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

Molecular mechanisms of fluoride toxicity

Spermatogenesis is an extremely active replicative process capable of generating approxi mately 1,000 sperm a second. The high rates of cell division inherent in this process imply correspondingly high rates of mitochondrial oxygen consumption by the germinal epithelium. However, the poor vascularization of the testes means that oxygen tensions in this tissue are low1 and that competition for this vital element within the testes is extremely intense. Since both spermatogenesis2 and Leydig cell steroidogenesis3,4 are vulnerable to oxidative stress, the low oxygen tension that characterizes this tissue may be an important component of the mechanisms by which the testes protects itself from free radical-mediated damage. In addition, the testes contain an elaborate array of antioxidant enzymes and free radical scavengers to ensure that the twin spermatogenic and steroidogenic functions of this organ are not impacted by oxidative stress. These antioxidant defence systems are of major importance because peroxidative damage is currently regarded as the single most important cause of impaired testicular function underpinning the pathological consequences of a wide range of conditions from testicular torsion to diabetes and xenobiotic exposure. This chapter sets out the specific nature of these antioxidant defence systems and also reviews the factors that have been found to impair their activity, precipitating a state of oxidative stress in the testes and impairing the latter’s ability to produce viable spermatozoa capable of initiating and supporting embryonic development.

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Antioxidant systems and oxidative stress in the testes.

Antioxidants delay or inhibit lipid oxidation at low concentration. Tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids, phospholipids, and sterols are natural antioxidants in foods. Antioxidants inhibit the oxidation of foods by scavenging free radicals, chelating prooxidative metals, quenching singlet oxygen and photosensitizers, and inactivating lipoxygenase. Antioxidants show interactions, such as synergism (tocopherols and ascorbic acids), antagonism (α-tocopherol and caffeic acid), and simple addition. Synergism occurs when one antioxidant is regenerated by others, when one antioxidant protects another antioxidant by its sacrificial oxidation, and when 2 or more antioxidants show different antioxidant mechanisms.

Mechanisms of Antioxidants in the Oxidation of Foods

The effect of ascorbic acid supplementation on sperm quality, lipid peroxidation and testosterone levels of male Wistar rats.

Aim: To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid. Methods: The testicular Δ 5 , 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, peroxidase and catalase activities along with the levels of malondialdehyde (MDA) and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress. The plasma testosterone (T) level was measured by immunoassay. Various germ cells at stage VII of spermatogenic cycle were quantified from testicular stained sections. Results: Cyclophosphamide treatment results in a significant inhibition in the testicular Δ 5 , 3β-HSD and 17β-HSD activities, a decrease in plasma T level and a diminution in the counts of various germ cells. Moreover, this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis. All these changes were reversed by ascorbic acid co-administration. Conclusion: Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.

Protective effect of ascorbic acid on cyclophosphamide- induced testicular gametogenic and androgenic disorders in male rats.

The present work examined the changes in testicular activities in relation to testicular oxidative stress in cyclophosphamide as well as human chorionic gonadotrophin (hCG) co-treated cyclophosphamide treated Wistar strain rats. Testicular activities were evaluated by the quantification of spermatogenesis and by the measurement of steroidogenic key enzyme activities along with plasma levels of testosterone. Testicular oxidative stress in relation to cyclophosphamide treatment was monitored by the study of products of free radicals like conjugated dienes and malondialdehyde (MDA) as well as the activity of testicular antioxidant enzymes like peroxidase and catalase. Cyclophosphamide treatment at the dose of 5 mg/kg body weight/day for 28 days resulted a significant diminution in the activities of testicular Δ5, 3β-hydroxysteroid dehydrogenase (Δ5, 3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) activities, plasma level of testosterone along with significant reduction in the number of germ cells...

Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress.

Testicular toxicity in sodium fluoride treated rats: association with oxidative stress.

The present study was undertaken to find out the adverse effects of cyclophosphamide on testicular activities along with testicular oxidative stress at its therapeutic dose and the protective effects of alpha-tocopherol succinate on testicular dysfunctions induced by cyclophosphamide in mature albino rats. A significant diminution in the activities of testicular delta 5, 3 beta-hydroxysteroid dehydrogenase (HSD) and 17 beta-hydroxysteroid dehydrogenase (HSD) along with significant reduction in the plasma level of testosterone and number of spermatogonia-A (ASg), preleptotene spermatocytes (pLSc), midpachytene spermatocytes (mPSc) and step 7 spermatids (7Sd) at stage VII of spermatogenic cycle were observed following cyclophosphamide treatment. Oxidative stress was also noted in testis, which was enlightened by significant elevation in the level of malondialdehyde (MDA) and conjugated dienes along with significant reduction in the activities of testicular peroxidase and catalase. Co-administration of alpha-tocopherol succinate in cyclophosphamide-treated rats resulted a significant restoration of all the above-mentioned parameters to the control level. The results of our experiment suggest that cyclophosphamide treatment at its clinical dose is associated with antigonadal activities as well as induction of oxidative stress in gonad that can be ameliorated significantly by alpha-tocopherol succinate co-administration. So, our data have some potential clinical implications.

Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress.

Effect of human chorionic gonadotrophin coadministration on ovarian steroidogenic and folliculogenic activities in cyclophosphamide treated albino rats.

Ujjal Baran Das

Papers

Protective effect of ascorbic acid on cyclophosphamide- induced testicular gametogenic and androgenic disorders in male rats.

Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress.

Testicular toxicity in sodium fluoride treated rats: association with oxidative stress.

Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress.

Effect of human chorionic gonadotrophin coadministration on ovarian steroidogenic and folliculogenic activities in cyclophosphamide treated albino rats.