Identification of Sperm Oxidative Stress from Clinical History

The various causes of male infertility are outlined in Fig. 16.1, with the majority of these sources of sperm dysfunction being relatively easy to identify through history alone. The mnemonic "Testicular" is a helpful aide-memoire for recalling the underlying causes of male infertility, with sperm oxidative stress playing a pivotal role in the majority of these male infertility pathologies.

Exposure to [oxins such as heavy metals through the manufacture of lead acid batteries or soldering fumes is known to create sperm oxidative stress [10, 11] and lead to sperm DNA damage, infertility and miscarriage [12, 13]. Several environmental pollutants have been linked with testicular oxidative stress. Pesticides such as lindane [14], methoxychlor [15] and the herbicide dioxin-TCDD [16] have all been linked with testicular oxidative stress in rodent models. The commonly used preservative sulphur dioxide has also been shown to produce testicular oxidative stress in laboratory animals [17]. Air pollutants such as diesel particulate matter act as potent stimuli for leukocyte ROS generation [18, 19] . While no study has directly linked airborne pollutants with testicular oxidative stress, it is possible that this oxidative insult is responsible for the increase in sperm DNA damage seen following periods of airborne pollution [20] . Phthalates are chemicals used as a plastics softener and are contained in a wide range of food packaging and personal care products. Exposure to phthalates can occur via dietary consumption, dermal absorption or inhalation and

Male Infertility Causes Mnemonics
Fig. 16.1 The "Testicular" mnemonic summarising the common causes for male factor infertility. Those aetiologies in which oxidative stress plays a significant role in causing sperm dysfunction are highlighted in italics

has been linked with impaired spermatogenesis and increased sperm DNA damage [21-24], Oral administration of phthalate esters to rats is reported to increase the generation of ROS within the testis and a concomitant decrease in antioxidant levels, culminating in impaired spermatogenesis [25],

Diabetes is an ever increasing endocrine cause of sperm oxidative stress as obesity levels increase in the Western population. Poor glycaemic control has been linked with excessive systemic production of ROS and an increase in sperm DNA fragmentation levels [26] , Further studies by this group confirmed that type I diabetes is associated with an increase in the oxidative DNA adduct 8-OHdG in sperm, confirming that diabetes induced oxidative stress is at least partially responsible for the decline in sperm DNA quality seen in diabetic men [27]. Furthermore, animal studies using the streptozotocin-induced diabetic rat model have found a significant increase in testicular oxidative stress within 6 weeks of initiation of the diabetic state [28], while the antioxidant quercetin is capable of significant amelioration of the negative effects of diabetes on sperm quality [29]. This all suggests that oxidative stress is a major mediator of the decline in sperm function seen in diabetic men.

Thyroid dysfunction may also be an endocrine cause of sperm oxidative stress as both hyperthyroidism and hypothyroidism have been linked with systemic oxidative stress [30-32]. This systemic state of oxidative stress appears to extend to the testicle, since animal studies using experimentally induced hyperthyroidism and hypo-thyroidism have shown increased levels of lipid peroxidation products and reduced antioxidant status within the testicle tissue [33, 34] . Furthermore, a recent study examining the link between thyroid hormones and antioxidant capacity in seminal plasma of infertile men reported a significant positive correlation between seminal plasma antioxidant capacity and serum free thyroxin levels [35]. Therefore, screening of infertile men for thyroid dysfunction may be useful, especially since returning thyroid hormone status to normal has been shown to reduce systemic levels of oxidative stress within 1-2 months [30].

Oxidative stress is believed to be a major cause of erectile dysfunction, a common sexual cause of male infertility in the older man. Of some concern is the observation that as many as one in ten men aged in their 40s will also experience significant erectile dysfunction [36] . Penile erection is dependent upon vascular smooth muscle relaxation in erectile tissue and penile arteries, the principal mediator of relaxation being nitric oxide (NO). Evidence from basic scientific studies indicates that oxida-tive stress may be central to impaired cavernosal function in erectile dysfunction (ED) [37,38]. Increased inactivation ofNO by the superoxide ROS results in impaired penile NO transmission and smooth muscle relaxation. Furthermore, propagation of endothelial dysfunction by ROS may result in chronic impairment of penile vascular function, a process analogous to early atherogenesis. Furthermore, both animal models and human studies have shown that supplementation of the diet with antioxidants may significantly improve intracavernosal blood flow and erectile activity, supporting a pivotal role for oxidative stress in erectile dysfunction [39-41],

Psychological stress is known to produce a decline in sperm function and a state of systemic oxidative stress. Two prospective studies have linked a period of psychological stress with a reduction in sperm quality mediated by an increase in seminal plasma ROS generation and a reduction in antioxidant protection [42, 43]. Interestingly, after the removal of the psychological stressor (medical student exams in these observational studies), sperm function improved, suggesting that effective management of emotional stress may improve sperm function.

