Russian Journal of Developmental Biology

, Volume 50, Issue 4, pp 165–172 | Cite as

Apoptosis in Spermatozoa and Its Role in Deteriorating Semen Quality

  • A. N. NakidkinaEmail author
  • T. I. KuzminaEmail author


The importance of sperm DNA integrity is hard to overestimate since the quality of the genetic material in a sperm population is the key point for successful fertilization, the embryonic and subsequent development of offspring, and, therefore, the male reproductive potential. Apoptosis is essential for male gametes in the period from the time of appearance of the gonadal anlagen in the embryo to the moment of fertilization. This mechanism of programmed cell death is necessary to maintain the appropriate ratio between the germ cells and the Sertoli cells during prenatal development. The damaged cells are removed from the testicles in the adult specimens by the apoptosis pathway. A range of unfavorable effects can intensify this process. In addition, mature spermatozoa undergo apoptosis and subsequent phagocytosis in the female reproductive tract in order to prevent the inflammatory response triggered by the dead gamete destruction. The impaired process of apoptosis may cause developmental abnormalities in male gametes, infertility, and fertilization of oocyte by sperm with DNA damage followed by subsequent offspring death. Therefore, recent studies show that apoptosis is one of the main causes of sperm DNA fragmentation, which tends to become a significant problem under conditions for the widespread use of assisted reproductive technologies.


apoptosis sperm spermatogenesis oxidative stress DNA fragmentation 



The survey was performed under the state task of the Ministry of Education of the Russian Federation according to project no. АААА-А18-118021590132-9 (registered in the Center of Information Technologies and Systems for Executive Power Authorities, Russia).


  1. 1.
    Agger, K., Santoni-Rugiu, E., Holmberg, C., et al., Conditional E2F1 activation in transgenic mice causes testicular atrophy and dysplasia mimicking human cis, Oncogene, 2005, vol. 24, pp. 780–789.CrossRefPubMedGoogle Scholar
  2. 2.
    Aitken, R.J., The capacitation-apoptosis highway: oxysterols and mammalian sperm function, Biol. Reprod., 2011, vol. 85, pp. 9–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Aitken, R.J., Reactive oxygen species as mediators of sperm capacitation and pathological damage, Mol. Reprod. Dev., 2017, vol. 84, no. 10, pp. 1039–1052.CrossRefPubMedGoogle Scholar
  4. 4.
    Aitken, R.J. and Koppers, A.J., Apoptosis and DNA damage in human spermatozoa, Asian J. Androl., 2011, vol. 13, pp. 36–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Aitken, R.J., Findlay, J.K., Hutt, K.J., et al., Apoptosis in the germ line, Reproduction, 2011, vol. 141, pp. 139–150.CrossRefPubMedGoogle Scholar
  6. 6.
    Aitken, R.J., Whiting, S., De Iuliis, G.N., et al., Electrophilic aldehydes generated by sperm metabolism activate mitochondrial reactive oxygen species generation and apoptosis by targeting succinate dehydrogenase, J. Biol. Chem., 2012, vol. 287, pp. 33048–33060.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Aitken, R.J., Baker, M.A., and Nixon, B., Are sperm capacitation and apoptosis the opposite ends of a continuum driven by oxidative stress?, Asian J. Androl., 2015, vol. 17, pp. 633–639.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Allan, D.J., Harmon, B.V., and Kerr, J.F.R., Cell death in spermatogenesis, in Perspectives on Mammalian Cell Death, Oxford: Univ. Press, London, 1987, pp. 229–258.Google Scholar
  9. 9.
    Amaral, A., Lourenco, B., Marques, M., et al., Mitochondria functionality and sperm quality, Reproduction, 2013, vol. 146, no. 5, pp. 163–174.CrossRefGoogle Scholar
  10. 10.
    Anzar, M., He, L., Buhr, M.M., et al., Sperm apoptosis in fresh and cryopreserved bull semen detected by flow cytometry and its relationship with fertility, Biol. Reprod., 2002, vol. 66, pp. 354–360.CrossRefPubMedGoogle Scholar
  11. 11.
    Baker, M.A., Weinberg, A., Hetherington, L., et al., Defining the mechanisms by which the reactive oxygen species by-product, 4-hydroxynonenal, affects human sperm cell function, Biol. Reprod., 2015, vol. 92, no. 4, p. 108.PubMedGoogle Scholar
  12. 12.
