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Oxidative stress and male infertility

Nature Reviews Urology volume 14, pages 470–485 (2017)Cite this article

Subjects

Key Points

  • Male infertility is a complex lifestyle-related disorder

  • Oxidative stress has adverse effects on the structural and functional integrity of sperm and is a major cause of defective sperm function and male infertility

  • Oxidative stress causes damage to both mitochondrial and nuclear DNA and also affects the sperm epigenome, resulting in infertility, recurrent pregnancy loss, poor pregnancy outcomes and an increased disease burden in the offspring

  • Spermatozoa are most vulnerable to oxidative stress and oxidative DNA damage (ODD) as these cells have limited antioxidant defence mechanisms and a limited capacity for detection and repair of DNA damage

  • A number of intrinsic and extrinsic factors can regulate oxidative stress, and these must be maintained at moderate levels for optimal sperm function and the maintenance of cellular homeostasis and redox-sensitive signal-transduction pathways

  • Simple lifestyle modifications and interventions can substantially reduce levels of testicular inflammation, oxidative stress and ODD and improve the quality of life of infertile couples

Abstract

DNA damage, largely owing to oxidative stress, is a leading cause of defective sperm function. High levels of oxidative stress result in damage to sperm DNA, RNA transcripts, and telomeres and, therefore might provide a common underlying aetiology of male infertility and recurrent pregnancy loss, in addition to congenital malformations, complex neuropsychiatric disorders, and childhood cancers in children fathered by men with defective sperm cells. Spermatozoa are highly vulnerable to oxidative stress owing to limited levels of antioxidant defence and a single, limited DNA-damage detection and repair mechanism. Oxidative stress is predominantly caused by a host of lifestyle-related factors, the majority of which are modifiable. Antioxidant regimens and lifestyle modifications could both be plausible therapeutic approaches that enable the burden of oxidative-stress-induced male factor infertility to be overcome. Lifestyle interventions including yoga and meditation can substantially improve the integrity of sperm DNA by reducing levels of oxidative DNA damage, regulating oxidative stress and by increasing the expression of genes responsible for DNA repair, cell-cycle control and anti-inflammatory effects. Oxidative stress is caused by various modifiable factors, and the use of simple interventions can decrease levels of oxidative stress, and therefore reduce the incidence of both infertility and complex diseases in the resultant offspring.

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Figure 1: Causes and consequences of seminal oxidative stress and oxidative DNA damage.

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References

  1. Rowe, P. J. & Comhaire, F. H. WHO manual for the standardized investigation and diagnosis of the infertile male (Cambridge Univ. Press, 2000).

    Google Scholar 

  2. Inhorn, M. C. & Patrizio, P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum. Reprod. Update 21, 411–426 (2015).

    Article  PubMed  Google Scholar 

  3. Jarow, J. P. et al. Best practice policies for male infertility. J. Urol. 167, 2138–2144 (2002).

    Article  PubMed  Google Scholar 

  4. Aitken, R. J., Buckingham, D. W. & West, K. M. Reactive oxygen species and human spermatozoa: analysis of the cellular mechanisms involved in luminol- and lucigenin-dependent chemiluminescence. J. Cell. Physiol. 151, 466–477 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Aitken, J. & Fisher, H. Reactive oxygen species generation and human spermatozoa: the balance of benefit and risk. Bioessays 16, 259–267 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Agarwal, A., Prabakaran, S. & Allamaneni, S. What an andrologist/urologist should know about free radicals and why. Urology 67, 2–8 (2006).

    Article  PubMed  Google Scholar 

  7. Aitken, R. J. & Curry, B. J. 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. 14, 367–381 (2011). Defective human spermatozoa is characterized by the presence of large amounts of DNA damage, which is largely oxidative in nature and closely associated with defects in spermiogenesis, which are further associated with reduced fertility, increased rates of miscarriage, and an enhanced risk of disease in the offspring.

    Article  CAS  PubMed  Google Scholar 

  8. Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44–84 (2007). Overproduction of free radicals such as reactive oxygen species and reactive nitrogen species leads to oxidative stress, which is associated with the pathophysiology of various human diseases including cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer disease and Parkinson disease), rheumatoid arthritis, and ageing.

    Article  CAS  PubMed  Google Scholar 

  9. Aitken, R. J., Baker, M. A. & Sawyer, D. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Aitken, R. J. & Baker, M. A. Oxidative stress, sperm survival and fertility control. Mol. Cell. Endocrinol. 250, 66–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Agarwal, A., Virk, G., Ong, C. & du Plessis, S. S. Effect of oxidative stress on male reproduction. World J. Mens Health 32, 1–17 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Venkatesh, S. et al. Clinical implications of oxidative stress & sperm DNA damage in normozoospermic infertile men. Indian J. Med. Res. 134, 396 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Aitken, R. J. et al. Sperm motility is lost in vitro as a consequence of mitochondrial free radical production and the generation of electrophilic aldehydes but can be significantly rescued by the presence of nucleophilic thiols. Biol. Reprod. 87, 110 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. De Lamirande, E. & Gagnon, C. Reactive oxygen species and human spermatozoa: I. Effects on the motility of intact spermatozoa and on sperm axonemes. J. Androl. 13, 368–368 (1992).

    CAS  PubMed  Google Scholar 

  15. Aitken, R. J., De Iuliis, G. N. & McLachlan, R. I. Biological and clinical significance of DNA damage in the male germ line. Int. J. Androl. 32, 46–56 (2009). Development of appropriate therapeutic strategies to complement the assessment of sperm DNA damage is very much essential for the treatment of patients with male infertility as DNA damage in the male germ line is a major risk factor for adverse clinical outcomes including poor fertilization, impaired development of the pre-implantation embryo, miscarriage and an increased risk of morbidities and mortality in the offspring.

    Article  CAS  PubMed  Google Scholar 

  16. Kumar, K. et al. Predictive value of DNA integrity analysis in idiopathic recurrent pregnancy loss following spontaneous conception. J. Assist. Reprod. Genet. 29, 861–867 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Høst, E., Lindenberg, S. & Smidt-Jensen, S. The role of DNA strand breaks in human spermatozoa used for IVF and ICSI. Acta Obstet. Gynecol. Scand. 79, 559–563 (2000).

    Article  PubMed  Google Scholar 

  18. Kumar, S. B., Yadav, R., Yadav, R. K., Tolahunase, M. & Dada, R. Telomerase activity and cellular aging might be positively modified by a yoga-based lifestyle intervention. J. Altern. Complement. Med. 21, 370–372 (2015). Yoga and meditation based lifestyle interventions are an adjunct to modern medicine as they enable reversal of the accumulation of markers of ageing such as oxidative stress, telomerase activity and oxidative DNA damage which are further associated with delaying or preventing the onset of several lifestyle-related disorders.

    Article  PubMed  Google Scholar 

  19. Kumar, S., Chawla, B., Bisht, S., Yadav, R. & Dada, R. Tobacco use increases oxidative DNA damage in sperm-possible etiology of childhood cancer. Asian Pac. J. Cancer Prev. 16, 6967–6972 (2014). Smoking is associated with free radical production resulting in high levels of DNA damage in human sperm and can affect the integrity of sperm DNA, which might result in increased incidences of childhood cancer in the offspring.

    Article  Google Scholar 

  20. Aitken, R. J. Human spermatozoa: revelations on the road to conception. F1000Prime Rep. 5, 39 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Aitken, R. J., Smith, T. B., Jobling, M. S., Baker, M. A. & De Iuliis, G. N. Oxidative stress and male reproductive health. Asian J. Androl. 16, 31 (2014). Age, environmental or lifestyle-related factors cause oxidative stress in the male germ line, which not only disrupts the integrity of sperm DNA but also limits its fertilizing potential as a result of collateral damage to proteins and lipids in the sperm plasma membrane which might cause childhood cancers or other diseases in the next generation.

    Article  CAS  PubMed  Google Scholar 

  22. Baccetti, B. & Afzelius, B. A. The biology of the sperm cell. Monogr. Dev. Biol. 10, 1–254 (1976).

    Google Scholar 

  23. McGhee, J. & Felsenfeld, G. Nucleosome structure. Annu. Rev. Biochem. 49, 1115–1156 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. Finch, J. & Klug, A. Solenoidal model for superstructure in chromatin. Proc. Natl Acad. Sci. USA 73, 1897–1901 (1976).

    Article  CAS  PubMed  Google Scholar 

  25. Aoki, V. W. & Carrell, D. T. Human protamines and the developing spermatid: their structure, function, expression and relationship with male infertility. Asian J. Androl. 5, 315–324 (2003).

    CAS  PubMed  Google Scholar 

  26. Oliva, R. & Dixon, G. H. Vertebrate protamine genes and the histone-to-protamine replacement reaction. Prog. Nucleic Acid Res. Mol. Biol. 40, 25–94 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Steger, K., Pauls, K., Klonisch, T., Franke, F. E. & Bergmann, M. Expression of protamine-1 and-2 mRNA during human spermiogenesis. Mol. Hum. Reprod. 6, 219–225 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Kosower, N. S., Katayose, H. & Yanagimachi, R. Thiol-disulfide status and acridine orange fluorescence of mammalian sperm nuclei. J. Androl. 13, 342–348 (1992).

    CAS  PubMed  Google Scholar 

  29. Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Oliva, R. Protamines and male infertility. Hum. Reprod. Update 12, 417–435 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Venkatesh, S., Kumar, R., Deka, D., Deecaraman, M. & Dada, R. Analysis of sperm nuclear protein gene polymorphisms and DNA integrity in infertile men. Syst. Biol. Reprod. Med. 57, 124–132 (2011). Sperm nuclear proteins, the protamines (PRM) and transition nuclear proteins (TNP) have crucial roles in sperm nuclear condensation, and single-nucleotide polymorphisms in the PRM and/or TNP genes are associated with higher levels of sperm DNA fragmentation and thus, male infertility.

    Article  CAS  PubMed  Google Scholar 

  32. Steger, K. et al. Both protamine-1 to protamine-2 mRNA ratio and Bcl2 mRNA content in testicular spermatids and ejaculated spermatozoa discriminate between fertile and infertile men. Hum. Reprod. 23, 11–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Balhorn, R., Reed, S. & Tanphaichitr, N. Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males. Experientia 44, 52–55 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Aoki, V. W., Christensen, G. L., Atkins, J. F. & Carrell, D. T. Identification of novel polymorphisms in the nuclear protein genes and their relationship with human sperm protamine deficiency and severe male infertility. Fertil. Steril. 86, 1416–1422 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Jiang, W. et al. Polymorphisms in protamine 1 and protamine 2 predict the risk of male infertility: a meta-analysis. Sci. Rep. 5, 15300 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. MacLeod, J. The role of oxygen in the metabolism and motility of human spermatozoa. Am. J. Physiol. 138, 512–518 (1943).

    Article  CAS  Google Scholar 

  37. Storey, B. T. Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa. Mol. Hum. Reprod. 3, 203–213 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Gomez, E., Irvine, D. & Aitken, R. Evaluation of a spectrophotometric assay for the measurement of malondialdehyde and 4-hydroxy-alkenals in human spermatozoa: relationships with semen quality and sperm function. Int. J. Androl. 21, 81–94 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Aitken, R. J., Clarkson, J. S. & Fishel, S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol. Reprod. 41, 183–197 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Aitken, R., Harkiss, D., Knox, W., Paterson, M. & Irvine, D. A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation. J. Cell Sci. 111, 645–656 (1998).

    CAS  PubMed  Google Scholar 

  41. Koppers, A. J., Garg, M. L. & Aitken, R. J. Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa. Free Radic. Biol. Med. 48, 112–119 (2010). Defective human spermatozoa are characterized by an abnormally high fatty acid content that, in their unesterified, unsaturated form, promote the generation of reactive oxygen species by sperm mitochondria, thus creating a state of oxidative stress with a concomitant loss of functional competence.