The processing of sperm by centrifugation for later use in assisted reproductive treatment (IVF, IUI) is an example of [atrogenic generation of sperm oxidative stress. Centrifugation is known to enhance the production of free radicals by sperm [1,4], while also bringing sperm in close proximity to ROS producing leukocytes in the cellular pellet. This, together with the fact that centrifugation removes sperm from their protective bath of antioxidants contained in seminal plasma, is a potent inducer of sperm oxidative damage [44] . In addition, cryopreservation of sperm, another commonly used technique in ART, is associated with an increase in sperm oxidative stress [45, 46]. Furthermore, medications prescribed to patients are another potential cause of iatrogenic oxidative stress. Drugs such as aspirin and paracetamol (acetaminophen) can produce oxidative stress by increasing cytochrome P450 activity, thereby boosting ROS generation [47]. The SSRI class of anti-depressants has been linked with reduced libido and impaired ejaculatory frequency [48]. This results in sperm being stored for prolonged periods in the epididymis where they are potentially exposed to oxidative attack, resulting in a decline in sperm DNA integrity [49].

Infective causes for sperm oxidative stress include local infections such as Male Accessory Gland Infection (MAGI) or systemic infections such as Hepatitis, HIV, TB and Malaria. Leukocytes are professional producers of free radicals, releasing ROS at relatively high concentrations to destroy infective pathogens. Therefore, it is not surprising that activation of the immune system within the male reproductive tract is likely to result in sperm oxidative damage. Up to 50% of men will experience prostatitis at some point in their lives, with prostatitis becoming chronic in 10% of men [50]. Bacteria responsible for prostate infection may originate from the urinary tract or can be sexually transmitted [51]. Typical non-STD pathogens include streptococci (Streptococcus viridans and S. pyogens), coagulase-negative staphylococci (Staphylococcus epidermidis, S. haemolyticus), gram-negative bacteria (Escherichia coli, Proteus mirabilis) and atypical mycoplasma strains (Ureaplasma urealyticum, Mycoplasma hominis). All of these pathogens will create an acute inflammatory response with an influx of leukocytes into the genital tract and a resulting increase in ROS production [52-55]. Men prone to recurrent genitourinary tract infections, such as paraplegics, have been confirmed to have high degrees of sperm oxidative pathology [56, 57]. Current or past Chlamydia infection has also been linked with an increase in oxidative damage to sperm [58] . Viral infections such as Herpes may initiate oxidative damage to sperm. Herpes simplex DNA is found in 4-50% of infertile men's semen [59, 60], with acute HSV infection being associated with a tenfold increase in the rate of leukospermia [61, 62], Given the well-recognised link between leukospermia and seminal ROS levels, together with the observation of a reduction in sperm motility in men positive for seminal HSV DNA [59], it is likely that HSV is a viral pathogen involved in oxidative stress.

Several chronic systemic infections have been linked with increased oxidative stress throughout the body. Human immunodeficiency virus (HIV) infection is associated with an increase in leukocyte number and activation within semen [ 63] . Hepatitis B and C infection has been also correlated with significant hepatic oxida-tive stress [64, 65]. At present, it is unknown if this oxidative stress extends to the semen, but impaired sperm motility seen in Hepatitis B and C patients [66, 67] makes this likely. Finally, chronic infections such as Tuberculosis [68], Leprosy [69], Malaria [70] and Chagas Disease [71[ have been all linked with elevated degrees of systemic oxidative stress. While no study has directly linked these chronic infectious diseases with sperm oxidative stress, it is unlikely that the male reproductive tract would be spared from this systemic oxidative insult.

Similarly, non-infective inflammatory stimuli such as occurs following a vasec-tomy reversal will produce sperm oxidative stress. Following a vasectomy, sperm are able to cross the blood-testis immune privilege barrier and activate an inflammatory response [72]. Even after successful reanastamosis of the vas, there is ongoing immune recognition of sperm resulting in a sterile inflammatory response which can harm sperm function [73, 74]. Chronic non-bacterial prostatitis (NIH Category III), a chronic inflammation of the prostate in the absence infection, has been reported by several groups to be associated with elevated levels of seminal oxidative stress [75-77], Chronic non-bacterial prostatitis affects 10% of men during their lifetime [50] and is believed to be caused by an adverse autoimmune response to seminal or prostate antigens, leading to an increase in pro-inflammatory cytokines and activated ROS producing leukocytes within the semen [78, 79].

