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Reactive Oxygen Species and Male Fertility

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (6 December 2019) | Viewed by 56790

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Dr. Cristian O'Flaherty

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Guest Editor

Department of Surgery (Urology Division), Faculty of Medicine, McGill University, Montreal, QC, Canada
Interests: spermatology; sperm capacitation; sperm motility; fertilization; cell signaling; redox signaling; oxidative stress; reactive oxygen species; lipid peroxidation; DNA integrity; male infertility

Special Issue Information

Dear Colleagues,

Reactive oxygen species (ROS) are inevitable by-products of aerobic cells. A delicate balance between ROS production and antioxidant defenses is essential to assure cell function. This is also true for the spermatozoon—the male gamete with the unique goal of carrying and delivering the paternal genome into the oocyte. Oxidative stress promotes damage in the lipids, proteins, and DNA of spermatozoa, and this oxidative damage is associated with infertility. The ROS-dependent damage could occur at different stages of the production and maturation of the sperm. Thus, spermatogenesis, epididymal maturation, or the processes needed to acquire fertilizing ability can be affected by oxidative stress.

On the other hand, low and controlled levels of ROS are necessary to trigger and regulate sperm function. When ejaculated, spermatozoa are incapable of fertilizing the egg. They must reside in the oviduct of the female genital tract to undergo a yet-to-be-understood biochemical process called capacitation. Once capacitated, the spermatozoon undergoes the exocytotic event called acrosome reaction, and fertilizes the oocyte. ROS regulate the different molecular mechanisms such as sperm motility, capacitation, and acrosome reaction to assure fertilization.

This Special Issue welcomes original research and literature reviews concerning the role of reactive oxygen species in the following areas: spermatogenesis, epididymal maturation, sperm motility, capacitation, acrosome reaction, and male fertility. Moreover, the role of antioxidants in the regulation of male fertility as well as basic and clinical studies using antioxidant-based strategies for the treatment of male infertility are also welcome.

Dr. Cristian O'Flaherty
Guest Editor

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Keywords

spermatogenesis
epididymal maturation
sperm capacitation
acrosome reaction
sperm motility
sperm–egg interaction
male infertility
antioxidant treatments for male infertility
male reproduction

Published Papers (11 papers)

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Editorial

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5 pages, 226 KiB

Open AccessEditorial

Reactive Oxygen Species and Male Fertility

by Cristian O’Flaherty

Antioxidants 2020, 9(4), 287; https://doi.org/10.3390/antiox9040287 - 29 Mar 2020

Cited by 17 | Viewed by 2829

Abstract

Human infertility affects ~15% of couples worldwide, and it is now recognized that in half of these cases, the causes of infertility can be traced to men [...] Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

Research

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16 pages, 4618 KiB

Open AccessArticle

Long-Term Adverse Effects of Oxidative Stress on Rat Epididymis and Spermatozoa

by Pei You Wu, Eleonora Scarlata and Cristian O’Flaherty

Antioxidants 2020, 9(2), 170; https://doi.org/10.3390/antiox9020170 - 19 Feb 2020

Cited by 48 | Viewed by 3983

Abstract

Oxidative stress is a common culprit of several conditions associated with male fertility. High levels of reactive oxygen species (ROS) promote impairment of sperm quality mainly by decreasing motility and increasing the levels of DNA oxidation. Oxidative stress is a common feature of environmental pollutants, chemotherapy and other chemicals, smoke, toxins, radiation, and diseases that can have negative effects on fertility. Peroxiredoxins (PRDXs) are antioxidant enzymes associated with the protection of mammalian spermatozoa against oxidative stress and the regulation of sperm viability and capacitation. In the present study, we aimed to determine the long-term effects of oxidative stress in the testis, epididymis and spermatozoa using the rat model. Adult male rats were treated with tert-butyl hydroperoxide (t-BHP) or saline (control group), and reproductive organs and spermatozoa were collected at 3, 6, and 9 weeks after the end of treatment. We determined sperm DNA oxidation and motility, and levels of lipid peroxidation and protein expression of antioxidant enzymes in epididymis and testis. We observed that cauda epididymal spermatozoa displayed low motility and high DNA oxidation levels at all times. Lipid peroxidation was higher in caput and cauda epididymis of treated rats at 3 and 6 weeks but was similar to control levels at 9 weeks. PRDX6 was upregulated in the epididymis due to t-BHP; PRDX1 and catalase, although not significant, followed similar trend of increase. Testis of treated rats did not show signs of oxidative stress nor upregulation of antioxidant enzymes. We concluded that t-BHP-dependent oxidative stress promoted long-term changes in the epididymis and maturing spermatozoa that result in the impairment of sperm quality. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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12 pages, 2434 KiB

Open AccessArticle

The Exacerbation of Aging and Oxidative Stress in the Epididymis of Sod1 Null Mice

by Anaīs Noblanc, Alicia Klaassen and Bernard Robaire

Antioxidants 2020, 9(2), 151; https://doi.org/10.3390/antiox9020151 - 11 Feb 2020

Cited by 16 | Viewed by 2789

Abstract

There is growing evidence that the quality of spermatozoa decreases with age and that children of older fathers have a higher incidence of birth defects and genetic mutations. The free radical theory of aging proposes that changes with aging are due to the accumulation of damage induced by exposure to excess reactive oxygen species. We showed previously that absence of the superoxide dismutase 1 (Sod1) antioxidant gene results in impaired mechanisms of repairing DNA damage in the testis in young Sod1^−/− mice. In this study, we examined the effects of aging and the Sod^−/− mutation on mice epididymal histology and the expression of markers of oxidative damage. We found that both oxidative nucleic acid damage (via 8-hydroxyguanosine) and lipid peroxidation (via 4-hydroxynonenal) increased with age and in Sod1^−/− mice. These findings indicate that lack of SOD1 results in an exacerbation of the oxidative damage accumulation-related aging phenotype. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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14 pages, 1887 KiB

Open AccessArticle

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

by Cristian O’Flaherty, Annie Boisvert, Gurpreet Manku and Martine Culty

Antioxidants 2020, 9(1), 32; https://doi.org/10.3390/antiox9010032 - 30 Dec 2019

Cited by 18 | Viewed by 3371

Abstract

Peroxiredoxins (PRDXs) are antioxidant enzymes that protect cells from oxidative stress and play a role in reactive oxygen species (ROS)-mediated signaling. We reported that PRDXs are critical for human fertility by maintaining sperm viability and regulating ROS levels during capacitation. Moreover, studies on Prdx6^−/− mice revealed the essential role of PRDX6 in the viability, motility, and fertility competence of spermatozoa. Although PRDXs are abundant in the testis and spermatozoa, their potential role at different phases of spermatogenesis and in perinatal germ cells is unknown. Here, we examined the expression and role of PRDXs in isolated rat neonatal gonocytes, the precursors of spermatogonia, including spermatogonial stem cells. Gene array, qPCR analyses showed that PRDX1, 2, 3, 5, and 6 transcripts are among the most abundant antioxidant genes in postnatal day (PND) 3 gonocytes, while immunofluorescence confirmed the expression of PRDX1, 2, and 6 proteins. The role of PRDXs in gonocyte viability was examined using PRDX inhibitors, revealing that the 2-Cys PRDXs and PRDX6 peroxidases activities are critical for gonocytes viability in basal condition, likely preventing an excessive accumulation of endogenous ROS in the cells. In contrast to its crucial role in spermatozoa, PRDX6 independent phospholipase A₂ (iPLA₂) activity was not critical in gonocytes in basal conditions. However, under conditions of H₂O₂-induced oxidative stress, all these enzymatic activities were critical to maintain gonocyte viability. The inhibition of PRDXs promoted a two-fold increase in lipid peroxidation and prevented gonocyte differentiation. These results suggest that ROS are produced in neonatal gonocytes, where they are maintained by PRDXs at levels that are non-toxic and permissive for cell differentiation. These findings show that PRDXs play a major role in the antioxidant machinery of gonocytes, to maintain cell viability and allow for differentiation. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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18 pages, 3286 KiB

Open AccessArticle

GSTO2 Isoforms Participate in the Oxidative Regulation of the Plasmalemma in Eutherian Spermatozoa during Capacitation

by Lauren E. Hamilton, Michal Zigo, Jiude Mao, Wei Xu, Peter Sutovsky, Cristian O’Flaherty and Richard Oko

Antioxidants 2019, 8(12), 601; https://doi.org/10.3390/antiox8120601 - 29 Nov 2019

Cited by 10 | Viewed by 3037

Abstract

In addition to perinuclear theca anchored glutathione-s-transferase omega 2 (GSTO2), whose function is to participate in sperm nuclear decondensation during fertilization (Biol Reprod. 2019, 101:368–376), we herein provide evidence that GSTO2 is acquired on the sperm plasmalemma during epididymal maturation. This novel membrane localization was reinforced by the isolation and identification of biotin-conjugated surface proteins from ejaculated and capacitated boar and mouse spermatozoa, prompting us to hypothesize that GSTO2 has an oxidative/reductive role in regulating sperm function during capacitation. Utilizing an inhibitor specific to the active site of GSTO2 in spermatozoa, inhibition of this enzyme led to a decrease in tyrosine phosphorylation late in the capacitation process, followed by an expected decrease in acrosome exocytosis and motility. These changes were accompanied by an increase in reactive oxygen species (ROS) levels and membrane lipid peroxidation and culminated in a significant decrease in the percentage of oocytes successfully penetrated by sperm during in vitro fertilization. We conclude that GSTO2 participates in the regulation of sperm function during capacitation, most likely through protection against oxidative stress on the sperm surface. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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Review

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22 pages, 1332 KiB

Open AccessReview

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

by Karolina Nowicka-Bauer and Brett Nixon

Antioxidants 2020, 9(2), 134; https://doi.org/10.3390/antiox9020134 - 04 Feb 2020

Cited by 109 | Viewed by 7268

Abstract

A state of oxidative stress (OS) and the presence of reactive oxygen species (ROS) in the male reproductive tract are strongly correlated with infertility. While physiological levels of ROS are necessary for normal sperm functioning, elevated ROS production can overwhelm the cell’s limited antioxidant defenses leading to dysfunction and loss of fertilizing potential. Among the deleterious pleiotropic impacts arising from OS, sperm motility appears to be particularly vulnerable. Here, we present a mechanistic account for how OS contributes to altered sperm motility profiles. In our model, it is suggested that the abundant polyunsaturated fatty acids (PUFAs) residing in the sperm membrane serve to sensitize the male germ cell to ROS attack by virtue of their ability to act as substrates for lipid peroxidation (LPO) cascades. Upon initiation, LPO leads to dramatic remodeling of the composition and biophysical properties of sperm membranes and, in the case of the mitochondria, this manifests in a dissipation of membrane potential, electron leakage, increased ROS production and reduced capacity for energy production. This situation is exacerbated by the production of cytotoxic LPO byproducts such as 4-hydroxynonenal, which dysregulate molecules associated with sperm bioenergetic pathways as well as the structural and signaling components of the motility apparatus. The impact of ROS also extends to lesions in the paternal genome, as is commonly seen in the defective spermatozoa of asthenozoospermic males. Concluding, the presence of OS in the male reproductive tract is strongly and positively correlated with reduced sperm motility and fertilizing potential, thus providing a rational target for the development of new therapeutic interventions. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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19 pages, 1232 KiB

Open AccessReview

The Importance of Oxidative Stress in Determining the Functionality of Mammalian Spermatozoa: A Two-Edged Sword

by Robert J. Aitken and Joel R. Drevet

Antioxidants 2020, 9(2), 111; https://doi.org/10.3390/antiox9020111 - 27 Jan 2020

Cited by 127 | Viewed by 8313

Abstract

This article addresses the importance of oxidative processes in both the generation of functional gametes and the aetiology of defective sperm function. Functionally, sperm capacitation is recognized as a redox-regulated process, wherein a low level of reactive oxygen species (ROS) generation is intimately involved in driving such events as the stimulation of tyrosine phosphorylation, the facilitation of cholesterol efflux and the promotion of cAMP generation. However, the continuous generation of ROS ultimately creates problems for spermatozoa because their unique physical architecture and unusual biochemical composition means that they are vulnerable to oxidative stress. As a consequence, they are heavily dependent on the antioxidant protection afforded by the fluids in the male and female reproductive tracts and, during the precarious process of insemination, seminal plasma. If this antioxidant protection should be compromised for any reason, then the spermatozoa experience pathological oxidative damage. In addition, situations may prevail that cause the spermatozoa to become exposed to high levels of ROS emanating either from other cells in the immediate vicinity (particularly neutrophils) or from the spermatozoa themselves. The environmental and lifestyle factors that promote ROS generation by the spermatozoa are reviewed in this article, as are the techniques that might be used in a diagnostic context to identify patients whose reproductive capacity is under oxidative threat. Understanding the strengths and weaknesses of ROS-monitoring methodologies is critical if we are to effectively identify those patients for whom treatment with antioxidants might be considered a rational management strategy. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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14 pages, 1652 KiB

Open AccessReview

Oxidation of Sperm Nucleus in Mammals: A Physiological Necessity to Some Extent with Adverse Impacts on Oocyte and Offspring

by Joël R. Drevet and Robert John Aitken

Antioxidants 2020, 9(2), 95; https://doi.org/10.3390/antiox9020095 - 23 Jan 2020

Cited by 41 | Viewed by 3818

Abstract

Sperm cells have long been known to be good producers of reactive oxygen species, while they are also known to be particularly sensitive to oxidative damage affecting their structures and functions. As with all organic cellular components, sperm nuclear components and, in particular, nucleic acids undergo oxidative alterations that have recently been shown to be commonly encountered in clinical practice. This review will attempt to provide an overview of this situation. After a brief coverage of the biological reasons why the sperm nucleus and associated DNA are sensitive to oxidative damage, a summary of the most recent results concerning the oxidation of sperm DNA in animal and human models will be presented. The study will then attempt to cover the possible consequences of sperm nuclear oxidation on male fertility and beyond. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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19 pages, 1997 KiB