    Article  CAS  PubMed  Google Scholar 

  42. Semchyshyn, H. M. & Lushchak, V. I. in Oxidative Stress — Molecular Mechanisms and Biological Effects 15–46 (InTech, 2012).

    Google Scholar 

  43. Dianov, G. L. et al. Base excision repair in nuclear and mitochondrial DNA. Prog. Nucleic Acid Res. Mol. Biol. 68, 285–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Shamsi, M. B. et al. Mitochondrial DNA mutations in etiopathogenesis of male infertility. Indian J. Urol. 24, 150 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Feng, C., Song, Y., Zou, Y. & Mao, X. Mutation of MTCYB and MTATP6 is associated with asthenospermia [Chinese]. Zhonghua Nan Ke Xue 14, 321–323 (2008).

    CAS  PubMed  Google Scholar 

  46. Turner, C. et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum. Genet. 112, 303–309 (2003).

    PubMed  Google Scholar 

  47. Venkatesh, S., Deecaraman, M., Kumar, R., Shamsi, M. & Dada, R. Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mtDNA) mutations in male infertility. Indian J. Med. Res. 129, 127–137 (2009).

    CAS  PubMed  Google Scholar 

  48. Aitken, R. & West, K. Analysis of the relationship between reactive oxygen species production and leucocyte infiltration in fractions of human semen separated on Percoll gradients. Int. J. Androl. 13, 433–451 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Mishra, S., Kumar, R., Malhotra, N., Singh, N. & Dada, R. Mild oxidative stress is beneficial for sperm telomere length maintenance. World J. Methodol. 6, 163 (2016). Telomere maintenance is complex trait and mild oxidative stress can increase telomere length; however, severe oxidative stress results in shorter telomere lengths, and thus a delicate balance needs to be established in order to maximize the beneficial effects of free radicals and prevent the harmful effects caused by supraphysiological levels of such molecules.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kumar, K., Thilagavathi, J., Deka, D. & Dada, R. Unexplained early pregnancy loss: role of paternal DNA. Indian J. Med. Res. 136, 296 (2012).

    PubMed  PubMed Central  Google Scholar 

  51. Kodama, H., Yamaguchi, R., Fukuda, J., Kasai, H. & Tanaka, T. Increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. Fertil. Steril. 68, 519–524 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Dorostghoal, M., Kazeminejad, S., Shahbazian, N., Pourmehdi, M. & Jabbari, A. Oxidative stress status and sperm DNA fragmentation in fertile and infertile men. Andrologia http://dx.doi.org/10.1111/and.12762 (2017).

  53. Iommiello, V. M. et al. Ejaculate oxidative stress is related with sperm DNA fragmentation and round cells. Int. J. Endocrinol. 2015, 321901 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bay, B., Mortensen, E. L., Hvidtjørn, D. & Kesmodel, U. S. Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study. BMJ 347, f3978 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Davies, M. J. et al. Reproductive technologies and the risk of birth defects. N. Engl. J. Med. 366, 1803–1813 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Bauer, N. C., Corbett, A. H. & Doetsch, P. W. The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res. 43, 10083–10101 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Li, Z., Yang, J. & Huang, H. Oxidative stress induces H2AX phosphorylation in human spermatozoa. FEBS Lett. 580, 6161–6168 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Hosen, M. B., Islam, M. R., Begum, F., Kabir, Y. & Howlader, M. Z. H. Oxidative stress induced sperm DNA damage, a possible reason for male infertility. Iran. J. Reprod. Med. 13, 525–532 (2015).

    PubMed  PubMed Central  Google Scholar 

  59. Iyama, T. & Wilson, D. M. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst.) 12, 620–636 (2013).

    Article  CAS  Google Scholar 

  60. Aitken, R. J. & Krausz, C. Oxidative stress, DNA damage and the Y chromosome. Reproduction 122, 497–506 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Lenzi, A. et al. Fatty acid composition of spermatozoa and immature germ cells. Mol. Hum. Reprod. 6, 226–231 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Aitken, R. J., Wingate, J. K., De Iuliis, G. N., Koppers, A. J. & McLaughlin, E. A. Cis-unsaturated fatty acids stimulate reactive oxygen species generation and lipid peroxidation in human spermatozoa. J. Clin. Endocrinol. Metab. 91, 4154–4163 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Koppers, A. J., De Iuliis, G. N., Finnie, J. M., McLaughlin, E. A. & Aitken, R. J. Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa. J. Clin. Endocrinol. Metab. 93, 3199–3207 (2008). The findings of this study highlight the potential importance of aberrant mitochondrial activity in the aetiology of defective sperm function, which remains one of the major causes of human infertility.

    Article  CAS  PubMed  Google Scholar 

  64. Tremellen, K. Oxidative stress and male infertility — a clinical perspective. Hum. Reprod. Update 14, 243–258 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Aitken, R. J., Koopman, P. & Lewis, S. E. Seeds of concern. Nature 432, 48–52 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Pasqualotto, F. F., Sharma, R. K., Nelson, D. R., Thomas, A. J. & Agarwal, A. Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation. Fertil. Steril. 73, 459–464 (2000). Reactive oxygen species generated by leukocytes, especially polymorphonuclear leukocytes (PML), or granulocytes, can have a deleterious effect on human spermatozoa, as shown by a marked loss of sperm motility and a reduced capacity for oocyte penetration. PML are a major source of the reactive oxygen species that affect human sperm.

    Article  CAS  PubMed  Google Scholar 

  67. Gdoura, R. et al. Screening for bacterial pathogens in semen samples from infertile men with and without leukocytospermia. Andrologia 40, 209–218 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Sadri-Ardekani, H. & Akhondi, M. Identification and treatment of leukocytospermia in infertile men. J. Reprod. Infertil. 7, 401–411 (2007).

    Google Scholar 

  69. Baker, M. A. & Aitken, R. J. Reactive oxygen species in spermatozoa: methods for monitoring and significance for the origins of genetic disease and infertility. Reprod. Biol. Endocrinol. 3, 67 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Agarwal, A. & Allamaneni, S. The effect of sperm DNA damage on assisted reproduction outcomes. Minerva Ginecol. 56, 235–245 (2004).

    CAS  PubMed  Google Scholar 

  71. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).

    Article  PubMed  Google Scholar 

  72. Pacher, P., Beckman, J. S. & Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Singh, R. P., Sharad, S. & Kapur, S. Free radicals and oxidative stress in neurodegenerative diseases: relevance of dietary antioxidants. J. Indian Acad. Clin. Med. 5, 218–225 (2004).

    Google Scholar 

  74. Ho, E., Galougahi, K. K., Liu, C.-C., Bhindi, R. & Figtree, G. A. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol. 1, 483–491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Halliwell, B. & Whiteman, M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br. J. Pharmacol. 142, 231–255 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Aitken, R. J. & Roman, S. D. Antioxidant systems and oxidative stress in the testes. Oxid. Med. Cell. Longev. 1, 15–24 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Klungland, A. & Bjelland, S. Oxidative damage to purines in DNA: role of mammalian Ogg1. DNA Repair 6, 481–488 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Guz, J. et al. Comparison of oxidative stress/DNA damage in semen and blood of fertile and infertile men. PLoS ONE 8, e68490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. De Iuliis, G. N. 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. 81, 517–524 (2009). This study suggests that elevated levels of spontaneous 8OHdG formation as observed in the defective spermatozoa are associated with high rates of ROS formation, enhanced rates of DNA damage, and limited chromatin remodelling.

    Article  CAS  PubMed  Google Scholar 

  80. Smith, T. B. et al. The presence of a truncated base excision repair pathway in human spermatozoa that is mediated by OGG1. J. Cell Sci. 126, 1488–1497 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Tamburrino, L. et al. Mechanisms and clinical correlates of sperm DNA damage. Asian J. Androl. 14, 24–31 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Kumar, S., Murarka, S., Mishra, V. & Gautam, A. Environmental & lifestyle factors in deterioration of male reproductive health. Indian J. Med. Res. 140, 29 (2014). The findings of the study indicate that various lifestyle factors such as tobacco smoking, chewing and alcohol use as well as exposure to toxic agents might be attributed to the risk of declining semen quality and increases in oxidative stress and sperm DNA damage.

    Google Scholar 

  83. Misner, S. & Florian, T. A. Organically grown foods versus non-organically grown foods (College of Agriculture and Life Sciences, Univ. of Arizona, 2013).

    Google Scholar 

  84. Wright, C., Milne, S. & Leeson, H. Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. Reprod. Biomed. Online 28, 684–703 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Walczak-Jedrzejowska, R., Wolski, J. K. & Slowikowska-Hilczer, J. The role of oxidative stress and antioxidants in male fertility. Cent. European J. Urol. 66, 60–67 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Fusco, D., Colloca, G., Monaco, M. R. L. & Cesari, M. Effects of antioxidant supplementation on the aging process. Clin. Interv. Aging 2, 377–387 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Tolahunase, M. et al. Yoga and meditation promotes quality of life by decreasing depression severity and cellular aging in male infertility: randomized controlled trial. Presented at the 42nd American Society of Andrology Annual Meeting (2017).

  88. Kanherkar, R. R. et al. Epigenetic mechanisms of integrative medicine. Evid. Based Complement. Alternat. Med. 2017, 4365429 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Kovac, J. R. et al. The effects of advanced paternal age on fertility. Asian J. Androl. 15, 723–728 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. de Souza-Pinto, N. C., Hogue, B. A. & Bohr, V. A. DNA repair and aging in mouse liver: 8-oxodG glycosylase activity increase in mitochondrial but not in nuclear extracts. Free Radic. Biol. Med. 30, 916–923 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Paul, C. & Robaire, B. Ageing of the male germ line. Nat. Rev. Urol. 10, 227–234 (2013). Advanced paternal age is associated with a decline in function of the male reproductive system, sperm quality, and fertility owing to age-associated accumulation of DNA damage and mutations or age-associated germ cell loss, which is further correlated with paternal contribution to chromosomal damage and genetic health problems in the children.

    Article  CAS  PubMed  Google Scholar 

  93. Zheng, P., Schramm, R. D. & Latham, K. E. Developmental regulation and in vitro culture effects on expression of DNA repair and cell cycle checkpoint control genes in rhesus monkey oocytes and embryos. Biol. Reprod. 72, 1359–1369 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Smith, T. B., De Iuliis, G., Lord, T. & Aitken, R. J. The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line. Reproduction 146, 253–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Kong, A. et al. Rate of de novo mutations and the importance of father/'s age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Abbas, H. A., El Rafei, R., Charafeddine, L. & Yunis, K. Effects of advanced paternal age on reproduction and outcomes in offspring. Neoreviews 16, e69–e83 (2015).

    Article  Google Scholar 

  97. Andrew, S. E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat. Genet. 4, 398–403 (1993).

    Article  CAS  Google Scholar 

  98. Yip, B. H., Pawitan, Y. & Czene, K. Parental age and risk of childhood cancers: a population-based cohort study from Sweden. Int. J. Epidemiol. 35, 1495–1503 (2006).

    Article  PubMed  Google Scholar 

  99. Wiener-Megnazi, Z., Auslender, R. & Dirnfeld, M. Advanced paternal age and reproductive outcome. Asian J. Androl. 14, 69–76 (2012).

    Article  PubMed  Google Scholar 

  100. Jenkins, T. G., Aston, K. I., Pflueger, C., Cairns, B. R. & Carrell, D. T. Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet. 10, e1004458 (2014). This study indicates that alterations in the age-associated methylation of candidate genes in sperm might contribute to the increased incidence of neuropsychiatric, and other disorders in the offspring of older males.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Feinberg, J. I. et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int. J. Epidemiol. 44, 1199–1210 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Richthoff, J., Elzanaty, S., Rylander, L., Hagmar, L. & Giwercman, A. Association between tobacco exposure and reproductive parameters in adolescent males. Int. J. Androl. 31, 31–39 (2008).

    PubMed  Google Scholar 

  103. Calogero, A. et al. Cigarette smoke extract immobilizes human spermatozoa and induces sperm apoptosis. Reprod. Biomed. Online 19, 564–571 (2009).

    Article  PubMed  Google Scholar 

  104. Saleh, R. A. et al. Leukocytospermia is associated with increased reactive oxygen species production by human spermatozoa. Fertil. Steril. 78, 1215–1224 (2002).

    Article  PubMed  Google Scholar 

  105. Zenzes, M. T. Smoking and reproduction: gene damage to human gametes and embryos. Hum. Reprod. Update 6, 122–131 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Trummer, H., Habermann, H., Haas, J. & Pummer, K. The impact of cigarette smoking on human semen parameters and hormones. Hum. Reprod. 17, 1554–1559 (2002).

    Article  PubMed  Google Scholar 

  107. Gautam, S., Chawla, B., Kumar, S. B., Bisht, S. & Dada, R. Sperm DNA damage in non-familial sporadic heritable retinoblastoma (NFSHRb). Clin. Epidemiol. Global Health 3, S20–S25 (2015).

    Article  Google Scholar 

  108. Monsefi, M., Alaee, S., Moradshahi, A. & Rohani, L. Cadmium-induced infertility in male mice. Environ. Toxicol. 25, 94–102 (2010).

    CAS  PubMed  Google Scholar 

  109. Harlev, A., Agarwal, A., Gunes, S. O., Shetty, A. & du Plessis, S. S. Smoking and male infertility: an evidence-based review. World J. Mens Health 33, 143–160 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Sharma, R., Harlev, A., Agarwal, A. & Esteves, S. C. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization laboratory methods for the examination of human semen. Eur. Urol. 70, 635–645 (2016).

    Article  PubMed  Google Scholar 

  111. La Vignera, S., Condorelli, R. A., Balercia, G., Vicari, E. & Calogero, A. E. Does alcohol have any effect on male reproductive function? A review of literature. Asian J. Androl. 15, 221–225 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Muthusami, K. & Chinnaswamy, P. Effect of chronic alcoholism on male fertility hormones and semen quality. Fertil. Steril. 84, 919–924 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. A. Faiq, M., Dada, R., Sharma, R., Saluja, D. & Dada, T. CYP1B1: a unique gene with unique characteristics. Curr. Drug Metab. 15, 893–914 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Malhi, H. & Gores, G. J. Cellular and molecular mechanisms of liver injury. Gastroenterology 134, 1641–1654 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Queiroz, E. K. & Waissmann, W. Occupational exposure and effects on the male reproductive system. Cad. Saúde Pública 22, 485–493 (2006).

    Article  PubMed  Google Scholar 

  116. Whitacre, D. M. & Gunther, F. A. Reviews of Environmental Contamination and Toxicology (Springer, 2010).

    Book  Google Scholar 

  117. Lee, E. et al. Effect of di(n-butyl) phthalate on testicular oxidative damage and antioxidant enzymes in hyperthyroid rats. Environ. Toxicol. 22, 245–255 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Zhu, W. & Qiao, J. Male reproductive toxicity of bisphenol A [Chinese]. Zhonghua Nan Ke Xue 21, 1026–1030 (2015).

    CAS  PubMed  Google Scholar 

  119. Aitken, R. J., Findlay, J. K., Hutt, K. J. & Kerr, J. B. Apoptosis in the germ line. Reproduction 141, 139–150 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Rucker, E. B. et al. Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis. Mol. Endocrinol. 14, 1038–1052 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Manku, G. & Culty, J. Dynamic changes in the expression of apoptosis-related genes in differentiating gonocytes and in seminomas. Asian J. Androl. 17, 403–414 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Aitken, R. J. & Baker, M. A. Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development. Int. J. Dev. Biol. 57, 265–272 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Li, Y.-J. et al. Bisphenol A exposure induces apoptosis and up-regulation of Fas/FasL and Caspase-3 expression in the testes of mice. Toxicol. Sci. 108, 427–436 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Shaha, C., Tripathi, R. & Mishra, D. P. Male germ cell apoptosis: regulation and biology. Phil. Trans. R. Soc. B Biol. Sci. 365, 1501–1515 (2010).

    Article  CAS  Google Scholar 

  125. Aitken, R. J. & Koppers, A. J. Apoptosis and DNA damage in human spermatozoa. Asian J. Androl. 13, 36–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Greco, E. et al. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J. Androl. 26, 349–353 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Havrylyuk, A., Chopyak, V., Boyko, Y., Kril, I. & Kurpisz, M. Cytokines in the blood and semen of infertile patients. Cent. Eur. J. Immunol. 40, 337–344 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pentikäinen, V. et al. Nuclear factor-κB activation in human testicular apoptosis. Am. J. Pathol. 160, 205–218 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Rousseaux, S. et al. Epigenetic reprogramming of the male genome during gametogenesis and in the zygote. Reprod. Biomed. Online 16, 492–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Urdinguio, R. G. et al. Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility. Hum. Reprod. 30, 1014–1028 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Faure, A. et al. Misregulation of histone acetylation in Sertoli cell-only syndrome and testicular cancer. Mol. Hum. Reprod. 9, 757–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Murrell, A. et al. An association between variants in the IGF2 gene and Beckwith–Wiedemann syndrome: interaction between genotype and epigenotype. Hum. Mol. Genet. 13, 247–255 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Marees, T. et al. Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study. Hum. Reprod. 24, 3220–3224 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Jenkins, T. G. et al. Decreased fecundity and sperm DNA methylation patterns. Fertil. Steril. 105, 51–57.e3 (2016).

    Article  CAS  PubMed  Google Scholar 

  135. Dinesh, V., Shamsi, M. & Dada, R. Supraphysiological free radical levels and their pathogenesis in male infertility. Reprod. Syst. Sex. Disord. 1, 2 (2012).

    Google Scholar 

  136. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Gaskins, A. J. et al. Physical activity and television watching in relation to semen quality in young men. Br. J. Sports Med. 49, 265–270 (2015).

    Article  PubMed  Google Scholar 

  138. Tolahunase, M., Sagar, R. & Dada, R. Impact of yoga and meditation on cellular aging in apparently healthy individuals: a prospective, open-label single-arm exploratory study. Oxid. Med. Cell. Longev. 2017, 7928981 (2017). Adoption of yoga and meditation based lifestyle intervention is associated with a decline in levels of cardinal biomarkers of cellular aging and oxidative stress and thus may be associated with delaying the aging process, prevent the onset of multifactorial complex lifestyle diseases, promote mental, physical, and reproductive health, and prolong youthful healthy life.

    PubMed  PubMed Central  Google Scholar 

  139. Shamsi, M., Dada, R. & Dinesh, V. Supraphysiological free radical levels and their pathogenesis in male infertility. Reprod. Syst. Sex. Disord. 1, 114 (2012).

    Google Scholar 

  140. Thilagavathi, J. et al. Analysis of sperm telomere length in men with idiopathic infertility. Arch. Gynecol. Obstet. 287, 803–807 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Burns, W. R., Sabanegh, E., Dada, R., Rein, B. & Agarwal, A. Is male infertility a forerunner to cancer? Int. Braz. J. Urol. 36, 527–536 (2010).

    Article  PubMed  Google Scholar 

  142. Jacobsen, R. et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 321, 789–792 (2000). Infertile men with specific semen characteristics such as a low semen concentration, poor motility of the spermatozoa, and a high proportion of morphologically abnormal spermatozoa are 1.6 times more likely to develop testicular cancer than fertile men.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Benoff, S. et al. Cadmium concentrations in blood and seminal plasma: correlations with sperm number and motility in three male populations (infertility patients, artificial insemination donors, and unselected volunteers). Mol. Med. 15, 248–262 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Richardson, L. L., Pedigo, C. & Handel, M. A. Expression of deoxyribonucleic acid repair enzymes during spermatogenesis in mice. Biol. Reprod. 62, 789–796 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Devouassoux-Shisheboran, M. et al. Expression of hMLH1 and hMSH2 and assessment of microsatellite instability in testicular and mediastinal germ cell tumours. Mol. Hum. Reprod. 7, 1099–1105 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  CAS  PubMed  Google Scholar 

  147. West, A. & Lähdetie, J. p21WAF1 expression during spermatogenesis of the normal and X-irradiated rat. Int. J. Radiat. Biol. 71, 283–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  148. Tan, M. et al. Transcriptional activation of the human glutathione peroxidase promoter by p53. J. Biol. Chem. 274, 12061–12066 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Yoon, K. A., Nakamura, Y. & Arakawa, H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J. Hum. Genet. 49, 134–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Hu, W. et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA 107, 7455–7460 (2010).

    Article  PubMed  Google Scholar 

  151. Kumar, S. B. et al. Improvement in sperm DNA quality following simple life style intervention: a study in fathers of children with non-familial sporadic heritable retinoblastoma. J. Clin. Case Rep. 5, 509 (2015).

    Google Scholar 

  152. Dada, T. et al. Effect of yoga and meditation based intervention on intraocular pressure, quality of life, oxidative stress and gene expression pattern in primary open angle glaucoma: a randomized controlled trial [abstract]. Invest. Opthalmol. Vis. Sci. 57 (2016).

  153. Ménézo, Y. J. et al. Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect. Reprod. Biomed. Online 14, 418–421 (2007).

    Article  PubMed  Google Scholar 

  154. Imamovic Kumalic, S. & Pinter, B. Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. Biomed Res. Int. 2014, 426951 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Zini, A., San Gabriel, M. & Baazeem, A. Antioxidants and sperm DNA damage: a clinical perspective. J. Assist. Reprod. Genet. 26, 427–432 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Gharagozloo, P. et al. A novel antioxidant formulation designed to treat male infertility associated with oxidative stress: promising preclinical evidence from animal models. Hum. Reprod. 31, 252–262 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Keskes-Ammar, L. et al. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch. Androl. 49, 83–94 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Verma, A. & Kanwar, K. Effect of vitamin E on human sperm motility and lipid peroxidation in vitro. Asian J. Androl. 1, 151–154 (1999).

    CAS  PubMed  Google Scholar 

  159. Patel, S. R. & Sigman, M. Antioxidant therapy in male infertility. Urol. Clin. North Am. 35, 319–330 (2008).

    Article  PubMed  Google Scholar 

  160. Aly, H. & Mantawy, M. Comparative effects of zinc, selenium and vitamin E or their combination on carbohydrate metabolizing enzymes and oxidative stress in streptozotocine-induced diabetic rats. Eur. Rev. Med. Pharmacol. Sci. 16, 66–78 (2012).

    CAS  PubMed  Google Scholar 

  161. Lü, J. M., Lin, P. H., Yao, Q. & Chen, C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J. Cell. Mol. Med. 14, 840–860 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Lobo, V., Patil, A., Phatak, A. & Chandra, N. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn. Rev. 4, 118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Krinsky, N. I. Mechanism of action of biological antioxidants. Exp. Biol. Med. 200, 248–254 (1992).

    Article  CAS  Google Scholar 

  164. Dorland. Dorland's Illustrated Medical Dictionary 32nd edn (Elsevier Health Sciences, 2011).

  165. Lane, J. D., Seskevich, J. E. & Pieper, C. F. Brief meditation training can improve perceived stress and negative mood. Altern. Ther. Health Med. 13, 38–44 (2007).

    PubMed  Google Scholar 

  166. Carlson, L. E., Speca, M., Patel, K. D. & Goodey, E. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress, and immune parameters in breast and prostate cancer outpatients. Psychosom. Med. 65, 571–581 (2003).