Chronic inflammation and oxidative stress are highly prevalent in patients with chronic kidney disease and end-stage renal disease [80]. Surprisingly, even when uraemia is reversed by haemodialysis, a persisting state of chronic inflammation and oxidative stress persists [81, 82] , Furthermore, renal transplant patients with stable renal function and no obvious signs of immune rejection of their graft also have elevated levels of oxidative stress [83]. This systemic state of oxidative stress may at least account for some of the observed impaired sperm function seen in renal patients. Furthermore, patients with haemoglobinopathies such as beta-thalassaemia major have high degrees of systemic oxidative stress [84], with this oxidative damage confirmed to involve sperm [85]. The likely cause of oxidative stress is iron overload from multiple blood transfusions. Iron is a potent pro-oxidant capable of redox cycling when not safely bound to transferrin in the blood or stored as ferritin in tissue. Likewise, men with haemochromatosis are likely to have oxidative damage to their sperm caused by excess iron stores.

Cancer and its treatment by chemotherapy and radiation are known to be a potent systemic oxidative insult, potentially impairing sperm function. Drugs such as the chemotherapy agent cyclophosphamide have been linked with sperm oxidative stress. Administration of cyclophosphamide to animals is reported to increase testicular malondialdehyde (MDA) levels and produce a fall in testicular catalase, implying the presence of oxidative stress [86, 87]. Similarly, radiation exposure has been shown to cause a systemic inflammatory reaction and increase in oxidative stress in both the irradiated tissue and non-irradiated bystander normal tissue [88, 89]. DNA fragments of apoptotic irradiated cancer cells are released into the intercellular space and interact with the DNA-binding receptors of the bystander non-irradiated cells, initiating activation of lymphocyte signalling pathways associated with synthesis of reactive oxygen and nitrogen species, thereby inducing secondary oxidative stress [90]. Finally, the patient with untreated cancer often exhibits oxidative stress as a part of the normal malignant metabolic response [91-94]. This may account for the usual impairment in semen quality often seen in these patients when they attend fertility clinics for semen cryopreservation prior to initiation of potentially sterilising cancer therapy [95].

In the vast majority of infertile men, no clear cause for sperm dysfunction is found on routine history and examination—making idiopathic infertility a common finding. However, recent research suggests that infertility of unknown origin often has an oxidative stress basis. The ability of sperm to produce ROS inversely correlates with their maturational state. During spermatogenesis, there is a loss of cytoplasm to allow the sperm to form its condensed, elongated form. Immature teratozoospermic sperm are often characterised by the presence of excess cytoplasmic residues in the mid-piece. These residues are rich in the enzyme glucose-6-phosphate dehydrogenase (G6PD), an enzyme which controls the rate of glucose flux and intracellular production of beta-nicotinamide adenine dinucleotide phosphate (NADPH) through the hexose monophosphate shunt. NADPH is used to fuel the generation of ROS via NADPH oxidase located within the sperm membrane [96]. As a result, teratozoospermic sperm produce increased amounts of ROS compared to morphologically normal sperm. Interestingly, however, even normozoospermic men in an infertile relationship produce higher amounts of ROS than fertile men [97], Why this occurs is not fully understood but may include subtle metabolic defects in the sperm leading to excessive production of ROS from the mitochondrial respiratory chain [98].

Lifestyle causes of oxidative stress such as obesity, smoking and alcohol abuse are likely to be a common cause of oxidative male infertility. Obesity has recently been linked with excessive production of ROS in semen, possibly mediated by the systemic inflammatory response observed in the obese state [99-101]. Furthermore, accumulation of adipose tissue within the groin region results in heating of the testicle which has been linked with oxidative stress and reduced sperm quality [102-104]. Animal studies suggest that high fat diets may also cause sperm themselves to produce excess ROS through an as yet unidentified process [105] , Finally, a "fast food" diet low in vegetables and fresh fruits, all too common in today's overweight Western society, is likely to be deficient in dietary antioxidants and therefore place these men at increased risk of sperm oxidative stress. Dietary deficiencies have been linked with sperm oxi-dative damage by several research groups. The AGES study examined the self-reported dietary intake of various antioxidants and nutrients (vitamins C and E, beta-carotene, folate and zinc) in a group of healthy non-smokers and observed a significant correlation between vitamin C intake and sperm concentration and between vitamin E intake and total progressively motile sperm [106] , These observations are also consistent with earlier reports of a significant link between seminal plasma vitamin E levels and an increase in percentage of motile sperm [107] and low seminal plasma vitamin C levels with increased levels of sperm DNA damage [108],

