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

The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy.

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Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

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

Oxidative stress results from the imbalance between production of the reactive oxygen species (ROS) and the protective effect of the antioxidant system responsible for their neutralization and removal. An excess of ROS causes a pathological reaction resulting in damage to cells and tissues. Spermatozoa are particularly vulnerable to the harmful effects of ROS. Oxidative stress affects their activity, damages DNA structure, and accelerates apoptosis, all of which consequently decrease their numbers, hinders motility and development of normal morphology, and impairs function. This leads to disturbances in fertility or embryo development disorder. The main cellular source of ROS in the semen are immature sperm cells and white blood cells. The increase in the number of leukocytes may be due to infection and inflammation, but can also be secondary to harmful environmental factors, long sexual abstinence, or varicocele. The protective antioxidant system in the semen is composed of enzymes, as well as nonenzymatic substances, which closely interact with each other to ensure optimal protection against ROS. Non-enzymatic antioxidants include vitamins A, E, C, and B complex, glutathione, pantothenic acid, coenzyme Q10 and carnitine, and micronutrients such as zinc, selenium, and copper. It seems that a deficiency of any of them can cause a decrease in total antioxidant status. In vitro and in vivo that studies demonstrate many antioxidants possess a beneficial effect on fertility and, therefore, their use is recommended as supportive therapy for the treatment of infertility in men.

The role of oxidative stress and antioxidants in male fertility.

Free radicals are molecules with one or more unpaired electron(s) commonly found in seminal plasma. Physiologically, free radicals control sperm maturation, capacitation and hyperactivation, the acrosome reaction, and sperm-oocyte fusion. Pathologically, free radicals induce lipid peroxidation, DNA damage and apoptosis of spermatozoa. The present review deals with both the beneficial and detrimental effects of free radicals on sperm function.

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Free radicals: Their beneficial and detrimental effects on sperm function.

Epidemiological studies regarding male infertility have revealed that more and more infertile men suffer from acute or chronic inflammation of the genitourinary tract, which often occurs without any symptoms. The inflammatory reactions within the male genital tract are inevitably connected with oxidative stress. Growing evidence indicates that imbalance between prooxidative and anti-oxidative substances in semen leads to metabolic and functional disorders of male germ cells and may be a primary cause of some types of infertility. The infectious factor and local tissue damage can lead to the infiltration of leukocytes to the inflammatory site. This is in an obvious way connected to the production and release of large amounts of reactive oxygen species (ROS), which trigger immune responses directed against the infectious agent, and the simultaneous secretion of numerous biological substances, thereby escalating the inflammation. Some of these factors are proteases and proinflammatory cytokines. Extended exposure of spermatozoa to ROS may lead to the peroxidation of sperm membrane lipids. Many studies point to the combined activities of inflammatory mediators in exerting toxic effects on spermatozoa. The local influences of biologically active substances released by activated leukocytes in the course of the inflammatory response and the mutual interactions of various factors (bacteria, leukocytes, proinflammatory cytokines) at the site represent a complex puzzle.

Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa

Cytokines in the male reproductive tract and their role in infertility disorders.

Bacteria trigger oxygen radical release and sperm lipid peroxidation in in vitro model of semen inflammation.

We have examined the effect of white blood cells (WBCs), various proinflammatory cytokines, or a combination of the two on the peroxidation of human sperm membrane lipids in in vitro conditions. Six recombinant cytokines, such as interleukin-1beta (IL-1beta), IL-6, IL-8, IL-12, IL-18, and tumor necrosis factor alpha (TNF-alpha), used singly or in combinations, were analyzed. WBCs were isolated from the whole heparinized blood using a density gradient technique (Histopaque 1.077). Spermatozoa were isolated from semen samples with normal sperm parameters by both the swim-up technique (swim-up fraction) and by a discontinuous Percoll gradient centrifugation (90% and 47% Percoll fractions). Peroxidative damage to sperm membrane lipids was assessed by determining the concentration of malondialdehyde (MDA) in lysates of spermatozoa using high-performance liquid chromatography (HPLC). There were no statistically significant differences in MDA concentrations between sperm fractions incubated with cytokines and respective controls (spermatozoa alone). In spermatozoa isolated by the swim-up technique, the MDA level was significantly higher only after incubation with IL-6 and IL-8 plus WBCs when compared to sperm incubated with leukocytes alone (0.62 +/- 0.21 micromol/L and 0.42 +/- 0.22 micromol/L, respectively; P < .05). In spermatozoa recovered from the 47% Percoll, only a combination of IL-12 and IL-18 used together with WBCs was linked with a significant increase in MDA concentration (from 0.41 +/- 0.13 micromol/L to 0.65 +/- 0.19 micromol/L; P < .05). The results obtained suggest that cytokines produced during the inflammatory process intensify the level of oxidative stress caused by leukocytes, which may have serious consequences for sperm membrane integrity.

Proinflammatory Cytokines as an Intermediate Factor Enhancing Lipid Sperm Membrane Peroxidation in In Vitro Conditions

The invasion of the male reproductive tract by microorganisms, and its subsequent consequences for sperm fertilizing potential, has been intensely discussed. The role of the bacteria that are responsible for the colonization and contamination of the male urogenital tract, rather than its infection, in diminished sperm parameters raises the most controversy. There are numerous premises suggesting that bacterial semen infection is associated with male infertility. However, the molecular mechanism by which the fertility is affected is complex and multifactorial, and still presents a puzzle. Some authors have suggested that direct interactions between bacteria and human spermatozoa facilitate sperm immobilization, affect sperm morphology, and thus weaken the ability of sperm to fertilize. On the other hand, the massive infiltration of activated leukocytes into the inflammatory site may be associated with impairment of sperm fertilizing potential, due to oxidative, apoptotic, and immune processes. This review presents current research trends and aims to summarize the present knowledge of semen inflammation and causative bacterial agents in the male urogenital tract, with its consequence on seminological parameters, and male fertility status.

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Monika Fraczek

Papers

Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa

Cytokines in the male reproductive tract and their role in infertility disorders.

Bacteria trigger oxygen radical release and sperm lipid peroxidation in in vitro model of semen inflammation.

Proinflammatory Cytokines as an Intermediate Factor Enhancing Lipid Sperm Membrane Peroxidation in In Vitro Conditions

Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen