Table of Contents
Advances in Andrology
Volume 2014, Article ID 626374, 15 pages
http://dx.doi.org/10.1155/2014/626374
Review Article

The Enzymatic Antioxidant System of Human Spermatozoa

1The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9
2Departments of Surgery (Urology Division), McGill University, Montreal, QC, Canada H3G 1A4
3Obstetrics and Gynecology, McGill University, Montreal, QC, Canada H3A 1A1
4Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6
5Urology Research Laboratory, Royal Victoria Hospital, Room H6.46, 687 Avenue des Pins Ouest, Montreal, QC, Canada H3A 1A1

Received 25 February 2014; Accepted 19 June 2014; Published 10 July 2014

Academic Editor: Mónica Hebe Vazquez-Levin

Copyright © 2014 Cristian O’Flaherty. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The ejaculated spermatozoon, as an aerobic cell, must fight against toxic levels of reactive oxygen species (ROS) generated by its own metabolism but also by other sources such as abnormal spermatozoa, chemicals and toxicants, or the presence of leukocytes in semen. Mammalian spermatozoa are extremely sensitive to oxidative stress, a condition occurring when there is a net increase in ROS levels within the cell. Opportunely, this specialized cell has a battery of antioxidant enzymes (superoxide dismutase, peroxiredoxins, thioredoxins, thioredoxins reductases, and glutathione s-transferases) working in concert to assure normal sperm function. Any impairment of the antioxidant enzymatic activities will promote severe oxidative damage which is observed as plasma membrane lipid peroxidation, oxidation of structural proteins and enzymes, and oxidation of DNA bases that lead to abnormal sperm function. Altogether, these damages occurring in spermatozoa are associated with male infertility. The present review contains a description of the enzymatic antioxidant system of the human spermatozoon and a reevaluation of the role of its different components and highlights the necessity of sufficient supply of reducing agents (NADPH and reduced glutathione) to guarantee normal sperm function.

1. Introduction

Mammalian and particularly human spermatozoa are sensitive to high levels of reactive oxygen species (ROS) [1, 2]. In the 40s, this toxic effect was first observed independently by different investigators: McLeod working with human and Tosic and Walton working with bull sperm samples; they found that the spermatozoon is very sensitive to high concentrations of hydrogen peroxide (H2O2) [35]. These pioneer works opened a new era of research in the biology of reproduction field to understand the mechanisms and players affected by toxic levels of ROS of sperm physiology. The oxidative stress is produced by a net increase of ROS levels because of an increase of their production and/or a decrease of antioxidant defences [6, 7]. It generates substantial damage to all components of the sperm cell; thus, significant levels of lipid peroxidation, protein, and DNA oxidation are seen in this situation [7, 8] and are often associated with infertility [912]. This damage is translated to changes in the plasma membrane fluidity, inactivation of key enzymes, and damage of the paternal DNA leading to impairment of sperm motility, mutations in the genomic message, and a variety of reproductive outcomes including, fertilization and embryo development failure, miscarriages, and abnormal offspring [7, 8, 1321]. Many pathological conditions such as infections of the male reproductive tract, cryptorchidism, varicocele, exposition to drugs (e.g., chemotherapeutics agents), environmental factors (e.g., plasticisers, dioxins), and aging have oxidative stress as a common component of their pathophysiological mechanisms [2225]. Therefore, the control of exogenous and/or endogenous ROS production and action is of paramount importance to assure maintaining normal sperm function.

On the other hand, low levels of ROS are essential for the spermatozoon to achieve fertilizing ability [2629]. Superoxide (), hydrogen peroxide (H2O2), and nitric oxide (NO) are produced by mammalian spermatozoa under capacitating conditions and triggered phosphorylation events in time dependent manners that culminate with the ability to induce the acrosome reaction upon specific physiological stimuli [27, 3038].

The purpose of this review is to update the knowledge on the antioxidant defences in the human spermatozoa to fight against oxidative stress and in their role as regulators of the redox signaling.

2. Oxidative Stress and Male Infertility

The oxidative damage due to high levels of ROS has been associated with men infertility in 30–80% of cases [912, 39]. It is intriguing why the spermatozoon, a highly specialized cell, shows high sensitivity to ROS; it is suggested that this is due to a large surface of plasma membrane with high quantities of polyunsaturated fatty acids susceptible to lipid peroxidation [17, 40]. What is even more intriguing is the fact that low amounts of ROS are essential for sperm activation to allow this cell to acquire fertilizing ability [28, 29, 41]. In light of this evidence, it is obvious that a well-regulated production and action of ROS must take place in the ejaculated spermatozoon to assure normal performance. Some protection against oxidative stress remains within the spermatozoa; the proper functioning of the antioxidant system, composed of non-enzymatic and enzymatic players, assures the health of the spermatozoon. Although the contribution of vitamins E and C, ubiquinol, and other antioxidant molecules is important for the spermatozoon protection, this review will be focused on the enzymatic antioxidant system.

3. Antioxidant Enzymes in Human Spermatozoa

Aerobic cells must fight a battle against ROS, the very reactive molecules that are end products of the oxidative phosphorylation using oxygen to obtain energy. The ROS that can be produced and act on spermatozoa are , H2O2, NO, and peroxynitrite (ONOO) which is the product of the combination of with NO. These molecules can react directly with lipids, proteins, and nucleic acid or can be combined with metals and trigger, for instance, lipid peroxidation [6, 42, 43].

ROS are produced exogenously by leukocytes present in the ejaculate or by the spermatozoa themselves. Particularly, defective spermatozoa produce significant levels of ROS that can be toxic for them and for healthy spermatozoa present in semen [44, 45].

The formation of the enzymatic antioxidant system, whose components vary among species, is a major achievement during spermatogenesis to guarantee the protection of spermatozoa against oxidative stress. Below there is a detailed description of each antioxidant enzyme and their relevance in human spermatozoa.

3.1. Superoxide Dismutase

Superoxide anion is a moderate reactive ROS with a short half-life (1 millisecond). In the cell, is converted into a strong oxidant ROS, H2O2, either spontaneously or by an enzymatic reaction catalyzed by superoxide dismutase (SOD) (see the following):

There is a wide difference in SOD activity among mammalian spermatozoa varying from ~10 times more than humans in donkey spermatozoa to ~0.2 times in bull or rabbit spermatozoa (Figure 1) [4649]. These different SOD activities are one of the causes of the variability in sensitivity to ROS that can be encountered in mammalian spermatozoa. Three SOD isoforms are present in aerobic cells: the cooper-zinc SOD (Cu-ZnSOD or SOD1) present in their cytosol, the manganese SOD (MnSOD or SOD2) present in mitochondria, and the secreted SOD (SOD3). It is important to clarify that, up to now, there is no study showing the presence of SOD isoforms in mammalian spermatozoa by either immunoblotting or immunocytochemistry. Thus, it is correct to define the scavenging capacity of spermatozoa as SOD-like activity [49, 50]. From studies measuring SOD-like activity, it was concluded that the protection by CuZn-SOD is limited in normal spermatozoa as they contain very little cytoplasm [45, 51]. The amounts of MnSOD and of SOD3 in human spermatozoa are negligible [52]. Interestingly, the seminal plasma is well equipped with SOD isoforms; the CuZn-SOD accounts for the 75% of enzymatic activity and the SOD3 for the other 25% [52] that can compensate for the limited SOD activity in the spermatozoon.

626374.fig.001
Figure 1: Comparison of SOD-like activity in spermatozoa from several mammals. The relative SOD-like activity in relation to that of human spermatozoa is present on the top of each bar. Considering SOD-like activity of human spermatozoa equal to 1, donkeys, rats, and stallions are those with the highest enzymatic activity. Data obtained from studies [4649].

It seems then that the protection against depends on active CuZn-SOD present in the spermatozoon; however, spermatozoa from infertile men have no variation in SOD-like activity regardless of whether their samples produce significant amount of ROS or not [50]. In other studies, it was found that infertile men have increased SOD-like activity in their spermatozoa, indicating that the infertility is associated with an increase of H2O2 production rather than a decrease in SOD-like activity [45, 53]. Particularly in this case, the increased SOD-like activity is a marker for abnormal spermatogenesis and/or epididymal maturation since more residual cytoplasm, containing this enzymatic activity, is present in the abnormal spermatozoa from infertile men [45]. In these abnormal spermatozoa, there is a net increase in as well due to the presence of higher amounts of glucose-6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentose phosphate pathway that produces NADPH which is used for the sperm oxidase to generate [45]. Then, dismutates (spontaneously or by enzymatic activity of SOD) to H2O2 which is the major culprit for damaging the spermatozoa [54].

An important role of SOD is to prevent the formation of hydroxyl radical (HO) that occurs when and H2O2 react with ferric ion (Fe3+) by the Haber-Weiss reaction [55]:

The HO is highly reactive, especially with lipids, promoting lipid peroxidation in human sperm membranes [47, 56]. Another important player in the protection against HO effects is the α-tocopherol or vitamin E that inhibits the propagation of lipid peroxidation cascades promoting a net decrease in the levels of oxidized lipids [56, 57].

3.2. Catalase

According to reaction (1), the spontaneous or enzymatic dismutation of promotes the formation of H2O2. This ROS is more stable than with a half-life of minutes to hours and it was shown to be highly toxic for spermatozoa from many species including humans [35]. It is then necessary that the spermatozoon has a way to remove H2O2. The first candidate to consider is catalase (CAT), an enzyme that converts H2O2 into oxygen and water according to the following reaction:

In somatic cells, CAT is abundant in the peroxisomes [58, 59]. The CAT activity is revealed when H2O2 diffuses to the peroxisomes, an event that is happening only when high concentrations of this ROS are present in the cell. During spermatogenesis, there is a removal of cytoplasm from the spermatids forming the residual body containing peroxisomes among other cytoplasmic structures [60, 61]. Immunoblotting studies demonstrated that bull spermatozoa do not contain CAT [62] and so far no similar studies have been conducted in human spermatozoa. Recently, it was demonstrated that the H2O2 scavenging capacity of human spermatozoa is not altered by the presence of sodium azide, a known inhibitor of CAT activity [63]. Based on the above, it is possible to conclude that CAT is absent or it is present in negligible amounts in human spermatozoa and therefore it is not a significant player in the antioxidant protection of the spermatozoon against high levels of H2O2.

Other enzymes capable of removing H2O2 are the peroxidases, represented by the glutathione peroxidase and peroxiredoxin family of antioxidant enzymes. These enzymes are also present in spermatozoa and they are considered candidates for the antioxidant protection against oxidative stress driven by H2O2 and other ROS.

3.3. Glutathione Peroxidases

The glutathione peroxidase (GPX) family is composed of 8 members that are distributed in different tissues but with differences among species [64]. They catalyze the reaction needed to remove H2O2 and other hydroperoxides using reduced glutathione (GSH):

In order to keep removing hydroperoxides, the oxidized glutathione (GS-SG) must be reduced back to GSH by the enzyme glutathione reductase (GRD) using NADPH as reducing agent:

There are selenium- (Se-) dependent and selenium-independent GPXs: the first group is represented by GPX1 to 4 and the second group by GPX5 to 8 [6569]. Glutathione peroxidases can also reduce ONOO [64], a very reactive ROS capable of harming cells promoting tyrosine nitration in proteins involved in motility and sperm capacitation [70, 71]. Of great importance for spermatozoa is the presence of the selenoprotein phospholipid hydroperoxide GPX4 (also known as PHGPX), a structural protein which is essential for normal formation of the mitochondrial sheath and constitutes approximately 50% of the sperm midpiece protein content localized in the mitochondrial helix [72]. Male mice lacking the mitochondrial PHGPX (mGPX4) are infertile with abnormal and less motile spermatozoa than wild type animals [73, 74]. The need for mGPX4 to assure normal sperm function has been also demonstrated in humans since infertile men have shown low sperm motility with abnormal morphology [75]. It is important to highlight that what is relevant for fertility is the ability of mGPX4 to interact with hydroperoxides to form the mitochondrial sheath during spermiogenesis and not its antioxidant activity which is less than 3% of the total PHGPX protein content in ejaculated spermatozoa and can be only obtained after in vitro solubilisation with high concentrations of dithiothreitol (0.1 M) in the presence of guanidine [72]. Selenium is essential to assure normal GPX4 function during spermiogenesis as it was confirmed by the presence of abnormal spermatozoa with poor motility observed in selenium-deficient mice [76] or large domestic animals living in Se-deficient areas (for review see [77]).

The sperm chromatin formation during spermiogenesis is accomplished in part by the nuclear isoform of GPX4 (snGPX4); this enzyme mediates the oxidation of thiols groups of protamines by hydroperoxides. However, other enzymes may play significant role in the formation of sperm chromatin because the nGPX4−/− mice are fertile [78]. It is possible then that other proteins are involved in the sperm chromatin remodelling and potential candidates are peroxiredoxins (see Section 3.5).

The contribution of GPXs to the protection against ROS is limited in human spermatozoa since, contrary to rodents, human spermatozoa, testes, or seminal plasma lacks GPX2, GPX3, and GPX5 [79, 80] and GPX4 is insoluble and enzymatically inactive in mature ejaculated spermatozoa [72, 78, 81]. The role of GPX1 in human sperm is controversial because in many studies GPX1 activity was measured using cumene hydroperoxide and NADPH [82]; substrates are also used by other enzymes such as peroxiredoxins (see Section 3.5). Up to now, there is no report demonstrating the presence of GPX1 in spermatozoa by either immunocytochemistry or immunoblotting. It seems that the role of GPX1 as important antioxidant enzyme is questionable because Gpx1−/− males are fertile and they are not susceptible to oxidative stress [83] and lipid peroxidation does not increase in human spermatozoa incubated with H2O2 in the presence of carmustine (inhibitor of glutathione reductase (GRD)) or diethyl maleate (binds to GSH making it nonaccessible for GPX/GRD system) that affects the GPX/GRD system activity [63].

3.4. Glutathione Transferases

Glutathione S-transferases are antioxidant enzymes participating in the detoxification of cells and organs by conjugating the xenobiotics and other toxic compounds with GSH (see reaction below):

It has been suggested that GSTs play a role as proteins participating in the sperm-zona binding in caprine and humans [84, 85]. The GSTs participate in the antioxidant protection since infertile men with a null genotype for GST-Mu1 have spermatozoa with significant oxidative damage [86]. It is interesting to note that not all the GST isoforms may play a significant role in the protection of spermatozoa against oxidative stress; for example, the levels of GST A1-1 and P1-1 in seminal plasma are similar in fertile or infertile men [87]. Recently, it was reported that GSTM1, GSTT1, and GSTZ1 polymorphisms seem not to be associated with sperm quality in humans, but only GSTT1 was associated with reduced sperm concentration [88]. Based on all these studies, it is evident that GSTs are playing different roles depending on the isoform considered and more research is necessary to have a complete picture of the participation of this large family of antioxidant enzymes in male reproduction.

3.5. Peroxiredoxins

Peroxiredoxins (PRDXs) are thiol-dependent peroxidases highly expressed from yeast to humans that do not require selenium or heme group to have enzymatic activity [8998]. These acidic proteins contain one or two Cys residues at the active site which are required for their activity [95] and are used to classify them in three groups: 2-Cys PRDXs (isoforms 1 to 4), atypical 2-Cys PRDX (isoform 5), and 1-Cys PRDX (isoform 6) (Table 1). They can reduce a variety of reactive oxygen species such as organic and inorganic hydroperoxides and ONOO [99101]. Although ONOO can be scavenged by GPXs and PRDXs, the latter preferentially catalyze its fast reduction [102]. After H2O2 (or other ROS) are bound to the Cys residues in the active site, the enzyme becomes inactive; it is then necessary for the activity of the thioredoxin- (TRX-) thioredoxin reductase (TRD) system [96, 97, 103] in the case of PRDX1 to 5 or the GSTpi/GSH for PRDX6 [104, 105] to activate PRDXs again. As an example, the reaction of PRDX with H2O2 is presented in the following reaction:

tab1
Table 1: Characterization of peroxiredoxins.

Hydrogen peroxide rapidly reacts with PRDXs oxidizing their SH at the active site even at low levels [106110] (Figure 3). Particularly in human spermatozoa, PRDX6 is able to react with H2O2 concentrations as low as 50 μM that is able to induce capacitation [29, 37, 110]. These biochemical characteristics allow PRDXs to participate in the cellular redox signaling to promote physiological events and they have a major role as H2O2 scavengers and sensors [6, 111, 112]. This role is emphasized by their wide subcellular distribution (cytosol, nucleus, mitochondria, endoplasmic reticulum, and plasma membrane [96, 97, 113117]). Studies in human spermatozoa revealed that the 6 isoforms are differentially localized in the subcellular compartments (Figure 2) that contain at least two members of the PRDX family [110].

626374.fig.002
Figure 2: Subcellular localization of antioxidant enzymes in the human spermatozoon. See description in the text.
626374.fig.003
Figure 3: PRDX6 differentially reacts with different ROS in human spermatozoa. Percoll-washed spermatozoa were incubated with different concentrations of H2O2, ONOO, or tert-buthyl hydroperoxide (tert-BHP) for 30 min at 37°C and then sperm proteins were electrophoresed and immunoblotted with anti-PRDX6 antibody as previously described [110]. PRDX6 is present as a doublet observed in absence of H2O2 or 0.05 mM ONOO that becomes a single band with high intensity upon increased concentrations of ROS. High levels of H2O2 (but not of ONOO or tert-BHP) generate the formation of high molecular mass complexes. Representative blot from other four experiments performed with different healthy donors.

PRDX1, mainly a cytosolic enzyme in somatic cells, is located in the Triton-insoluble; immunocytochemistry studies revealed its presence in the equatorial region, nucleus, and flagellum of human spermatozoa [63, 110]. Three distinctive bands (23, 42, and 54 kDa), detected with the anti-PRDX1 antibody, are present in the Triton-X100 insoluble fraction, with the exception of p54 that is found only in the Triton-soluble fraction. PRDX2 is present in the head (acrosome, nucleus, and equatorial region), plasma membrane, and flagellum. Specific signal of PRDX3 (mostly restricted in mitochondria of somatic cells) is found in the nucleus, flagellum, and mitochondria. PRDX4 is present as two isoforms of 27 and 31 kDa (p27 and p31, resp.) and it is located in the plasma membrane (p27), acrosome (p27 and p31), and cytosol (p27). Another isoform present in the mitochondria is PRDX5 which is located also in the plasma membrane, equatorial region, and acrosome. Noteworthy, plasma membrane and acrosome of boar spermatozoa contain PRDX5 and its involvement in sperm-egg interaction was suggested [118, 119].

PRDX6 is the isoform most abundant and widely distributed in all subcellular compartments of human spermatozoon [110]; infertile men have spermatozoa with low amounts of PRDX6 which is highly oxidized and therefore inactive [120]. Moreover, H2O2, organic hydroperoxides, and peroxynitrite are substrates of human sperm PRDX6; H2O2 is the only ROS able to form high molecular mass complexes (Figure 3) [110], denoting a wide protection capability against ROS of sperm by PRDX6 in humans. Altogether, these findings suggest a key role of this enzyme in the defence against oxidative stress.

The participation of PRDXs in the maintenance of sperm quality has been studied using knockout models Prdx4−/− males which showed reduced testis weight due to an increased apoptosis during spermatogenesis and their spermatozoa display high levels of DNA damage [121]. We recently communicated that males lacking PRDX6 gene show significant higher levels of DNA and protein oxidation and impaired motility compared to wild type controls [122]. Other knockout models for PRDXs have been developed, although the information regarding the reproductive phenotype is limited. It is important to highlight that animals lacking PRDX1 are tumor prone, their life span is reduced [123], and their tissues contain elevated levels of damaged DNA [124]. Additionally, cellular senescence is accelerated in PRDX2−/− mouse embryonic fibroblasts [125]. In these two knockout animals, severe anaemia is seen as part of the phenotype [108, 123]. Altogether, these animal models demonstrated the central role of PRDXs to fight against oxidative stress.

Studies on boar and mouse spermatozoa revealed that PRDX2 follows a similar path as GPX4; it is a soluble enzyme in spermatids but turns into an insoluble structural protein that colocalizes with the GPX isoform, becoming part of the mitochondrial sheath [126]. Immunocytochemistry studies revealed a broader localization of PRDX2 in the plasma membrane, mitochondrial sheath, flagellum, and head of human spermatozoa [63]. More studies are in the way to determine whether PRDX2 has similarities in solubility as was observed in mouse or boar [126].

In somatic cells, GPX1, GPX4, PRDX3, and PRDX5 are responsible for scavenging 99.9% of H2O2 consumption in mitochondria [127]. Sperm mitochondrion is the main source of the high levels of ROS associated with male infertility [21]. PRDXs are the major defence against increased levels of ROS in sperm mitochondria because GPX4, a structural protein associated with the mitochondrial sheath, does not have antioxidant activity and GPX1 activity is absent or present in negligible amounts. It is known that abnormal spermatozoa have significant high amount of unsaturated, unesterified fatty acid that promotes ROS generation by sperm mitochondria, generating an oxidative stress causing impairment of sperm function [21, 128]. Failure of the PRDXs system in mitochondria to remove H2O2 leads to an increase of toxic levels of this ROS that will compromise normal sperm function and evolve into male infertility [129].

Recently, it was reported that PRDXs play a significant role in the protection of human spermatozoa against oxidative stress [120]. In this study, the levels and the thiol oxidation status of PRDXs from spermatozoa of infertile men (with clinical varicocele or idiopathic infertility) were compared with those from healthy donors. Only the total amounts of PRDX1 and PRDX6 were lower in spermatozoa from infertile men compared to those from healthy donors. Moreover, it was observed that there is a great variability in the quantities of PRDX4 and PRDX5. The thiol oxidation status, an indication of inactive PRDXs, was higher in infertile men for PRDX1, PRDX5, and PRDX6 compared to healthy donors. Those samples with low amounts and highly thiol-oxidized PRDXs showed high levels of lipid peroxidation and DNA damage along with low motility [120]. Noteworthy, regression analyses revealed that these damages depend on the levels of thiol oxidation of PRDXs. Based on these data, it can be concluded that sufficient quantities of active PRDXs are needed to assure sperm competence.

3.6. Thioredoxins

The thioredoxins are small proteins widely distributed in both the plant and the animal kingdom. They are important reducers of disulfide groups in several proteins including PRDXs (see reaction (8)) [130132]. They work together with the thioredoxin reductases (see reaction (9)) forming the TRX/TRD system which requires reducing equivalents in the form of NADPH to accomplish its biological role as disulfide reducing and redox signaling regulators [130, 132134].

