Google Scholar
  20. 20.
    Chatterjee R, Haines GA, Perera DM, Goldstone A, Morris ID. Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia. Hum Reprod. 2000;15:762–6.PubMedGoogle Scholar
  21. 21.
    Check JH, Graziano V, Cohen R, Krotec J, Check ML. Effect of an abnormal sperm chromatin structural assay (SCSA) on pregnancy outcome following (IVF) with ICSI in previous IVF failures. Arch Androl. 2005;51:121–4.PubMedGoogle Scholar
  22. 22.
    Chohan KR, Griffin JT, Lafromboise M, De Jonge CJ, Carrell DT. Comparison of chromatin assays for DNA fragmentation evaluation in human sperm. J Androl. 2006;27:53–9.PubMedGoogle Scholar
  23. 23.
    Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity test predict pregnancy with in vitro fertilization? Fertil Steril. 2008;89:823–31.PubMedGoogle Scholar
  24. 24.
    Comhaire FH, Christophe AB, Zalata AA, Dhooge WS, Mahmoud AM, Depuydt CE. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000;63:159–65.PubMedGoogle Scholar
  25. 25.
    Corzett M, Mazrimas J, Balhorn R. Protamine 1: protamine 2 stoichiometry in the sperm of eutherian mammals. Mol Reprod Dev. 2002;61:519–27.PubMedGoogle Scholar
  26. 26.
    Cox GF, Burger J, Lip V, Mau UA, Sperling K, Wu BL, et al. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet. 2002;71:162–4.PubMedGoogle Scholar
  27. 27.
    Dadoune JP. The nuclear status of human sperm cells. Micron. 1995;26:323–45.PubMedGoogle Scholar
  28. 28.
    Dadoune JP, Mayaux MJ, Guihard-Moscato ML. Correlation between defects in chromatin condensation of human spermatozoa stained by aniline blue and semen characteristics. Andrologia. 1988;20:211–7.PubMedGoogle Scholar
  29. 29.
    Darzynkiewicz Z, Traganos F, Sharpless T, Melamed MR. Thermal denaturation of DNA in situ as studied by acridine orange staining and automated cytofluorometry. Exp Cell Res. 1975;90:411–28.PubMedGoogle Scholar
  30. 30.
    De Lamirande E, Gagnon C. The dark and bright sides of reactive oxygen species on sperm function. In: Gagnon C, editor. The male gamete: from basic science to clinical applications. IL: Cache River Press; 1999. p. 455–67.Google Scholar
  31. 31.
    DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156–60.PubMedGoogle Scholar
  32. 32.
    Donnelly ET, Steele EK, McClure N, Lewis SE. Assessment of DNA integrity and morphology of ejaculated spermatozoa from fertile and infertile men before and after cryopreservation. Hum Reprod. 2001;16:1191–9.PubMedGoogle Scholar
  33. 33.
    Duran EH, Morshedi M, Taylor S, Oehninger S. Sperm DNA quality predicts intrauterine insemination outcome: a prospective cohort study. Hum Reprod. 2002;17:3122–8.PubMedGoogle Scholar
  34. 34.
    Erenpreiss J, Bungum M, Spano M, Elzanaty S, Orbidans J, Giwercman A. Intra-individual variation in sperm chromatin structure assay parameters in men from infertile couples: clinical implications. Hum Reprod. 2006;21:2061–4.PubMedGoogle Scholar
  35. 35.
    Erenpreiss J, Hlevicka S, Zalkalns J, Erenpreisa J. Effect of leukocytospermia on sperm DNA integrity: a negative effect in abnormal semen samples. J Androl. 2002;23:717–23.PubMedGoogle Scholar
  36. 36.
    Erenpreiss J, Jepson K, Giwercman A, Tsarev I, Erenpreisa J, Spano M. Toluidine blue cytometry test for sperm DNA conformation: comparison with the flow cytometric sperm chromatin structure and TUNEL assays. Hum Reprod. 2004;19:2277–82.PubMedGoogle Scholar
  37. 37.
    Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 2006;12:466–72.PubMedGoogle Scholar
  38. 38.
    Evenson DP, Darzynkiewicz Z, Melamed MR. Relation of mammalian sperm chromatin heterogeneity to fertility. Science. 1980;210:1131–3.PubMedGoogle Scholar
  39. 39.
    Evenson DP, Jost LK, Baer RK, Turner TW, Schrader SM. Individuality of DNA denaturation patterns in human sperm as measured by the sperm chromatin structure assay. Reprod Toxicol. 1991;5:115–25.PubMedGoogle Scholar
  40. 40.
    Evenson DP, Jost LK, Marshall D, Zinaman MJ, Clegg E, Purvis K, et al. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod. 1999;14:1039–49.PubMedGoogle Scholar
  41. 41.
    Evenson DP, Larson KL, Jost LK. Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J Androl. 2002;23:25–43.PubMedGoogle Scholar
  42. 42.
    Fernandez JL, Muriel L, Goyanes V, Segrelles E, Gosalvez J, Enciso M, et al. Simple determination of human sperm DNA fragmentation with an improved sperm chromatin dispersion test. Fertil Steril. 2005;84:833–42.PubMedGoogle Scholar
  43. 43.
    Fischer MA, Willis J, Zini A. Human sperm DNA integrity: correlation with sperm cytoplasmic droplets. Urology. 2003;61:207–11.PubMedGoogle Scholar
  44. 44.
    Fuentes-Mascorro G, Serrano H, Rosado A. Sperm chromatin. Arch Androl. 2000;45:215–25.PubMedGoogle Scholar
  45. 45.
    Gandini L, Lombardo F, Paoli D, Caponecchia L, Familiari G, Verlengia C, et al. Study of apoptotic DNA fragmentation in human spermatozoa. Hum Reprod. 2000;15:830–9.PubMedGoogle Scholar
  46. 46.
    Gandini L, Lombardo F, Paoli D, Caruso F, Eleuteri P, Leter G, et al. Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum Reprod. 2004;19:1409–17.PubMedGoogle Scholar
  47. 47.
    Gatewood JM, Cook GR, Balhorn R, Bradbury EM, Schmid CW. Sequence-specific packaging of DNA in human sperm chromatin. Science. 1987;236:962–4.PubMedGoogle Scholar
  48. 48.
    Genesca A, Caballin MR, Miro R, Benet J, Germa JR, Egozcue J. Repair of human sperm chromosome aberrations in the hamster egg. Hum Genet. 1992;89:181–6.PubMedGoogle Scholar
  49. 49.
    Geva E, Lessing JB, Lerner-Geva L, Amit A. Free radicals, antioxidants and human spermatozoa: clinical implications. Hum Reprod. 1998;13:1422–4.PubMedGoogle Scholar
  50. 50.
    Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338–41.PubMedGoogle Scholar
  51. 51.
    Gomez E, Buckingham DW, Brindle J, Lanzafame F, Irvine DS, Aitken RJ. 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. 1996;17:276–87.PubMedGoogle Scholar
  52. 52.
    Gorczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res. 1993;53:1945–51.PubMedGoogle Scholar
  53. 53.
    Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet. 2003;361:1975–7.PubMedGoogle Scholar
  54. 54.
    Greco E, Romano S, Iacobelli M, Ferrero S, Baroni E, Minasi MG, et al. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod. 2005;20:2590–4.PubMedGoogle Scholar
  55. 55.
    Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med. 2001;345:1388–93.PubMedGoogle Scholar
  56. 56.
    Haines G, Marples B, Daniel P, Morris I. DNA damage in human and mouse spermatozoa after in vitro-irradiation assessed by the comet assay. Adv Exp Med Biol. 1998;444:79–91. discussion 92-73.PubMedGoogle Scholar
  57. 57.
    Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects–a systematic review. Hum Reprod. 2005;20:328–38.PubMedGoogle Scholar
  58. 58.
    Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725–30.PubMedGoogle Scholar
  59. 59.
    Henkel R, Hajimohammad M, Stalf T, Hoogendijk C, Mehnert C, Menkveld R, et al. Influence of deoxyribonucleic acid damage on fertilization and pregnancy. Fertil Steril. 2004;81:965–72.PubMedGoogle Scholar
  60. 60.
    Henkel R, Kierspel E, Hajimohammad M, Stalf T, Hoogendijk C, Mehnert C, et al. DNA fragmentation of spermatozoa and assisted reproduction technology. Reprod Biomed Online. 2003;7:477–84.PubMedGoogle Scholar
  61. 61.