Exposure to cigarette smoke is a well-established cause of both testicular and systemic oxidative stress and a clear cause of male sub-fertility. Smoking results in a 48% increase in seminal leukocyte concentrations and a 107% increase in seminal ROS levels [109] , Smokers have decreased levels of seminal plasma antioxidants such as vitamin E [110] and vitamin C [111], placing their sperm at additional risk of oxidative damage. This has been confirmed by the finding of a significant increase in levels of 8-OHdG within smoker's seminal plasma [110].

Excessive alcohol consumption causes an increased in systemic oxidative stress as ethanol stimulates the body's production of ROS, while many alcohol abusers have diets deficient in protective antioxidants [112]. A study of 46 alcoholic men of reproductive age has confirmed the presence of ethanol induced oxidative stress within the testicle by reporting a significant increase in serum lipid peroxidation by-products plus a drop in antioxidants [113].

The use of illicit drugs such as cocaine and MDMA (ecstasy) may produce sperm oxidative stress, as both have been linked with a systemic state of oxidative stress

[114,115], although only animal studies to date have confirmed the ability of these illicit drugs to impair sperm function [116, 117].

The presence of a varicocele, present in up to 40% of infertile men, is a common anatomical cause for sperm oxidative stress. Oxidative stress is now widely believed to be the principal underlying pathology linking varicocele with male infertility [118-125]. While it is not currently understood exactly how the presence of a vari-cocele produces sperm oxidative stress, suggested mechanism includes an elevation in scrotal temperature [126], genital tract inflammation [127] and acidification of seminal plasma inhibiting antioxidant enzyme activity [128]. The increase in varic-ocele-related ROS production is strongly correlated with a reduction in sperm DNA integrity when assessed by either TUNEL [122] or 8-hydroxy-2'-deoxyguanosine DNA oxidative metabolite levels [129].

Cryptorchidism is another common anatomical cause for male factor infertility in which the primary pathology is hypo-spermatogenesis due to deficient maturation of gonocytes to type A spermatogonia [130]. However, it has been reported that even in men with cryptorchidism surgically treated with orchidopexy early in life, there is a markedly elevated production of ROS by sperm and an associated increase in sperm DNA fragmentation compared to fertile controls [124]. Finally, testicular oxidative stress initiated from torsion of the spermatic cord is believed to be a cause of male infertility. It is reported that oxidative stress is precipitated by an inflammatory response to the ischemia-reperfusion injury in both the torted and contralateral testis. A prolonged period of ischemia, followed by surgical or spontaneous restoration of blood flow, leads to an influx of activated leukocytes into both testes [131] and a consequent increase in generation of free radicals [132]. Oxidative stress then leads to necrosis of the germinal cells with resulting sub-fertility or infertility.

Advanced paternal age is another potential cause of sperm oxidative stress. It has been known for a long time that sperm quality slowly declines with advancing age [133]. Several large studies have shown that systemic oxidative stress increases with advancing age [134]. but only recently has it been reported that this age-related oxidative insult definitely extends to the sperm themselves [135]. Animal studies using the Brown Norway rat, an established model of male reproductive ageing, confirm that older animal's sperm produce more free radicals than young animals and have a reduced enzymatic antioxidant activity, resulting in an increase in ROS mediated sperm DNA damage [136, 137]. Several studies have reported that sperm DNA damage increases with advancing age in both fertile [138] and infertile men [139,140]. It is possible that an increase in oxidative sperm DNA damage is one of the underlying pathologies behind this age-related decline in the paternal genome.

Finally, electromagnetic radiation in the form of mobile phone exposure has recently been shown to produce sperm oxidative stress . 141, 142]. As the vast majority of men in industrialised societies now use a mobile phone, this cause of sperm oxidative stress may become an endemic potential cause of male sub-fertility. Pulsed microwave radiation exposure, as occurs in workers who are in close proximity to radar equipment, has also been linked with a systemic state of oxidative stress [143] and a significant decline in sperm quality [144]. Low dose exposure to ionising radiation is commonly seen in medical workers in the radiology sector, nuclear facility employees, and some miners and aircraft personnel. Such low dose ionising radiation exposure has also been linked with a systemic state of oxidative stress [145] and a potential decline in semen quality [146].

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