In humans, and rodents at least, there are sperm specific isoforms called spermatid-specific TRX (SPTRX), which are present in the postmeiotic phase of the spermatogenesis and they are associated with the formation of the sperm tail [135, 136]. It is suggested that human SPTRX and human SPTRX are involved in stabilization by disulfide cross-linking of different tail structures during spermiogenesis [137]. A differential expression of these isoforms has been described during spermatogenesis; SPTRX expression peaks at steps 14–16 of the rat spermiogenesis whereas SPTRX is found in the fiber sheath at stages 15–19 [136, 138]. SPTRX appears to be required for the formation of fiber sheath but not in the fully differentiated mature spermatozoa; however, SPTRX remains associated with the fiber sheath in cauda epididymal and ejaculated spermatozoa [139]. These studies highlight the potential requirement of SPTRX in posttesticular events necessary for sperm maturation and activation required for fertilization [139]. The isoforms SPTRX and SPTRX present in normal spermatozoa were described [136, 138, 139]. Immunocytochemistry approaches denoted the presence of SPTRXs not only in the sperm flagellum but also in the head and midpiece, suggesting other functions for this enzyme in the spermatozoon [135].

The third isoform, SPTRX, is expressed at the spermatid level and probably required at later stages of spermiogenesis [139]. SPTRX is associated with the Golgi and the perinuclear region in spermatids and it was found only in abnormal human spermatozoa from infertile men [140], suggesting an incomplete spermiogenesis with retention of residual bodies and cytoplasmic droplets.

It was also reported in human spermatozoa the presence of TRX1, TRX2, and TRX-like-2 [139, 141] and the TRD1, TRD2, and thioredoxin glutathione reductase (TGR) [135, 139], necessary enzymes to reduce the oxidized TRXs isoforms (Figure 4). Thus, human spermatozoa have a TRX/TRD system that plays a role supporting antioxidant capabilities, for instance, by reducing PRDXs to protect the spermatozoon against oxidative stress.

626374.fig.004
Figure 4: Fate of 2-Cys PRDXs when scavenging ROS. 2-Cys PRDXs react with H2O2 and become oxidized and therefore inactive. The TRX/TRD can reduce PRDXs in order to allow another cycle of scavenging of ROS. To assure proper function of this system, glucose-6-P dehydrogenase (G6PDH) and/or NADP-dependent isocitrate dehydrogenase (NADP-ICDH) supply enough reducing equivalent in the form of NADPH. If there is a strong oxidative stress (with high amounts of intracellular H2O2, for example), 2-Cys PRDXs are sulfonated and inactive. This inactivation cannot be reversed by the TRX/TRD system and 2-Cys-PRDXs can only be reactivated by sulfiredoxin (SRX) or sestrin 1 (SESN1) and donors of thiol groups (-SH) like reduced glutathione.

4. Antioxidant Enzymes Working Together to Generate Healthy Spermatozoa and Assure Normal Sperm Function

Above, it was described in detail the function of each antioxidant enzyme present in human spermatozoa. It is important to highlight the interrelationships among certain isoforms that are working together to achieve a specific goal, such as supporting and assuring normal function in ejaculated spermatozoa. In light of the studies performed using knockout models and the evidence in infertile men [7375], mGPX plays an essential role during spermiogenesis in the generation of a normal mitochondrial sheath [72]. However, it is imperative to stress that its participation as an antioxidant enzyme in ejaculated spermatozoa is very limited if not completely absent [72]. In the case of snGPX, the exclusive role of this isoform in the formation and maintenance of the sperm chromatin structure is still controversial; it is known that snGPX participates in protamine thiol oxidation, but it was demonstrated that it is not essential as knockout mice lacking this enzyme are fertile [78]. Perhaps other proteins are participating in modeling the sperm chromatin since the animals lacking PRDX6 or TRX1 and TRX2 show abnormal sperm chromatin [122, 142].

An important group of antioxidant enzymes is the PRDX family in human spermatozoa and from other species; it is striking that the presence of all isoforms is differentially distributed in the sperm subcellular compartments [110] (Figure 2). The specific location of PRDXs and their behaviour in the presence of ROS suggest different roles for each isoform that surpass their traditional function as ROS scavengers. In this regard it is interesting to note the formation of high molecular mass complexes by PRDX1 and PRDX6 (but not for other PRDXs) when the human spermatozoa are exposed to a strong oxidative stress [110] similar to that seen in infertile men [120]. These complexes are formed by sulfonated PRDXs that were highly oxidized in order to protect other sperm proteins from being affected by high levels of ROS [110]. The addition to the sulfonic group promotes the change from antioxidant to chaperone activity in 2-Cys PRDXs [143147]. Sulfonated 2-Cys PRDXs can be reactivated to PRDX with antioxidant capacity again by either sulfiredoxin (SRX) or sestrin 1 (SESN1) [148152] (Figure 4). Studies are on the way to elucidate which proteins are present in these complexes and whether spermatozoa have SRX and/or SESN1 to reactivate thiol-oxidized 2-Cys PRDXs to better understand the role of PRDXs in the protection of human spermatozoa. A particular case is the hyperoxidation of PRDX6 that occurs in human spermatozoa as response to oxidative stress [110]. The sulfonated form of PRDX6 present in the high molecular mass complexes observed in spermatozoa treated with high concentrations of H2O2 or in infertile men [110, 120] cannot be reduced to its active form [153]; thus it is then probable that the sulfonated form of the sperm PRDX6 becomes irreversibly inactive and associated with impaired function.

A prerequisite for full PRDX activity is a functional TRX/TRD system, sufficient NAPDH and/or GSH availability [63] (Figure 4). The presence of TRX or specific TRX isoforms and their respective reductive enzymes TRD and TGR in the human spermatozoon accounts for the maintenance of reduced PRDX to guarantee full ROS scavenging capacity. In order to have this system working properly, it is essential to assure sufficient levels of NADPH, usually generated by glucose-6-phosphate dehydrogenase (G6PDH) of the Pentose Phosphate pathway [54, 154] and by the NADP-dependent isocitrate dehydrogenase (NADP-ICDH) [155]. The TRX/TRD system is useful to reduce 2-Cys PRDXs (PRDX1 to 4) and possibly atypical 2-Cys PRDX (PRDX5), but it is not clear how PRDX6 is reduced in the case of spermatozoa. The amount of GSH is very limited in mammalian spermatozoa [156, 157], thus the reduction of PRDX6 by GSH may not be possible after facing an oxidative stress. The limited PRDX6 reduction capabilities could be one of the causes of the sensitivity of spermatozoa from humans and other species to high concentrations of ROS. A mechanism for reduction of PRDX6 in somatic cells involves GSTpi [104, 105, 158]; although a potential candidate, it is still elusive whether GSTpi is present in the human spermatozoon. The finding that oxidative stress promotes the sulfonation of PRDX6 (an indication of protein hyperoxidation) present in the high molecular mass complexes of sperm under oxidative stress [110] and the presence of those complexes in sperm from infertile men [120] demand an answer as to whether there is a mechanism capable of reactivating sulfonated PRDX6 to its reduced form. It is known that SRX cannot reactivate the sulfonated PRDX6 [148], thus discarding the possibility of SRX as reducer for PRDX6 in spermatozoa. It is rather possible that the sulfonation of PRDX6 is irreversible and may be a cause of sperm impairment in infertile men [120]. Further research must be done to elucidate the mechanism that reduces PRDX6 in spermatozoa.

As it was mentioned at the beginning of this review, many conditions are associated with the generation of oxidative stress which promote abnormal sperm function and infertility [2225]. In healthy spermatozoa, high levels of , H2O2, NO, and ONOO are scavenged by the collaborative work among SOD, PRDXs, and the TRX/TRD system (Figure 5). In order to assure a full capacity of PRDX enzymatic activity a sufficient supply of NADPH is needed to allow the reduction of TRX by TRD after the former reduces the 2-Cys or atypical 2-Cys PRDXs (PRDX5). Moreover, enough concentration of GSH and probably GST activity are necessary to assure the reduction of 1-Cys PRDX (PRDX6). In the case of sufficient supply of NADPH by G6PDH and/or NADP-ICDH and enough GSH in the presence of GSTs, the PRDXs along with the TRX/TRD system scavenge ROS reducing their concentrations to nontoxic levels (Figure 5, panel on the left).

626374.fig.005
Figure 5: Antioxidant defence against oxidative stress in human spermatozoa and effects of availability of intracellular concentrations of NADPH and/or GSH on the antioxidant protection in human spermatozoa. The insufficient supply of NADPH and/or GSH, due to inactivation of G6PDH and probably NADP-ICDH by H2O2, promotes the establishment of a stronger oxidative stress that produces enzymatic inactivation of SOD and the formation of sulfonated form of 2-Cys PRDXs and of PRDX6, thus becoming impossible to reactivate their activity to fight against high levels of ROS and conducting impairment of sperm function and infertility.

However, this mechanism of protection is delicate and if the oxidative stress persists it can be affected by inactivation of its components, such as oxidation of PRDXs, as seen in infertile men [120]. The oxidation of PRDXs could be the result of direct effect of ROS on these enzymes or the inactivation of the TRX/TRD system when there is not enough NADPH as reducing equivalent. The lack of sufficient NADPH could be the consequence of G6PDH inactivation by high levels of H2O2 [54]. Similar fate of inactivation could have the NADP-ICDH [159], thus eliminating the possibility of assuring enough reducing equivalent to recycle the oxidized TRX required to reduce the thiol-oxidized 2-Cys PRDXs and PRDX5 (Figure 5, panel on the right).

The GSH reserved are very limited in spermatozoa [156, 157]; therefore, a strong oxidative stress may deplete these reserves and thus impact negatively on the reduction of thiol-oxidized PRDX6, with the consequence of having this enzyme completely inactive and impossible to scavenge any more ROS. Noteworthy is that hyperoxidation of PRDX6 will produce the sulfonated form that seems to be an irreversible state for the 1-Cys PRDX [148].

5. Conclusions

The enzymatic antioxidant system in human spermatozoon is very delicate and susceptible of inactivation by high levels of ROS. Because spermatozoa cannot respond to an oxidative stress with the synthesis of more antioxidant enzymes, it is imperative that the spermatozoon has enough amounts of these proteins to fight against the high level of ROS and assure normal sperm function. When thiol-oxidized PRDXs are present in high amounts and the TRX/TRD system cannot reduce them, there is a permanent oxidative damage that it is associated with impaired sperm function. More studies are needed to better understand the antioxidant system and how ROS are regulated in both healthy and pathological conditions to seek new therapeutic interventions for infertile men.

Abbreviations

ATP:Adenosine triphosphate
Cu/ZnSOD:Cooper/zinc superoxide dismutase (SOD1)
Cys:Cysteine residue
DEM:Diethyl maleate
DTT:Dithiothreitol
G6PDH:Glucose-6-phosphate dehydrogenase
GPX:Glutathione peroxidase
GRD:Glutathione reductase
GSH:Glutathione, reduced form
H2O2:Hydrogen peroxide
MnSOD:Manganese superoxide dismutase (SOD2)
NADP-ICDH:NADP-dependent isocitrate dehydrogenase
NADP+:Nicotinamide adenine dinucleotide phosphate, oxidized form
NADPH:Nicotinamide adenine dinucleotide phosphate, reduced form
NaN3:Sodium azide
Superoxide anion
ONOO:Peroxynitrite
PRDX:Peroxiredoxin
ROS:Reactive oxygen species
SH:Sulfhydryl (thiol) group
SO2:Sulfinic acid group
SESN1:Sestrin 1
SPTRX:Sperm specific thioredoxin
SRX:Sulfiredoxin
SS:Disulfide
TGR:Thioredoxin glutathione reductase
TRD:Thioredoxin reductase
TRX:Thioredoxin.

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The author would like to thank the volunteers that participated in the studies on the effects of ROS on PRDX6 presented in this review and Mr. Stefan Patrascu for his technical skills in those studies. This review was supported by the Fonds de Recherche en Santé Quebec, The Klaassen-Hawthorne Memorial Fellowship, The Urology Division, McGill University, and The Research Institute of the McGill University Health Centre.

