Oxidative stress occurs when the production of potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. Oxidative stress is a common pathology seen in approximately half of all infertile men. ROS, defined as including oxygen ions, free radicals and peroxides are generated by sperm and seminal leukocytes within semen and produce infertility by two key mechanisms. First, they damage the sperm membrane, decreasing sperm motility and its ability to fuse with the oocyte. Second, ROS can alter the sperm DNA, resulting in the passage of defective paternal DNA on to the conceptus. This review will provide an overview of oxidative biochemistry related to sperm health and will identify which men are most at risk of oxidative infertility. Finally, the review will outline methods available for diagnosing oxidative stress and the various treatments available.

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Oxidative stress and male infertility—a clinical perspective

Recent advances in understanding of male infertility have implicated two major causative factors, oxidative stress and Y chromosome deletions. A major cause of oxidative stress appears to be the high rate of reactive oxygen species generation associated with the retention of excess residual cytoplasm in the sperm midpiece. Other possible causes include the redox cycling of xenobiotics, and antioxidant depletion or apoptosis. Oxidative stress induces peroxidative damage in the sperm plasma membrane and DNA damage in both the mitochondrial and nuclear genomes. Nuclear DNA damage in the germ line of the father may be associated with pathology in the offspring, including childhood cancer and infertility. Gene deletions on the non-recombining region of the Y chromosome account for the infertility observed in about 15% of patients with azoospermia and 5-10% of subjects with severe oligozoospermia. The Y chromosome is particularly susceptible to gene deletions because of the inability of the haploid genome to deploy recombination repair in retrieving lost genetic information. Aberrant recombination, defective chromatin packaging, abortive apoptosis and oxidative stress may all be involved in the aetiology of DNA damage in the germ line. The factors responsible for Y chromosome deletions in spermatozoa remain unresolved but may be one facet of a central reproductive problem: controlling the amount of oxidative stress experienced by germ cells during their differentiation and maturation in the male reproductive tract.

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Oxidative stress, DNA damage and the Y chromosome.

clearly independent measures of sperm quality. Therefore, pathogenic ROS levels or poor-quality sperm chromatin structure may be considered indicative of male subfertility [1,2].IDIOPATHIC INFERTILITYMen with idiopathic infertility generally present with signiﬁcantly higher seminal ROS levels and lower antioxidant properties than healthy controls [3]. Therefore, it appears that the presence of OS in infertile normozoospermic men may be the cause behind previously unexplained cases of infertility. Similarly, sperm DNA damage analysis may reveal hidden sperm DNA abnormalities in infertile men with normal standard sperm values who were diagnosed with idiopathic infertility. The increase in sperm DNA damage in these patients may be partly related to high levels of seminal OS.Finally and importantly, some conditions may pass unnoticed but still affect the sperm genomic integrity. In one case report [4], a fertile patient who had inﬂuenza and a 1-day fever of 39.9 ∞ C presented with a relatively high percentage of sperm with damaged DNA (36%) 18 days after the onset of his fever.GENITAL TRACT INFECTIONSGenital tract infections are usually associated with leukocytospermia and elevated ROS levels, as leukocytes represent the major source of ROS production in ejaculates. Although leukocytes are a constant component of human ejaculates and virtually no semen sample is free of them, if the prevalence of leukocytes exceeds normal values (1 ¥ 10

/pdf/oxidative-stress-dna-damage-and-apoptosis-in-male-5eod5ckxjh.pdf

Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach

The ability of spermatozoa to generate reactive oxygen species (ROS) has been appreciated since the 1940s. It is a universal property of mature spermatozoa from all mammalian species and a major contributor to the oxidative stress responsible for defective sperm function. The mechanisms by which oxidative stress limits the functional competence of mammalian spermatozoa involve the peroxidation of lipids, the induction of oxidative DNA damage, and the formation of protein adducts. ROS production in these cells involves electron leakage from the sperm mitochondria, triggered by a multitude of factors that impede electron flow along the electron transport chain. The net result of mitochondrial ROS generation is to damage these organelles and initiate an intrinsic apoptotic cascade, as a consequence of which spermatozoa lose their motility, DNA integrity, and vitality. This pathway of programmed senescence also results in the exteriorization of phosphatidylserine, which may facilitate the silent phagocytosis of these cells in the aftermath of insemination, in turn influencing the female tract immune response to sperm antigens and future fertility. Despite the vulnerability of sperm to oxidative stress, it is also clear that normal sperm function depends on low levels of ROS generation in order to promote the signal transduction pathways associated with capacitation. Modulators of ROS generation by spermatozoa may therefore have clinical utility in regulating the fertilizing capacity of these cells and preventing the development of antisperm immunity. Achievement of these objectives will require a systematic evaluation of pro- and antioxidant strategies in vivo and in vitro.

https://onlinelibrary.wiley.com/doi/pdf/10.2164/jandrol.112.016535

Reactive Oxygen Species and Sperm Function—In Sickness and In Health

https://www.clevelandclinic.org/reproductiveresearchcenter/docs/agradoc129.pdf

Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele

Varicocele is associated with an oxidative stress condition. We have measured the antioxidant defenses of varicocele patients both at the local (seminal plasma) and systemic (blood plasma) levels. The antioxidant defenses, as evaluated by the total reactive antioxidant potential parameter, decrease both in the seminal (controls = 676 ± 128; patients = 386 ± 186) and blood (controls = 519 ± 63; patients = 268 ± 110) plasma of varicocele patients. Compared with controls, patients with both normal spermiograms and spermiograms altered in motility or morphology demonstrated lower values. The results obtained suggest that varicocele-associated oxidative stress is evidenced both at the local and systemic levels. This conclusion is supported by results showing that urinary spontaneous chemiluminescence is also significantly increased in the patients.

Andres Venégas

Papers

Varicocele-associated decrease in antioxidant defenses.