    Hikim AP, Lue Y, Yamamoto CM, Vera Y, Rodriguez S, Yen PH, et al. Key apoptotic pathways for heat-induced programmed germ cell death in the testis. Endocrinology. 2003;144:3167–75.PubMedGoogle Scholar
  62. 62.
    Host E, Lindenberg S, Kahn JA, Christensen F. DNA strand breaks in human sperm cells: a comparison between men with normal and oligozoospermic sperm samples. Acta Obstet Gynecol Scand. 1999;78:336–9.PubMedGoogle Scholar
  63. 63.
    Huang CC, Lin DP, Tsao HM, Cheng TC, Liu CH, Lee MS. Sperm DNA fragmentation negatively correlates with velocity and fertilization rates but might not affect pregnancy rates. Fertil Steril. 2005;84:130–40.PubMedGoogle Scholar
  64. 64.
    Hughes CM, Lewis SE, McKelvey-Martin VJ, Thompson W. A comparison of baseline and induced DNA damage in human spermatozoa from fertile and infertile men, using a modified comet assay. Mol Hum Reprod. 1996;2:613–9.PubMedGoogle Scholar
  65. 65.
    Irvine DS, Twigg JP, Gordon EL, Fulton N, Milne PA, Aitken RJ. DNA integrity in human spermatozoa: relationships with semen quality. J Androl. 2000;21:33–44.PubMedGoogle Scholar
  66. 66.
    Isaksson R, Gissler M, Tiitinen A. Obstetric outcome among women with unexplained infertility after IVF: a matched case-control study. Hum Reprod. 2002;17:1755–61.PubMedGoogle Scholar
  67. 67.
    Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, et al. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003;49:83–94.PubMedGoogle Scholar
  68. 68.
    Kierszenbaum AL. Transition nuclear proteins during spermiogenesis: unrepaired DNA breaks not allowed. Mol Reprod Dev. 2001;58:357–8.PubMedGoogle Scholar
  69. 69.
    Klaude M, Eriksson S, Nygren J, Ahnstrom G. The comet assay: mechanisms and technical considerations. Mutat Res. 1996;363:89–96.PubMedGoogle Scholar
  70. 70.
    Kobayashi H, Larson K, Sharma RK, Nelson DR, Evenson DP, Toma H, et al. DNA damage in patients with untreated cancer as measured by the sperm chromatin structure assay. Fertil Steril. 2001;75:469–75.PubMedGoogle Scholar
  71. 71.
    Kodama H, Yamaguchi R, Fukuda J, Kasai H, Tanaka T. Increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. Fertil Steril. 1997;68:519–24.PubMedGoogle Scholar
  72. 72.
    Kosower NS, Katayose H, Yanagimachi R. Thiol-disulfide status and acridine orange fluorescence of mammalian sperm nuclei. J Androl. 1992;13:342–8.PubMedGoogle Scholar
  73. 73.
    Labbe C, Martoriati A, Devaux A, Maisse G. Effect of sperm cryopreservation on sperm DNA stability and progeny development in rainbow trout. Mol Reprod Dev. 2001;60:397–404.PubMedGoogle Scholar
  74. 74.
    Laberge RM, Boissonneault G. On the nature and origin of DNA strand breaks in elongating spermatids. Biol Reprod. 2005;73:289–96.PubMedGoogle Scholar
  75. 75.
    Larson-Cook KL, Brannian JD, Hansen KA, Kasperson KM, Aamold ET, Evenson DP. Relationship between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertil Steril. 2003;80:895–902.PubMedGoogle Scholar
  76. 76.
    Larson KL, DeJonge CJ, Barnes AM, Jost LK, Evenson DP. Sperm chromatin structure assay parameters as predictors of failed pregnancy following assisted reproductive techniques. Hum Reprod. 2000;15:1717–22.PubMedGoogle Scholar
  77. 77.
    Lee CH, Cho YH. Aspects of mammalian spermatogenesis: electrophoretical analysis of protamines in mammalian species. Mol Cells. 1999;9:556–9.PubMedGoogle Scholar
  78. 78.
    Lee J, Richburg JH, Younkin SC, Boekelheide K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology. 1997;138:2081–8.PubMedGoogle Scholar
  79. 79.
    Li Z, Wang L, Cai J, Huang H. Correlation of sperm DNA damage with IVF and ICSI outcomes: a systematic review and meta-analysis. J Assist Reprod Genet. 2006;23:367–76.PubMedGoogle Scholar
  80. 80.