References

  1. B. T. Storey, “Mammalian sperm metabolism: oxygen and sugar, friend and foe,” International Journal of Developmental Biology, vol. 52, no. 5-6, pp. 427–437, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. R. J. Aitken, K. T. Jones, and S. A. Robertson, “Reactive oxygen species and sperm function—in sickness and in health,” Journal of Andrology, vol. 33, no. 6, pp. 1096–1106, 2012. View at Publisher · View at Google Scholar
  3. J. MacLeod, “The role of oxygen in the metabolism and motility of human spermatozoa,” American Journal of Physiology, vol. 138, pp. 512–518, 1943. View at Google Scholar
  4. J. Tosic and A. Walton, “Formation of hydrogen peroxide by spermatozoa and its inhibitory effect on respiration,” Nature, vol. 158, p. 485, 1946. View at Google Scholar · View at Scopus
  5. J. Tosic and A. Walton, “Metabolism of spermatozoa. The formation and elimination of hydrogen peroxide by spermatozoa and effects on motility and survival,” The Biochemical Journal, vol. 47, no. 2, pp. 199–212, 1950. View at Google Scholar · View at Scopus
  6. B. Halliwell, “Oxidative stress and neurodegeneration: where are we now?” Journal of Neurochemistry, vol. 97, no. 6, pp. 1634–1658, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. B. Halliwell and J. Gutteridge, “Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 187–267, Oxford University Press, New York, NY, USA, 2007. View at Google Scholar
  8. Y. Li, H. Zhu, K. L. Stansbury, and M. A. Trush, “Role of reactive oxygen species in multistage carcinogenesis,” in Oxygen Radicals and the Disease Process, C. E. Thomas and B. Kalyanaram, Eds., pp. 237–278, Academic Press, Amsterdam, The Netherlands, 1997. View at Google Scholar
  9. C. Gagnon, A. Iwasaki, E. De Lamirande, and N. Kovalski, “Reactive oxygen species and human spermatozoa,” Annals of the New York Academy of Sciences, vol. 637, pp. 436–444, 1991. View at Publisher · View at Google Scholar · View at Scopus
  10. E. de Lamirande and C. Gagnon, “Impact of reactive oxygen species on spermatozoa: a balancing act between beneficial and detrimental effects,” Human Reproduction, vol. 10, supplement 1, pp. 15–21, 1995. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Agarwal, S. Gupta, and S. Sikka, “The role of free radicals and antioxidants in reproduction,” Current Opinion in Obstetrics and Gynecology, vol. 18, no. 3, pp. 325–332, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. R. J. Aitken and M. A. Baker, “Oxidative stress, sperm survival and fertility control,” Molecular and Cellular Endocrinology, vol. 250, no. 1-2, pp. 66–69, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. E. de Lamirande and C. Gagnon, “Reactive oxygen species and human spermatozoa. I: effects on the motility of intact spermatozoa and on sperm axonemes,” Journal of Andrology, vol. 13, no. 5, pp. 368–378, 1992. View at Google Scholar · View at Scopus
  14. E. de Lamirande and C. Gagnon, “Reactive oxygen species and human spermatozoa: II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility,” Journal of Andrology, vol. 13, no. 5, pp. 379–386, 1992. View at Google Scholar · View at Scopus
  15. S. C. Sikka, M. Rajasekaran, and W. J. G. Hellstrom, “Role of oxidative stress and antioxidants in male infertility,” Journal of Andrology, vol. 16, no. 6, pp. 464–468, 1995. View at Google Scholar · View at Scopus
  16. J. F. Griveau and D. le Lannou, “Reactive oxygen species and human spermatozoa: physiology and pathology,” International Journal of Andrology, vol. 20, no. 2, pp. 61–69, 1997. View at Publisher · View at Google Scholar · View at Scopus
  17. B. T. Storey, “Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa,” Molecular Human Reproduction, vol. 3, no. 3, pp. 203–213, 1997. View at Publisher · View at Google Scholar · View at Scopus
  18. R. J. Aitken, E. Gordon, D. Harkiss et al., “Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa,” Biology of Reproduction, vol. 59, no. 5, pp. 1037–1046, 1998. View at Publisher · View at Google Scholar · View at Scopus
  19. G. Barroso, M. Morshedi, and S. Oehninger, “Analysis of DNA fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa,” Human Reproduction, vol. 15, no. 6, pp. 1338–1344, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. F. Gallon, C. Marchetti, N. Jouy, and P. Marchetti, “The functionality of mitochondria differentiates human spermatozoa with high and low fertilizing capability,” Fertility and Sterility, vol. 86, no. 5, pp. 1526–1530, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. A. J. Koppers, G. N. De Iuliis, J. M. Finnie, E. A. McLaughlin, and R. J. Aitken, “Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 8, pp. 3199–3207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. J. B. Anderson and R. C. N. Williamson, “Testicular torsion in bristol: a 25-year review,” British Journal of Surgery, vol. 75, no. 10, pp. 988–992, 1988. View at Publisher · View at Google Scholar · View at Scopus
  23. W. Brennemann, B. Stoffel-Wagner, A. Helmers, J. Mezger, N. Jäger, and D. Klingmüller, “Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer,” Journal of Urology, vol. 158, no. 3, pp. 844–850, 1997. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Hasegawa, G. Wilson, L. D. Russell, and M. L. Meistrich, “Radiation-induced cell death in the mouse testis: relationship to apoptosis,” Radiation Research, vol. 147, no. 4, pp. 457–467, 1997. View at Publisher · View at Google Scholar · View at Scopus
  25. R. Smith, H. Kaune, D. Parodi et al., “Increased sperm DNA damage in patients with varicocele: relationship with seminal oxidative stress,” Human Reproduction, vol. 21, no. 4, pp. 986–993, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. R. J. Aitken, D. Harkiss, W. Knox, M. Paterson, and D. S. Irvine, “A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation,” Journal of Cell Science, vol. 111, no. 5, pp. 645–656, 1998. View at Google Scholar · View at Scopus
  27. C. O'Flaherty and N. Beorlegui, “Role of superoxide anion and hydrogen peroxide in bovine acrosome reaction,” in Andrology in the 21st Century. Proceedings of the 7th International Congress of Andrology, B. Robaire, H. Chemes, and C. Morales, Eds., pp. 103–108, Medimond Publications, 2001. View at Google Scholar
  28. E. de Lamirande and C. O'Flaherty, “Sperm activation: role of reactive oxygen species and kinases,” Biochimica et Biophysica Acta—Proteins and Proteomics, vol. 1784, no. 1, pp. 106–115, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. E. de Lamirande and C. O'Flaherty, “Sperm capacitation as an oxidative event,” in Studies on Men's Health and Fertility, Oxidative Stress in Applied Basic Research and Clinical Practice, J. Aitken, J. Alvarez, and A. Agawarl, Eds., pp. 57–94, Springer Science, New York, NY, USA, 2012. View at Google Scholar
  30. P. E. Visconti, J. L. Bailey, G. D. Moore, D. Pan, P. Olds-Clarke, and G. S. Kopf, “Capacitation of mouse spermatozoa. 1. Correlation between the capacitation state and protein tyrosine phosphorylation,” Development, vol. 121, no. 4, pp. 1129–1137, 1995. View at Google Scholar · View at Scopus
  31. P. E. Visconti and G. S. Kopf, “Regulation of protein phosphorylation during sperm capacitation,” Biology of Reproduction, vol. 59, no. 1, pp. 1–6, 1998. View at Publisher · View at Google Scholar · View at Scopus
  32. C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Phosphorylation of the Arginine-X-X-(Serine/Threonine) motif in human sperm proteins during capacitation: modulation and protein kinase A dependency,” Molecular Human Reproduction, vol. 10, no. 5, pp. 355–363, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Reactive oxygen species and protein kinases modulate the level of phospho-MEK-like proteins during human sperm capacitation,” Biology of Reproduction, vol. 73, no. 1, pp. 94–105, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. P. C. Rodriguez, C. M. O'Flaherty, M. T. Beconi, and N. B. Beorlegui, “Nitric oxide induces acrosome reaction in cryopreserved bovine spermatozoa,” Andrologia, vol. 37, no. 5, pp. 166–172, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. P. C. Rodriguez, C. M. O'Flaherty, M. T. Beconi, and N. B. Beorlegui, “Nitric oxide-induced capacitation of cryopreserved bull spermatozoa and assessment of participating regulatory pathways,” Animal Reproduction Science, vol. 85, no. 3-4, pp. 231–242, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Positive role of reactive oxygen species in mammalian sperm capacitation: triggering and modulation of phosphorylation events,” Free Radical Biology and Medicine, vol. 41, no. 4, pp. 528–540, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. C. O'Flaherty, E. de Lamirande, and C. Gagnon, “Reactive oxygen species modulate independent protein phosphorylation pathways during human sperm capacitation,” Free Radical Biology and Medicine, vol. 40, no. 6, pp. 1045–1055, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. P. C. Rodriguez, L. B. Valdez, T. Zaobornyj, A. Boveris, and M. T. Beconi, “Nitric oxide and superoxide anion production during heparin-induced capacitation in cryopreserved bovine spermatozoa,” Reproduction in Domestic Animals, vol. 46, no. 1, pp. 74–81, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Tremellen, “Oxidative stress and male infertility—a clinical perspective,” Human Reproduction Update, vol. 14, no. 3, pp. 243–258, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. J. G. Alvarez, J. C. Touchstone, L. Blasco, and B. T. Storey, “Spontaneous lipid peroxidation and production of hydrogen peroxide and superoxide in human spermatozoa. Superoxide dismutase as major enzyme protectant against oxygen toxicity,” Journal of Andrology, vol. 8, no. 5, pp. 338–348, 1987. View at Google Scholar · View at Scopus