    Article  PubMed  Google Scholar 

  167. Selfe, T. K. & Innes, K. E. Mind-body therapies and osteoarthritis of the knee. Curr. Rheumatol. Rev. 5, 204 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Khalsa, D. S. & Newberg, A. in Enhancing Cognitive Fitness in Adults (eds Hartman-Stein, P. E. & La Rue, A.) 419–431 (Springer, 2011).

    Book  Google Scholar 

  169. Epel, E., Daubenmier, J., Moskowitz, J. T., Folkman, S. & Blackburn, E. Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres. Ann. NY Acad. Sci. 1172, 34–53 (2009).

    Article  PubMed  Google Scholar 

  170. Manikonda, J. et al. Contemplative meditation reduces ambulatory blood pressure and stress-induced hypertension: a randomized pilot trial. J. Hum. Hypertens. 22, 138–140 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Sinha, S., Singh, S. N., Monga, Y. & Ray, U. S. Improvement of glutathione and total antioxidant status with yoga. J. Altern. Complement. Med. 13, 1085–1090 (2007). The study reports that regular yoga can reduce oxidative stress by maintaining or improving levels of glutathione (reduced and oxidized) and antioxidant status in the body.

    Article  PubMed  Google Scholar 

  172. Innes, K. E., Bourguignon, C. & Taylor, A. G. Risk indices associated with the insulin resistance syndrome, cardiovascular disease, and possible protection with yoga: a systematic review. J. Am. Board Fam. Pract. 18, 491–519 (2005).

    Article  PubMed  Google Scholar 

  173. Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297, 842–857 (2007).

    Article  CAS  PubMed  Google Scholar 

  174. Rahal, A. et al. Oxidative stress, prooxidants, and antioxidants: the interplay. Biomed Res. Int. 2014, 761264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Bhasin, M. K. et al. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS ONE 8, e62817 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yadav, R. K., Magan, D., Mehta, N., Sharma, R. & Mahapatra, S. C. Efficacy of a short-term yoga-based lifestyle intervention in reducing stress and inflammation: preliminary results. J. Altern. Complement. Med. 18, 662–667 (2012).

    Article  PubMed  Google Scholar 

  177. Emamgholipour, S., Hossein-Nezhad, A. & Ansari, M. Can melatonin act as an antioxidant in hydrogen peroxide-induced oxidative stress model in human peripheral blood mononuclear cells? Biochem. Res. Int. 2016, 5857940 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Kaliman, P. et al. Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators. Psychoneuroendocrinology 40, 96–107 (2014).

    Article  CAS  PubMed  Google Scholar 

  179. Sharma, H. et al. Sudarshan Kriya practitioners exhibit better antioxidant status and lower blood lactate levels. Biol. Psychol. 63, 281–291 (2003).

    Article  PubMed  Google Scholar 

  180. Mahagita, C. Roles of meditation on alleviation of oxidative stress and improvement of antioxidant system. J. Med. Assoc. Thai. 93, S242–S254 (2010).

    PubMed  Google Scholar 

  181. Dada, R. et al. Yoga and meditation as a therapeutic intervention in oxidative stress and oxidative DNA damage to paternal genome. J. Yoga Phys. Ther. 5, 215 (2015).

    Article  Google Scholar 

  182. Tosic, J. & Walton, A. Formation of hydrogen peroxide by spermatozoa and its inhibitory effect on respiration. Nature 158, 485 (1946).

    Article  CAS  PubMed  Google Scholar 

  183. Yanagimachi, R., Yanagimachi, H. & Rogers, B. The use of zona-free animal ova as a test-system for the assessment of the fertilizing capacity of human spermatozoa. Biol. Reprod. 15, 471–476 (1976).

    Article  CAS  PubMed  Google Scholar 

  184. Shannon, P. & Curson, B. Kinetics of the aromatic l-amino acid oxidase from dead bovine spermatozoa and the effect of catalase on fertility of diluted bovine semen stored at 5 C and ambient temperatures. J. Reprod. Fertil. 64, 463–467 (1982).

    Article  CAS  PubMed  Google Scholar 

  185. Aitken, R. J. & Clarkson, J. S. 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 (1987).

    Article  CAS  PubMed  Google Scholar 

  186. Alvarez, J. G., Touchstone, J. C., Blasco, L. & Storey, B. T. Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity. J. Androl. 8, 338–348 (1987).

    Article  CAS  PubMed  Google Scholar 

  187. Aitken, R. J., Buckingham, D. W. & Fang, H. G. Analysis of the responses of human spermatozoa to A23187 employing a novel technique for assessing the acrosome reaction. J. Androl. 14, 132–141 (1993).

    CAS  PubMed  Google Scholar 

  188. Shen, J., Deininger, P., Hunt, J. D. & Zhao, H. 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as a potential survival biomarker in patients with nonsmall-cell lung cancer. Cancer 109, 574–580 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Evans, M. D., Dizdaroglu, M. & Cooke, M. S. Oxidative DNA damage and disease: induction, repair and significance. Mutat. Res. 567, 1–61 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Musiek, E. S., Yin, H., Milne, G. L. & Morrow, J. D. Recent advances in the biochemistry and clinical relevance of the isoprostane pathway. Lipids 40, 987–994 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell. Longev. 2014, 360438 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Schaur, R. J. Basic aspects of the biochemical reactivity of 4-hydroxynonenal. Mol. Aspects Med. 24, 149–159 (2003).

    Article  CAS  PubMed  Google Scholar 

  193. Zarkovic, N. 4-hydroxynonenal as a bioactive marker of pathophysiological processes. Mol. Aspects Med. 24, 281–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  194. Thannickal, V. J. & Fanburg, B. L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L1005–L1028 (2000).

    Article  CAS  PubMed  Google Scholar 

  195. Wang, Y. et al. Plasma total antioxidant capacity is associated with dietary intake and plasma level of antioxidants in postmenopausal women. J. Nutr. Biochem. 23, 1725–1731 (2012).

    Article  CAS  PubMed  Google Scholar 

  196. Zini, A. & Libman, J. Sperm DNA damage: clinical significance in the era of assisted reproduction. CMAJ 175, 495–500 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  197. 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. 53, 1945–1951 (1993).