    Bartke, A., Apoptosis of male germ cells, a generalized or a cell type-specific phenomenon?, Endocrinology, 1995, vol. 136, no. 1, pp. 3–4.CrossRefPubMedGoogle Scholar
  13. 13.
    Bejarano, I., Lozano, G.M., Ortiz, A., et al., Caspase 3 activation in human spermatozoa in response to hydrogen peroxide and progesterone, Fertil. Steril., 2008, vol. 90, pp. 1340–1347.CrossRefPubMedGoogle Scholar
  14. 14.
    Boitseva, E.N., Denisenko, V.Yu., and Kuz’mina, T.I., Evaluation of indicators of postejaculation maturation of spermatozoa of Bos taurus using a chlortetracycline test, Russ. J. Dev. Biol., 2015, vol. 46, no. 6, pp. 362–367.CrossRefGoogle Scholar
  15. 15.
    Boitseva, E.N., Bychkova, N.V., and Kuz’mina, T.I., Influence of highly dispersed silica nanoparticles on the apoptosis of Bos taurus sperm, Tsitologiya, 2017, vol. 59, no. 5, pp. 375–380.Google Scholar
  16. 16.
    Branco, C.S., Garcez, M.E., Pasqualotto, F.F., et al., Resveratrol and ascorbic acid prevent DNA damage induced by cryopreservation in human semen, Cryobiology, 2010, vol. 60, no. 2, pp. 235–237.CrossRefPubMedGoogle Scholar
  17. 17.
    Cai, J. and Jones, D.P., Superoxide in apoptosis. Mitochondrial generation triggered by cytochrome c loss, J. Biol. Chem., 1998, vol. 273, pp. 11401–11404.CrossRefPubMedGoogle Scholar
  18. 18.
    Chimento, A., Sirianni, R., Delalande, C., et al., 17 beta-estradiol activates rapid signaling pathways involved in rat pachytene spermatocytes apoptosis through GPR30 and ER alpha, Mol. Cell Endocrinol., 2010, vol. 320, pp. 136–144.CrossRefPubMedGoogle Scholar
  19. 19.
    Correia, J., Michelangeli, F., and Publicover, S., Regulation and roles of Ca2+ stores in human sperm, Reproduction, 2015, vol. 150, no. 2, pp. R65–R76.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dogan, S., Mason, M.C., Govindaraju, A., et al., Interrelationships between apoptosis and fertility in bull sperm, J. Reprod. Dev., 2013, vol. 59, no. 1, pp. 18–26.CrossRefPubMedGoogle Scholar
  21. 21.
    Gallardo Bolaños, J.M., Miró Morán, Á., Balao da Silva, C.M., et al., Autophagy and apoptosis have a role in the survival or death of stallion spermatozoa during conservation in refrigeration, PLoS One, 2012, vol. 7, no. 1. e30688.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Grad, I., Cederroth, C.R., Walicki, J., et al., The molecular chaperone Hsp90ais required for meiotic progression of spermatocytes beyond pachytene in the mouse, PLoS One, 2010, vol. 5, no. 12. e15770.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Grunewald, S., Kriegel, C., Baumann, T., et al., Interactions between apoptotic signal transduction and capacitation in human spermatozoa, Hum. Reprod., 2009, vol. 24, no. 9, pp. 2071–2078.CrossRefPubMedGoogle Scholar
  24. 24.
    De Iuliis, G.N., Thomson, L.K., Mitchell, L.A., et al., 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., 2009, vol. 81, pp. 517–524.CrossRefPubMedGoogle Scholar
  25. 25.
    Koppers, A.J., Mitchell, L.A., Wang, P., et al., Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa, Biochem. J., 2011, vol. 436, pp. 687–698.CrossRefPubMedGoogle Scholar
  26. 26.
    Kosir, R., Juvan, P., Perse, M., et al., Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis, PLoS One, 2012, vol. 7, no. 2. e31798.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kostro, K., Krakowski, L., Lisiecka, U., et al., Flow cytometric evaluation of sperm apoptosis in semen of silver foxes in the breeding period, Anim. Reprod. Sci., 2014, vol. 144, pp. 54–58.CrossRefPubMedGoogle Scholar
  28. 28.