  41. R. J. Aitken and B. J. Curry, “Redox regulation of human sperm function: from the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line,” Antioxidants and Redox Signaling, vol. 14, no. 3, pp. 367–381, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Halliwell and J. Gutteridge, “The chemistry of free radicals and related reactive species,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 30–74, Oxford University Press, New York, NY, USA, 2007. View at Google Scholar
  43. B. Halliwell, “Free radicals and antioxidants: updating a personal view,” Nutrition Reviews, vol. 70, no. 5, pp. 257–265, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Iwasaki and C. Gagnon, “Formation of reactive oxygen species in spermatozoa of infertile patients,” Fertility and Sterility, vol. 57, no. 2, pp. 409–416, 1992. View at Google Scholar · View at Scopus
  45. R. J. Aitken, D. W. Buckingham, A. Carreras, and D. S. Irvine, “Superoxide dismutase in human sperm suspensions: relationship with cellular composition, oxidative stress, and sperm function,” Free Radical Biology and Medicine, vol. 21, no. 4, pp. 495–504, 1996. View at Publisher · View at Google Scholar · View at Scopus
  46. M. R. F. Mennella and R. Jones, “Properties of spermatozoal superoxide dismutase and lack of involvement of superoxides in metal-ion-catalysed lipid-peroxidation reactions in semen,” Biochemical Journal, vol. 191, no. 2, pp. 289–297, 1980. View at Google Scholar · View at Scopus
  47. J. G. Alvarez and B. T. Storey, “Lipid peroxidation and the reactions of superoxide and hydrogen peroxide in mouse spermatozoa,” Biology of Reproduction, vol. 30, no. 4, pp. 833–841, 1984. View at Publisher · View at Google Scholar · View at Scopus
  48. F. Tramer, F. Rocco, F. Micali, G. Sandri, and E. Panfil, “Antioxidant systems in rat epididymal spermatozoa,” Biology of Reproduction, vol. 59, no. 4, pp. 753–758, 1998. View at Publisher · View at Google Scholar · View at Scopus
  49. P. Cassani, M. T. Beconi, and C. O'Flaherty, “Relationship between total superoxide dismutase activity with lipid peroxidation, dynamics and morphological parameters in canine semen,” Animal Reproduction Science, vol. 86, no. 1-2, pp. 163–173, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Zini, E. de Lamirande, and C. Gagnon, “Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa,” International Journal of Andrology, vol. 16, no. 3, pp. 183–188, 1993. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Aitken, C. Krausz, and D. Buckingham, “Relationships between biochemical markers for residual sperm cytoplasm, reactive oxygen species generation, and the presence of leukocytes and precursor germ cells in human sperm suspensions,” Molecular Reproduction and Development, vol. 39, no. 3, pp. 268–279, 1994. View at Publisher · View at Google Scholar · View at Scopus
  52. R. Peeker, L. Abramsson, and S. L. Marklund, “Superoxide dismutase isoenzymes in human seminal plasma and spermatozoa,” Molecular Human Reproduction, vol. 3, no. 12, pp. 1061–1066, 1997. View at Publisher · View at Google Scholar · View at Scopus
  53. A. Zini, K. Garrels, and D. Phang, “Antioxidant activity in the semen of fertile and infertile men,” Urology, vol. 55, no. 6, pp. 922–926, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. J. F. Griveau, E. Dumont, P. Renard, J. P. Callegari, and D. Le Lannou, “Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa,” Journal of Reproduction and Fertility, vol. 103, no. 1, pp. 17–26, 1995. View at Publisher · View at Google Scholar · View at Scopus
  55. J. P. Kehrer, “The Haber-Weiss reaction and mechanisms of toxicity,” Toxicology, vol. 149, no. 1, pp. 43–50, 2000. View at Publisher · View at Google Scholar · View at Scopus
  56. J. G. Alvarez and R. J. Aitken, “Lipid peroxidation in human spermatozoa,” in Studies on Men's Health and Fertility, A. Agarwal, R. J. Aitken, and J. G. Alvarez, Eds., pp. 119–130, Humana Press, New York, NY, USA, 2012. View at Google Scholar
  57. I. S. Young and J. McEneny, “Lipoprotein oxidation and atherosclerosis,” Biochemical Society Transactions, vol. 29, no. 2, pp. 358–362, 2001. View at Publisher · View at Google Scholar · View at Scopus
  58. B. Chance, H. Sies, and A. Boveris, “Hydroperoxide metabolism in mammalian organs,” Physiological Reviews, vol. 59, no. 3, pp. 527–605, 1979. View at Google Scholar · View at Scopus
  59. M. Schrader and H. D. Fahimi, “Mammalian peroxisomes and reactive oxygen species,” Histochemistry and Cell Biology, vol. 122, no. 4, pp. 383–393, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. G. H. Lüers, S. Thiele, A. Schad, A. Völkl, S. Yokota, and J. Seitz, “Peroxisomes are present in murine spermatogonia and disappear during the course of spermatogenesis,” Histochemistry and Cell Biology, vol. 125, no. 6, pp. 693–703, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. A. Nenicu, G. H. Lüers, W. Kovacs, M. Bergmann, and E. Baumgart-Vogt, “Peroxisomes in human and mouse testis: differential expression of peroxisomal proteins in germ cells and distinct somatic cell types of the testis,” Biology of Reproduction, vol. 77, no. 6, pp. 1060–1072, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Lapointe, R. Sullivan, and M. Sirard, “Binding of a bovine oviductal fluid catalase to mammalian spermatozoa,” Biology of Reproduction, vol. 58, no. 3, pp. 747–753, 1998. View at Publisher · View at Google Scholar · View at Scopus
  63. C. O'Flaherty, “Peroxiredoxins, hidden players in the antioxidant defence of human spermatozoa,” Basic and Clinical Andrology, vol. 24, article 4, 2014. View at Publisher · View at Google Scholar
  64. H. Sies, V. S. Sharov, L. Klotz, and K. Briviba, “Glutathione peroxidase protects against peroxynitrite-mediated oxidations: a new function for selenoproteins as peroxynitrite reductase,” Journal of Biological Chemistry, vol. 272, no. 44, pp. 27812–27817, 1997. View at Publisher · View at Google Scholar · View at Scopus
  65. K. Takahashi, N. Avissar, J. Whitin, and H. Cohen, “Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme,” Archives of Biochemistry and Biophysics, vol. 256, no. 2, pp. 677–686, 1987. View at Publisher · View at Google Scholar · View at Scopus
  66. N. B. Ghyselinck, C. Jimenez, Y. Courty, and J. P. Dufaure, “Androgen-dependent messenger RNA(s) related to secretory proteins in the mouse epididymis,” Journal of Reproduction and Fertility, vol. 85, no. 2, pp. 631–639, 1989. View at Publisher · View at Google Scholar · View at Scopus
  67. F.-. Chu, J. H. Doroshow, and R. S. Esworthy, “Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI,” The Journal of Biological Chemistry, vol. 268, no. 4, pp. 2571–2576, 1993. View at Google Scholar · View at Scopus
  68. F. Ursini, M. Maiorino, and C. Gregolin, “The selenoenzyme phospholipid hydroperoxide glutathione peroxidase,” Biochimica et Biophysica Acta—General Subjects, vol. 839, no. 1, pp. 62–70, 1985. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Herbette, P. Roeckel-Drevet, and J. R. Drevet, “Seleno-independent glutathione peroxidases: More than simple antioxidant scavengers,” The FEBS Journal, vol. 274, no. 9, pp. 2163–2180, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. A. Vignini, L. Nanetti, E. Buldreghini et al., “The production of peroxynitrite by human spermatozoa may affect sperm motility through the formation of protein nitrotyrosine,” Fertility and Sterility, vol. 85, no. 4, pp. 947–953, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. T. Morielli and C. O'Flaherty, “Oxidative stress promotes protein tyrosine nitration and S-glutathionylation impairing motility and capacitation in human spermatozoa,” Free Radical Biology and Medicine, vol. 53, article S137, 2012. View at Google Scholar