    Lopes S, Sun JG, Jurisicova A, Meriano J, Casper RF. Sperm deoxyribonucleic acid fragmentation is increased in poor-quality semen samples and correlates with failed fertilization in intracytoplasmic sperm injection. Fertil Steril. 1998;69:528–32.PubMedGoogle Scholar
  81. 81.
    Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet. 2003;40:62–4.PubMedGoogle Scholar
  82. 82.
    Mallidis C, Howard EJ, Baker HW. Variation of semen quality in normal men. Int J Androl. 1991;14:99–107.PubMedGoogle Scholar
  83. 83.
    Marcon L, Boissonneault G. Transient DNA strand breaks during mouse and human spermiogenesis new insights in stage specificity and link to chromatin remodeling. Biol Reprod. 2004;70:910–8.PubMedGoogle Scholar
  84. 84.
    McGhee JD, Felsenfeld G, Eisenberg H. Nucleosome structure and conformational changes. Biophys J. 1980;32:261–70.PubMedGoogle Scholar
  85. 85.
    McPherson S, Longo FJ. Chromatin structure-function alterations during mammalian spermatogenesis: DNA nicking and repair in elongating spermatids. Eur J Histochem. 1993;37:109–28.PubMedGoogle Scholar
  86. 86.
    McVicar CM, McClure N, Williamson K, Dalzell LH, Lewis SE. Incidence of Fas positivity and deoxyribonucleic acid double-stranded breaks in human ejaculated sperm. Fertil Steril. 2004;81(Suppl 1):767–74.PubMedGoogle Scholar
  87. 87.
    Mello ML. Induced metachromasia in bull spermatozoa. Histochemistry. 1982;74:387–92.PubMedGoogle Scholar
  88. 88.
    Morris ID. Sperm DNA damage and cancer treatment. Int J Androl. 2002;25:255–61.PubMedGoogle Scholar
  89. 89.
    Morris ID, Ilott S, Dixon L, Brison DR. 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. 2002;17:990–8.PubMedGoogle Scholar
  90. 90.
    Mosher WD, Pratt WF. Fecundity and infertility in the United States: incidence and trends. Fertil Steril. 1991;56:192–3.PubMedGoogle Scholar
  91. 91.
    Muratori M, Marchiani S, Maggi M, Forti G, Baldi E. Origin and biological significance of DNA fragmentation in human spermatozoa. Front Biosci. 2006;11:1491–9.PubMedGoogle Scholar
  92. 92.
    Muratori M, Piomboni P, Baldi E, Filimberti E, Pecchioli P, Moretti E, et al. Functional and ultrastructural features of DNA-fragmented human sperm. J Androl. 2000;21:903–12.PubMedGoogle Scholar
  93. 93.
    Muriel L, Garrido N, Fernandez JL, Remohi J, Pellicer A, de los Santos MJ, et al. Value of the sperm deoxyribonucleic acid fragmentation level, as measured by the sperm chromatin dispersion test, in the outcome of in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril. 2006;85:371–83.PubMedGoogle Scholar
  94. 94.
    Oliva R. Protamines and male infertility. Hum Reprod Update. 2006;12:417–35.PubMedGoogle Scholar
  95. 95.
    Ollero M, Gil-Guzman E, Lopez MC, Sharma RK, Agarwal A, Larson K, et al. 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.PubMedGoogle Scholar
  96. 96.
    Olson CK, Keppler-Noreuil KM, Romitti PA, Budelier WT, Ryan G, Sparks AE, et al. In vitro fertilization is associated with an increase in major birth defects. Fertil Steril. 2005;84:1308–15.PubMedGoogle Scholar
  97. 97.
    Paul C, Povey JE, Lawrence NJ, Selfridge J, Melton DW, Sanders PTK. Delection of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of DNA breaks and germ cell loss. PLoS ONE. 2007;10:1–10.Google Scholar
  98. 98.
    Payne JF, Raburn DJ, Couchman GM, Price TM, Jamison MG, Walmer DK. Redefining the relationship between sperm deoxyribonucleic acid fragmentation as measured by the sperm chromatin structure assay and outcomes of assisted reproductive techniques. Fertil Steril. 2005;84:356–64.PubMedGoogle Scholar
  99. 99.