    Krakowski, L., Obara, J., Wachocka, A., et al., Assessment of extent of apoptosis and DNA defragmentation in chilled semen of stallions during the breeding season, Reprod. Domest. Anim., 2013, vol. 48, no. 5, pp. 826–832.CrossRefPubMedGoogle Scholar
  29. 29.
    Kushnareva, Y., Murphy, A.N., and Andreyev, A., Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation–reduction state, Biochem. J., 2002, vol. 368, pp. 545–553.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lasso, J.L., Noiles, E.E., Alvarez, J.G., et al., Mechanism of superoxide dismutase loss from human sperm cells during cryopreservation, J. Androl., 1994, vol. 15, no. 3, pp. 255–265.PubMedGoogle Scholar
  31. 31.
    Li, Z., Lin, Q., Liu, R., et al., Protective effects of ascorbate and catalase on human spermatozoa during cryopreservation, J. Androl., 2010, vol. 31, no. 5, pp. 437–444.CrossRefPubMedGoogle Scholar
  32. 32.
    Lin, Y.C., Yao, P.L., and Richburg, J.H., FasL gene-deficient mice display a limited disruption in spermatogenesis and inhibition of mono-(2-ethylhexyl) phthalate-induced germ cell apoptosis, Toxicol. Sci., 2010, vol. 114, pp. 335–345.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu, Z., Zhou, S., Liao, L., et al., Jmjd1a demethylase-regulated histone modification is essential for camp-response element modulator-regulated gene expression and spermatogenesis, J. Biol. Chem., 2010, vol. 285, pp. 2758–2770.CrossRefPubMedGoogle Scholar
  34. 34.
    Lu, C. and Thompson, C.B., Metabolic regulation of epigenetics, Cell Metab., 2012, vol. 16, pp. 9–17.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Maione, B., Pittoggi, C., Achene, L., et al., Activation of endogenous nucleases in mature sperm cells upon interaction with exogenous DNA, DNA Cell Biol., 1997, vol. 16, no. 9, pp. 1087–1097.CrossRefPubMedGoogle Scholar
  36. 36.
    Marchetti, C., Obert, G., Deffosez, A., et al., Study of mitochondrial membrane potential, reactive oxygen species, DNA fragmentation and cell viability by flow cytometry in human sperm, Hum. Reprod., 2002, vol. 17, pp. 1257–1265.CrossRefPubMedGoogle Scholar
  37. 37.
    Martí, E., Pérez‑Pé, R., Colás, C., et al., Study of apoptosis-related markers in ram spermatozoa, Anim. Reprod. Sci., 2008, vol. 106, nos. 1–2, pp. 113–132.CrossRefPubMedGoogle Scholar
  38. 38.
    Martin, G., Sabido, O., Durand, P., et al., Cryopreservation induces an apoptosis-like mechanism in bull sperm, Biol. Reprod., 2004, vol. 71, pp. 28–37.CrossRefPubMedGoogle Scholar
  39. 39.
    Martin, G., Cagnon, N., Sabido, O., et al., Kinetics of occurrence of some features of apoptosis during the cryopreservation process of bovine spermatozoa, Hum. Reprod., 2007, vol. 22, pp. 380–388.CrossRefPubMedGoogle Scholar
  40. 40.
    Meditsinskaya khimiya i klinicheskoe primenenie dioksida kremniya (Medicinal Chemistry and Clinical Application of Silica), Chuiko, A.A., Ed., Kiev: Naukova Dumka, 2003.Google Scholar
  41. 41.
    Mendoza, N., Casao, A., Pérez-Pé, R., et al., New insights into the mechanisms of ram sperm protection by seminal plasma proteins, Biol. Reprod., 2013, vol. 88, no. 6, p. 149.CrossRefPubMedGoogle Scholar
  42. 42.
    Miething, A., Germ-cell death during prespermatogenesis in the testis of the golden hamster, Cell Tissue Res., 1992, vol. 267, no. 3, pp. 583–590.CrossRefPubMedGoogle Scholar
  43. 43.
    Muratori, M., Tamburrino, L., Marchiani, S., et al., Investigation on the origin of sperm DNA fragmentation: role of apoptosis, immaturity and oxidative stress, Mol. Med., 2015, vol. 21, pp. 109–122.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Nastasienko, N.S., Kuzema, P.O., Galagan, N.P., et al., Investigation of the biological activity of silica modified with di- and trimethylsilyl groups and sorbitol with respect to bovine sperm cells by photon correlation spectroscopy, Fizika Zhivogo, 2010, vol. 18, no. 3, pp. 99–106.Google Scholar
  45. 45.
    Novotny, G.W., Sonne, S.B., Nielsen, J.E., et al., Translational repression of E2F1 mRNA in carcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster, Cell Death Differ., 2007, vol. 14, pp. 879–882.CrossRefPubMedGoogle Scholar
  46. 46.
    Oehninger, S., Morshedi, M., Weng, S., et al., Presence and significance of somatic cell apoptosis markers in human ejaculated spermatozoa, Reprod. Biomed. Online, 2003, vol. 7, pp. 469–476.CrossRefPubMedGoogle Scholar
  47. 47.
    Ortega-Ferrusola, C., Sotillo-Galan, Y., Varela-Fernandez, E., et al., Detection of “apoptosis-like” changes during the cryopreservation process in equine sperm, J. Androl., 2008, vol. 29, pp. 213–221.CrossRefPubMedGoogle Scholar
  48. 48.
    Ortega-Ferrusola, C., Gonzalez Fernandez, L., Salazar Sandoval, C., et al., Inhibition of the mitochondrial permeability transition pore reduces “apoptosis like” changes during cryopreservation of stallion spermatozoa, Theriogenology, 2010, vol. 74, pp. 458–465.CrossRefPubMedGoogle Scholar
  49. 49.
    Paasch, U., Grunewald, S., Fitzl, G., et al., Deterioration of plasma membrane is associated with activation of caspases in human spermatozoa, J. Androl., 2003, vol. 24, pp. 246–252.CrossRefPubMedGoogle Scholar
  50. 50.
    Paasch, U., Sharma, R.K., Gupta, A.K., et al., Cryopreservation and thawing is associated with varying extent of activation of apoptotic machinery in subsets of ejaculated human spermatozoa, Biol. Reprod., 2004, vol. 71, no. 6, pp. 1828–1837.CrossRefPubMedGoogle Scholar
  51. 51.
    Paoli, D., Lombardo, F., Lenzi, A., et al., Sperm cryopreservation: effects on chromatin structure, Adv. Exp. Med. Biol., 2014, vol. 791, pp. 137–150.CrossRefPubMedGoogle Scholar
  52. 52.
    Pena, F.J., Johannisson, A., Wallgren, M., et al., Assessment of fresh and frozen-thawed boar semen using an annexin-V assay: a new method of evaluating sperm membrane integrity, Theriogenology, 2003, vol. 60, pp. 677–689.CrossRefPubMedGoogle Scholar
  53. 53.
    Rotgers, E., Nurmio, M., Pietilä, E., et al., E2F1 controls germ cell apoptosis during the first wave of spermatogenesis, Andrology, 2015, vol. 3, no. 5, pp. 1000–1014.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Said, T.M., Gaglani, A., and Agarwal, A., Implication of apoptosis in sperm cryoinjury, Reprod. Biomed. Online, 2010, vol. 21, no. 4, pp. 456–462.CrossRefPubMedGoogle Scholar
  55. 55.
    Sakkas, D., Mariethoz, E., Manicardi, G., et al., Origin of DNA damage in ejaculated human spermatozoa, Rev. Reprod., 1999a, vol. 4, pp. 31–37.CrossRefPubMedGoogle Scholar
  56. 56.
    Sakkas, D., Mariethoz, E., and St. John, J.C., Abnormal sperm parameters in humans are indicative of an abortive apoptotic mechanism linked to the Fas-mediated pathway, Exp. Cell Res., 1999b, vol. 251, pp. 350–355.CrossRefPubMedGoogle Scholar
  57. 57.
    Sakkas, D., Seli, E., Manicardi, G.C., et al., The presence of abnormal spermatozoa in the ejaculate: did apoptosis fail?, Hum. Fertil. (Camb.), 2004, vol. 7, pp. 99–103.CrossRefGoogle Scholar
  58. 58.
    Shukla, K.K., Mahdi, A.A., and Rajender, S., Apoptosis, spermatogenesis and male infertility, Front. Biosci., 2012, vol. 4, pp. 746–754.CrossRefGoogle Scholar
  59. 59.