Open AccessReview

From Past to Present: The Link Between Reactive Oxygen Species in Sperm and Male Infertility

by Ana Izabel Silva Balbin Villaverde, Jacob Netherton and Mark A. Baker

Antioxidants 2019, 8(12), 616; https://doi.org/10.3390/antiox8120616 - 03 Dec 2019

Cited by 34 | Viewed by 5223

Abstract

Reactive oxygen species (ROS) can be generated in mammalian cells via both enzymatic and non-enzymatic mechanisms. In sperm cells, while ROS may function as signalling molecules for some physiological pathways, the oxidative stress arising from the ubiquitous production of these compounds has been implicated in the pathogenesis of male infertility. In vitro studies have undoubtedly shown that spermatozoa are indeed susceptible to free radicals. However, many reports correlating ROS with sperm function impairment are based on an oxidative stress scenario created in vitro, lacking a more concrete observation of the real capacity of sperm in the production of ROS. Furthermore, sample contamination by leukocytes and the drawbacks of many dyes and techniques used to measure ROS also greatly impact the reliability of most studies in this field. Therefore, in addition to a careful scrutiny of the data already available, many aspects of the relationship between ROS and sperm physiopathology are still in need of further controlled and solid experiments before any definitive conclusions are drawn. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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23 pages, 1042 KiB

Open AccessReview

Redox Regulation and Oxidative Stress: The Particular Case of the Stallion Spermatozoa

by Fernando J. Peña, Cristian O’Flaherty, José M. Ortiz Rodríguez, Francisco E. Martín Cano, Gemma L. Gaitskell-Phillips, María C. Gil and Cristina Ortega Ferrusola

Antioxidants 2019, 8(11), 567; https://doi.org/10.3390/antiox8110567 - 19 Nov 2019

Cited by 57 | Viewed by 5167

Abstract

Redox regulation and oxidative stress have become areas of major interest in spermatology. Alteration of redox homeostasis is recognized as a significant cause of male factor infertility and is behind the damage that spermatozoa experience after freezing and thawing or conservation in a liquid state. While for a long time, oxidative stress was just considered an overproduction of reactive oxygen species, nowadays it is considered as a consequence of redox deregulation. Many essential aspects of spermatozoa functionality are redox regulated, with reversible oxidation of thiols in cysteine residues of key proteins acting as an “on–off” switch controlling sperm function. However, if deregulation occurs, these residues may experience irreversible oxidation and oxidative stress, leading to malfunction and ultimately death of the spermatozoa. Stallion spermatozoa are “professional producers” of reactive oxygen species due to their intense mitochondrial activity, and thus sophisticated systems to control redox homeostasis are also characteristic of the spermatozoa in the horse. As a result, and combined with the fact that embryos can easily be collected in this species, horses are a good model for the study of redox biology in the spermatozoa and its impact on the embryo. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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21 pages, 1211 KiB

Open AccessReview

Antioxidants and Male Fertility: From Molecular Studies to Clinical Evidence

by David Martin-Hidalgo, Maria Julia Bragado, Ana R. Batista, Pedro F. Oliveira and Marco G. Alves

Antioxidants 2019, 8(4), 89; https://doi.org/10.3390/antiox8040089 - 05 Apr 2019

Cited by 113 | Viewed by 10160

Abstract

Spermatozoa are physiologically exposed to reactive oxygen species (ROS) that play a pivotal role on several sperm functions through activation of different intracellular mechanisms involved in physiological functions such as sperm capacitation associated-events. However, ROS overproduction depletes sperm antioxidant system, which leads to a condition of oxidative stress (OS). Subfertile and infertile men are known to present higher amount of ROS in the reproductive tract which causes sperm DNA damage and results in lower fertility and pregnancy rates. Thus, there is a growing number of couples seeking fertility treatment and assisted reproductive technologies (ART) due to OS-related problems in the male partner. Interestingly, although ART can be successfully used, it is also related with an increase in ROS production. This has led to a debate if antioxidants should be proposed as part of a fertility treatment in an attempt to decrease non-physiological elevated levels of ROS. However, the rationale behind oral antioxidants intake and positive effects on male reproduction outcome is only supported by few studies. In addition, it is unclear whether negative effects may arise from oral antioxidants intake. Although there are some contrasting reports, oral consumption of compounds with antioxidant activity appears to improve sperm parameters, such as motility and concentration, and decrease DNA damage, but there is not sufficient evidence that fertility rates and live birth really improve after antioxidants intake. Moreover, it depends on the type of antioxidants, treatment duration, and even the diagnostics of the man’s fertility, among other factors. Literature also suggests that the main advantage of antioxidant therapy is to extend sperm preservation to be used during ART. Herein, we discuss ROS production and its relevance in male fertility and antioxidant therapy with focus on molecular mechanisms and clinical evidence. Full article

(This article belongs to the Special Issue Reactive Oxygen Species and Male Fertility)

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