    Potts RJ, Newbury CJ, Smith G, Notarianni LJ, Jefferies TM. Sperm chromatin damage associated with male smoking. Mutat Res. 1999;423:103–11.PubMedGoogle Scholar
  100. 100.
    Rigler R, Killander D, Bolund L, Ringertz NR. Cytochemical characterization of deoxyribonucleoprotein in individual cell nuclei. Techniques for obtaining heat denaturation curves with the aid of acridine orange microfluorimetry and ultraviolet microspectrophotometry. Exp Cell Res. 1969;55:215–24.PubMedGoogle Scholar
  101. 101.
    Rodriguez I, Ody C, Araki K, Garcia I, Vassalli P. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. Embo J. 1997;16:2262–70.PubMedGoogle Scholar
  102. 102.
    Sailer BL, Jost LK, Evenson DP. Mammalian sperm DNA susceptibility to in situ denaturation associated with the presence of DNA strand breaks as measured by the terminal deoxynucleotidyl transferase assay. J Androl. 1995;16:80–7.PubMedGoogle Scholar
  103. 103.
    Sakkas D, Mariethoz E, Manicardi G, Bizzaro D, Bianchi PG, Bianchi U. Origin of DNA damage in ejaculated human spermatozoa. Rev Reprod. 1999;4:31–7.PubMedGoogle Scholar
  104. 104.
    Sakkas D, Seli E, Bizzaro D, Tarozzi N, Manicardi GC. Abnormal spermatozoa in the ejaculate: abortive apoptosis and faulty nuclear remodelling during spermatogenesis. Reprod Biomed Online. 2003;7:428–32.PubMedCrossRefGoogle Scholar
  105. 105.
    Saleh RA, Agarwal A, Nada EA, El-Tonsy MH, Sharma RK, Meyer A, et al. Negative effects of increased sperm DNA damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. Fertil Steril. 2003;79(Suppl 3):1597–605.PubMedGoogle Scholar
  106. 106.
    Saleh RA, Agarwal A, Nelson DR, Nada EA, El-Tonsy MH, Alvarez JG, et al. Increased sperm nuclear DNA damage in normozoospermic infertile men: a prospective study. Fertil Steril. 2002;78:313–8.PubMedGoogle Scholar
  107. 107.
    Saleh RA, Agarwal A, Sharma RK, Said TM, Sikka SC, Thomas AJ Jr. Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril. 2003;80:1431–6.PubMedGoogle Scholar
  108. 108.
    Seli E, Gardner DK, Schoolcraft WB, Moffatt O, Sakkas D. Extent of nuclear DNA damage in ejaculated spermatozoa impacts on blastocyst development after in vitro fertilization. Fertil Steril. 2004;82:378–83.PubMedGoogle Scholar
  109. 109.
    Seli E, Sakkas D. Spermatozoal nuclear determinants of reproductive outcome: implications for ART. Hum Reprod Update. 2005;11:337–49.PubMedGoogle Scholar
  110. 110.
    Sergerie M, Laforest G, Boulanger K, Bissonnette F, Bleau G. Longitudinal study of sperm DNA fragmentation as measured by terminal uridine nick end-labelling assay. Hum Reprod. 2005;20:1921–7.PubMedGoogle Scholar
  111. 111.
    Sergerie M, Laforest G, Bujan L, Bissonnette F, Bleau G. Sperm DNA fragmentation: threshold value in male fertility. Hum Reprod. 2005;20:3446–51.PubMedGoogle Scholar
  112. 112.
    Singh NP, Stephens RE. X-ray induced DNA double-strand breaks in human sperm. Mutagenesis. 1998;13:75–9.PubMedGoogle Scholar
  113. 113.
    Sinha Hikim AP, Swerdloff RS. Hormonal and genetic control of germ cell apoptosis in the testis. Rev Reprod. 1999;4:38–47.PubMedGoogle Scholar
  114. 114.
    Spano M, Bonde JP, Hjollund HI, Kolstad HA, Cordelli E, Leter G. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril. 2000;73:43–50.PubMedGoogle Scholar
  115. 115.
    Spano M, Seli E, Bizzaro D, Manicardi GC, Sakkas D. The significance of sperm nuclear DNA strand breaks on reproductive outcome. Curr Opin Obstet Gynecol. 2005;17:255–60.PubMedGoogle Scholar
  116. 116.