    Stephan, H., Polzar, B., Rauch, F., et al., Distribution of deoxyribonuclease I (DNase I) and p53 in rat testis and their correlation with apoptosis, Histochem. Cell Biol., 1996, vol. 106, no. 4, pp. 383–393.CrossRefPubMedGoogle Scholar
  60. 60.
    Taylor, S.L., Weng, S.L., Fox, P., et al., Somatic cell apoptosis markers and pathways in human ejaculated sperm: potential utility as indicators of sperm quality, Mol. Hum. Reprod., 2004, vol. 10, pp. 825–834.CrossRefPubMedGoogle Scholar
  61. 61.
    Taylor, K., Roberts, P., Sanders, K., et al., Effect of antioxidant supplementation of cryopreservation medium on post-thaw integrity of human spermatozoa, Reprod. Biomed. Online, 2009, vol. 18, no. 2, pp. 184–189.CrossRefPubMedGoogle Scholar
  62. 62.
    Thomson, L.K., Fleming, S.D., Aitken, R.J., et al., Cryopreservation-induced human sperm DNA damage is predominantly mediated by oxidative stress rather than apoptosis, Hum. Reprod., 2009, vol. 24, no. 9, pp. 2061–2070.CrossRefPubMedGoogle Scholar
  63. 63.
    Tsounapi, P., Saito, M., Dimitriadis, F., et al., Antioxidant treatment with edaravone or taurine ameliorates diabetes-induced testicular dysfunction in the rat, Mol. Cell Biochem., 2012, vol. 369, pp. 195–204.CrossRefPubMedGoogle Scholar
  64. 64.
    Del Valle, I., Mendoza, N., Casao, A., et al., Significance of non-conventional parameters in the evaluation of cooling-induced damage to ram spermatozoa diluted in three different media, Reprod. Domest. Anim., 2010, vol. 45, pp. e260–e268.CrossRefPubMedGoogle Scholar
  65. 65.
    Varum, S., Bento, C., Sousa, A.P., et al., Characterization of human sperm populations using conventional parameters, surface ubiquitination, and apoptotic markers, Fertil. Steril., 2007, vol. 87, no. 3, pp. 572–583.CrossRefPubMedGoogle Scholar
  66. 66.
    Vasicek, J., Pivko, J., and Chrenek, P., Reproductive performance of New Zealand White rabbits after depletion of apoptotic spermatozoa, Folia Biol. (Krakow), 2014, vol. 62, no. 2, pp. 109–117.CrossRefGoogle Scholar
  67. 67.
    Vaux, D.L. and Korsmeyer, S.J., Cell death in development, Cell, 1999, vol. 96, pp. 245–254.CrossRefPubMedGoogle Scholar
  68. 68.
    Weil, M., Jacobson, M.D., and Raff, M.C., Are caspases involved in the death of cells with a transcriptionally inactive nucleus? Sperm and chicken erythrocytes, J. Cell Sci., 1998, vol. 111, pp. 2707–2715.PubMedGoogle Scholar
  69. 69.
    Weng, S.L., Taylor, S.L., Morshedi, M., et al., Caspase activity and apoptotic markers in ejaculated human sperm, Mol. Hum. Reprod., 2002, vol. 8, no. 11, pp. 984–991.CrossRefPubMedGoogle Scholar
  70. 70.
    Yamasaki, L., Jacks, T., Bronson, R., et al., Tumor induction and tissue atrophy in mice lacking E2F-1, Cell, 1996, vol. 85, pp. 537–548.CrossRefPubMedGoogle Scholar
  71. 71.
    Youle, R.J. and Strasser, A., The BCL-2 protein family: opposing activities that mediate cell death, Nat. Rev. Mol. Cell Biol., 2008, vol. 9, no. 1, pp. 47–59.CrossRefPubMedGoogle Scholar
  72. 72.
    Zeng, C., Tang, K., He, L., et al., Effects of glycerol on apoptotic signaling pathways during boar spermatozoa cryopreservation, Cryobiology, 2014, vol. 68, pp. 395–404.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  1. 1.All-Russia Research Institute of Farm Animal Genetics and Breeding, Ernst VIZh Federal Science Center for Animal HusbandryPushkin, St. PetersburgRussia

Personalised recommendations