    CAS  PubMed  Google Scholar 

  198. Singh, N. P., McCoy, M. T., Tice, R. R. & Schneider, E. L. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res. 175, 184–191 (1988).

    Article  CAS  PubMed  Google Scholar 

  199. Shamsi, M. B., Imam, S. N. & Dada, R. Sperm DNA integrity assays: diagnostic and prognostic challenges and implications in management of infertility. J. Assist. Reprod. Genet. 28, 1073–1085 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Twigg, J. et al. Iatrogenic DNA damage induced in human spermatozoa during sperm preparation: protective significance of seminal plasma. Mol. Hum. Reprod. 4, 439–445 (1998).

    Article  CAS  PubMed  Google Scholar 

  201. Nakamura, H. et al. Detection of oxidative stress in seminal plasma and fractionated sperm from subfertile male patients. Eur. J. Obstet. Gynecol. Reprod. Biol. 105, 155–160 (2002).

    Article  CAS  PubMed  Google Scholar 

  202. Darzynkiewicz, Z., Traganos, F., Sharpless, T. & Melamed, M. Thermal denaturation of DNA in situ as studied by acridine orange staining and automated cytofluorometry. Exp. Cell Res. 90, 411–428 (1975).

    Article  CAS  PubMed  Google Scholar 

  203. Zhang, X., Gabriel, M. S. & Zini, A. Sperm nuclear histone to protamine ratio in fertile and infertile men: evidence of heterogeneous subpopulations of spermatozoa in the ejaculate. J. Androl. 27, 414–420 (2006). The findings of the study suggest that infertile men possess a higher proportion of spermatozoa with an increased histone to protamine ratio than that of their fertile counterparts.

    Article  CAS  PubMed  Google Scholar 

  204. Sellami, A. et al. Assessment of chromatin maturity in human spermatozoa: useful aniline blue assay for routine diagnosis of male infertility. Adv. Urol. 2013, 578631 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Fernandez, J. L. et al. The sperm chromatin dispersion test: a simple method for the determination of sperm DNA fragmentation. J. Androl. 24, 59–66 (2003).

    Article  CAS  PubMed  Google Scholar 

  206. Mazzilli, F. et al. Human sperm cryopreservation and reactive oxygen species (ROS) production. Acta Eur. Fertil. 26, 145–148 (1994).

    Google Scholar 

  207. Lenzi, A. et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil. Steril. 79, 292–300 (2003).

    Article  PubMed  Google Scholar 

  208. Lenzi, A. et al. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil. Steril. 81, 1578–1584 (2004).

    Article  CAS  PubMed  Google Scholar 

  209. Balercia, G. et al. Coenzyme Q10 and male infertility. J. Endocrinol. Invest. 32, 626–632 (2009). This study suggests that Coenzyme Q 10 (CoQ 10 ) in human seminal fluid, has important metabolic and antioxidant functions; and shows a direct correlation with seminal parameters (count and motility), thus exogenous administration of CoQ 10 increases both ubiquinone and ubiquinol levels in semen and can be effective in improving sperm kinetic features in patients affected by idiopathic asthenozoospermia.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy, Laboratory for Molecular Reproduction and Genetics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Shilpa Bisht, Muneeb Faiq, Madhuri Tolahunase & Rima Dada

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  1. Shilpa Bisht
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  2. Muneeb Faiq
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  3. Madhuri Tolahunase
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All authors contributed equally to all aspects of the preparation of this manuscript.

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Glossary

Free radical

A free radical is an atom or molecule that is highly reactive because it contains an unpaired electron in the outer shell.

Capacitation

A process that sperm undergo as they travel through the woman's reproductive tract. Capacitation enables the sperm to penetrate the egg.

Oxidative stress

Results from an imbalance between the intracellular production of free radicals and the cellular defence mechanisms.

Antioxidant

Any substance that prevents or reduces damage caused by free-radicals (highly reactive chemicals containing oxygen) that attack other molecules and modify their chemical structure.

DNA fragmentation

Splitting of DNA strands into shorter pieces by endonucleolytic DNA cleavage at multiple sites. This process includes internucleosomal DNA fragmentation, which, along with chromatin condensation, is considered a hallmark of apoptosis.

Assisted reproductive techniques

(ART). All treatments or procedures that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of establishing a pregnancy.

Meditation

A practice of concentrated focus upon a sound, object, visualization, such as the breath, movement, or attention itself in order to increase awareness of the present moment, reduce stress, promote relaxation, and enhance personal and spiritual growth.

Yoga

A Hindu spiritual and ascetic discipline, a part of which, including breath control, simple meditation, and the adoption of specific bodily postures, is widely practiced for health and relaxation purposes.

Protamines

Proteins that bind with DNA in sperm cells, replacing histones and allowing chromosomes to become more highly condensed than is possible with histones.

Spermatogenesis

The production of sperm within the seminiferous tubules.

Asthenozoospermia

Low sperm motility.

Telomere length

A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protect the end of the chromosome from deterioration or from fusion with neighbouring chromosomes. Telomere length decreases with advancing cellular age, thus strategies that reduce the rate of telomere shortening might delay the cellular ageing process.

DNA methylation

Attachment of methyl (−CH3) groups to DNA, most commonly to cytosine bases.

Azoospermia

Semen containing no sperm, either because the testicles cannot produce sperm or because of a blockage in the reproductive tract.

Sertoli cell

A testicular cell responsible for nurturing the spermatids (immature sperm). These cells secrete inhibin, a hormone that regulates follicule-stimulating hormone (FSH) production by the pituitary gland. When stimulated by FSH, the Sertoli cell initiates spermatogenesis.

Genomic integrity

The active maintenance of all the genetic elements in the cells of an organism (including DNA, RNA and epigenetic determinants and appropriate developmental gene expression) for proper dynamic function.

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Bisht, S., Faiq, M., Tolahunase, M. et al. Oxidative stress and male infertility. Nat Rev Urol 14, 470–485 (2017). https://doi.org/10.1038/nrurol.2017.69

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