    Steger K, Pauls K, Klonisch T, Franke FE, Bergmann M. Expression of protamine-1 and -2 mRNA during human spermiogenesis. Mol Hum Reprod. 2000;6:219–25.PubMedGoogle Scholar
  117. 117.
    Suleiman SA, Ali ME, Zaki ZM, el-Malik EM, Nasr MA. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl. 1996;17:530–7.PubMedGoogle Scholar
  118. 118.
    Tejada RI, Mitchell JC, Norman A, Marik JJ, Friedman S. A test for the practical evaluation of male fertility by acridine orange (AO) fluorescence. Fertil Steril. 1984;42:87–91.PubMedGoogle Scholar
  119. 119.
    Tesarik J, Mendoza C, Greco E. Paternal effects acting during the first cell cycle of human preimplantation development after ICSI. Hum Reprod. 2002;17:184–9.PubMedGoogle Scholar
  120. 120.
    Thonneau P, Marchand S, Tallec A, Ferial ML, Ducot B, Lansac J, et al. Incidence and main causes of infertility in a resident population (1, 850, 000) of three French regions (1988–1989). Hum Reprod. 1991;6:811–6.PubMedGoogle Scholar
  121. 121.
    Tomlinson MJ, Moffatt O, Manicardi GC, Bizzaro D, Afnan M, Sakkas D. Interrelationships between seminal parameters and sperm nuclear DNA damage before and after density gradient centrifugation: implications for assisted conception. Hum Reprod. 2001;16:2160–5.PubMedGoogle Scholar
  122. 122.
    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.PubMedGoogle Scholar
  123. 123.
    Virro MR, Larson-Cook KL, Evenson DP. Sperm chromatin structure assay (SCSA) parameters are related to fertilization, blastocyst development, and ongoing pregnancy in in vitro fertilization and intracytoplasmic sperm injection cycles. Fertil Steril. 2004;81:1289–95.PubMedGoogle Scholar
  124. 124.
    Ward WS, Coffey DS. DNA packaging and organization in mammalian spermatozoa: comparison with somatic cells. Biol Reprod. 1991;44:569–74.PubMedGoogle Scholar
  125. 125.
    WorldHealthOrganization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. Cambridge: Cambridge University Press; 1999.Google Scholar
  126. 126.
    Zadori J, Kozinszky Z, Orvos H, Katona M, Kaali SG, Pal A. The incidence of major birth defects following in vitro fertilization. J Assist Reprod Genet. 2003;20:131–2.PubMedGoogle Scholar
  127. 127.
    Zini A, Bielecki R, Phang D, Zenzes MT. Correlations between two markers of sperm DNA integrity, DNA denaturation and DNA fragmentation, in fertile and infertile men. Fertil Steril. 2001;75:674–7.PubMedGoogle Scholar
  128. 128.
    Zini A, de Lamirande E, Gagnon C. Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa. Int J Androl. 1993;16:183–8.PubMedGoogle Scholar
  129. 129.
    Zini A, Fischer MA, Sharir S, Shayegan B, Phang D, Jarvi K. Prevalence of abnormal sperm DNA denaturation in fertile and infertile men. Urology. 2002;60:1069–72.PubMedGoogle Scholar
  130. 130.
    Zini A, Kamal K, Phang D, Willis J, Jarvi K. Biologic variability of sperm DNA denaturation in infertile men. Urology. 2001;58:258–61.PubMedGoogle Scholar
  131. 131.
    Zini A, Meriano J, Kader K, Jarvi K, Laskin CA, Cadesky K. Potential adverse effect of sperm DNA damage on embryo quality after ICSI. Hum Reprod. 2005;20:3476–80.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ryan T. Schulte
    • 1
  • Dana A. Ohl
    • 1
  • Mark Sigman
    • 2
  • Gary D. Smith
    • 1
    • 3
    • 4
    • 5
    • 6
  1. 1.Department of UrologyUniversity of MichiganAnn ArborUSA
  2. 2.Department of UrologyBrown Medical SchoolProvidenceUSA
  3. 3.Department of Obstetrics and GynecologyUniversity of MichiganAnn ArborUSA
  4. 4.Department of Integrated and Molecular PhysiologyUniversity of MichiganAnn ArborUSA
  5. 5.Department of Reproductive Sciences ProgramUniversity of MichiganAnn ArborUSA
  6. 6.Ann ArborUSA

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