  72. F. Ursini, S. Heim, M. Kiess et al., “Dual function of the selenoprotein PHGPx during sperm maturation,” Science, vol. 285, no. 5432, pp. 1393–1396, 1999. View at Publisher · View at Google Scholar · View at Scopus
  73. H. Imai, N. Hakkaku, R. Iwamoto et al., “Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice,” Journal of Biological Chemistry, vol. 284, no. 47, pp. 32522–32532, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Schneider, H. Förster, A. Boersma et al., “Mitochondrial glutathione peroxidase 4 disruption causes male infertility,” The FASEB Journal, vol. 23, no. 9, pp. 3233–3242, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. H. Imai, K. Suzuki, K. Ishizaka et al., “Failure of the expression of phospholipid hydroperoxide glutathione peroxidase in the spermatozoa of human infertile males,” Biology of Reproduction, vol. 64, no. 2, pp. 674–683, 2001. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Kaushal and M. P. Bansal, “Diminished reproductive potential of male mice in response to selenium-induced oxidative stress: involvement of HSP70, HSP70-2, and MSJ-1,” Journal of Biochemical and Molecular Toxicology, vol. 23, no. 2, pp. 125–136, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. L. Flohé, “Selenium in mammalian spermiogenesis,” Biological Chemistry, vol. 388, no. 10, pp. 987–995, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. M. Conrad, S. G. Moreno, F. Sinowatz et al., “The nuclear form of phospholipid hydroperoxide glutathione peroxidase is a protein thiol peroxidase contributing to sperm chromatin stability,” Molecular and Cellular Biology, vol. 25, no. 17, pp. 7637–7644, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. K. Williams, J. Frayne, and L. Hall, “Expression of extracellular glutathione peroxidase type 5 (GPX5) in the rat male reproductive tract,” Molecular Human Reproduction, vol. 4, no. 9, pp. 841–848, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. E. Chabory, C. Damon, A. Lenoir et al., “Mammalian glutathione peroxidases control acquisition and maintenance of spermatozoa integrity,” Journal of Animal Science, vol. 88, no. 4, pp. 1321–1331, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. C. Foresta, L. Flohé, A. Garolla, A. Roveri, F. Ursini, and M. Maiorino, “Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase,” Biology of Reproduction, vol. 67, no. 3, pp. 967–971, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. N. Garrido, M. Meseguer, J. Alvarez, C. Simón, A. Pellicer, and J. Remohí, “Relationship among standard semen parameters, glutathione peroxidase/glutathione reductase activity, and mRNA expression and reduced glutathione content in ejaculated spermatozoa from fertile and infertile men,” Fertility and Sterility, vol. 82, supplement 3, pp. 1059–1066, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. Y. Ho, J. Magnenat, R. T. Bronson et al., “Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia,” Journal of Biological Chemistry, vol. 272, no. 26, pp. 16644–16651, 1997. View at Publisher · View at Google Scholar · View at Scopus
  84. B. Gopalakrishnan, S. Aravinda, C. H. Pawshe et al., “Studies on glutathione S-transferases important for sperm function: evidence of catalytic activity-independent functions,” Biochemical Journal, vol. 329, no. 2, pp. 231–241, 1998. View at Google Scholar · View at Scopus
  85. T. Hemachand, B. Gopalakrishnan, D. M. Salunke, S. M. Totey, and C. Shaha, “Sperm plasma-membrane-associated glutathione S-transferases as gamete recognition molecules,” Journal of Cell Science, vol. 115, no. 10, pp. 2053–2065, 2002. View at Google Scholar · View at Scopus
  86. B. Aydemir, I. Onaran, A. R. Kiziler, B. Alici, and M. C. Akyolcu, “Increased oxidative damage of sperm and seminal plasma in men with idiopathic infertility is higher in patients with glutathione S-transferase Mu-1 null genotype,” Asian Journal of Andrology, vol. 9, no. 1, pp. 108–115, 2007. View at Publisher · View at Google Scholar · View at Scopus
  87. M. T. M. Raijmakers, H. M. J. Roelofs, E. A. P. Steegers et al., “Glutathione and glutathione S-transferases A1-1 and P1-1 in seminal plasma may play a role in protecting against oxidative damage to spermatozoa,” Fertility and Sterility, vol. 79, no. 1, pp. 169–172, 2003. View at Publisher · View at Google Scholar · View at Scopus
  88. A. F. Olshan, T. J. Luben, N. M. Hanley et al., “Preliminary examination of polymorphisms of GSTM1, GSTT1, and GSTZ1 in relation to semen quality,” Mutation Research—Fundamental and Molecular Mechanisms of Mutagenesis, vol. 688, no. 1-2, pp. 41–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. J. A. Ross, N. E. Watson Jr., and J. P. Jarow, “The effect of varicoceles on testicular blood flow in man,” Urology, vol. 44, no. 4, pp. 535–539, 1994. View at Publisher · View at Google Scholar · View at Scopus
  90. H. Z. Chae, S. J. Chung, and S. G. Rhee, “Thioredoxin-dependent peroxide reductase from yeast,” Journal of Biological Chemistry, vol. 269, no. 44, pp. 27670–27678, 1994. View at Google Scholar · View at Scopus
  91. T. Ishii, T. Kawane, S. Taketani, and S. Bannai, “Inhibition of the thiol-specific antioxidant activity of rat liver MSP23 protein by hemin,” Biochemical and Biophysical Research Communications, vol. 216, no. 3, pp. 970–975, 1995. View at Publisher · View at Google Scholar · View at Scopus
  92. D. Jin, H. Z. Chae, S. G. Rhee, and K. Jeang, “Regulatory role for a novel human thioredoxin peroxidase in NF-κB activation,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30952–30961, 1997. View at Publisher · View at Google Scholar · View at Scopus
  93. V. Syed and N. B. Hecht, “Rat pachytene spermatocytes down-regulate a pololike kinase and up- regulate a thiol-specific antioxidant protein, whereas sertoli cells down- regulate a phosphodiesterase and up-regulate an oxidative stress protein after exposure to methoxyethanol and methoxyacetic acid,” Endocrinology, vol. 139, no. 8, pp. 3503–3511, 1998. View at Publisher · View at Google Scholar · View at Scopus
  94. S. G. Rhee, S. W. Kang, L. E. Netto, M. S. Seo, and E. R. Stadtman, “A family of novel peroxidases, peroxiredoxins,” BioFactors, vol. 10, no. 2-3, pp. 207–209, 1999. View at Publisher · View at Google Scholar · View at Scopus
  95. S. G. Rhee, S. W. Kang, T.-S. Chang, W. Jeong, and K. Kim, “Peroxiredoxin, a novel family of peroxidases,” IUBMB Life, vol. 52, no. 1-2, pp. 35–41, 2001. View at Publisher · View at Google Scholar · View at Scopus
  96. Z. A. Wood, L. B. Poole, and P. A. Karplus, “Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling,” Science, vol. 300, no. 5619, pp. 650–653, 2003. View at Publisher · View at Google Scholar · View at Scopus
  97. Z. A. Wood, E. Schröder, J. R. Harris, and L. B. Poole, “Structure, mechanism and regulation of peroxiredoxins,” Trends in Biochemical Sciences, vol. 28, no. 1, pp. 32–40, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. G. R. Sue, Z. C. Ho, and K. Kim, “Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling,” Free Radical Biology and Medicine, vol. 38, no. 12, pp. 1543–1552, 2005. View at Google Scholar · View at Scopus
  99. P. Zhang, B. Liu, S. W. Kang, M. S. Seo, S. G. Rhee, and L. M. Obeid, “Thioredoxin peroxidase is a novel inhibitor of apoptosis with a mechanism distinct from that of Bcl-2,” The Journal of Biological Chemistry, vol. 272, no. 49, pp. 30615–30618, 1997. View at Publisher · View at Google Scholar · View at Scopus
  100. I. V. Peshenko and H. Shichi, “Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin to the cysteine sulfenic acid form by peroxide and peroxynitrite,” Free Radical Biology and Medicine, vol. 31, no. 3, pp. 292–303, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Dubuisson, D. V. Stricht, A. Clippe et al., “Human peroxiredoxin 5 is a peroxynitrite reductase,” FEBS Letters, vol. 571, no. 1-3, pp. 161–165, 2004. View at Publisher · View at Google Scholar · View at Scopus
  102. L. Flohé, S. Toppo, G. Cozza, and F. Ursini, “A comparison of thiol peroxidase mechanisms,” Antioxidants and Redox Signaling, vol. 15, no. 3, pp. 763–780, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. S. W. Kang, H. Z. Chae, M. S. Seo, K. Kim, I. C. Baines, and S. G. Rhee, “Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generatedin response to growth factors and tumor necrosis factor-α,” Journal of Biological Chemistry, vol. 273, no. 11, pp. 6297–6302, 1998. View at Publisher · View at Google Scholar · View at Scopus
  104. L. A. Ralat, Y. Manevich, A. B. Fisher, and R. F. Colman, “Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase π with activity changes in both enzymes,” Biochemistry, vol. 45, no. 2, pp. 360–372, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. L. A. Ralat, S. A. Misquitta, Y. Manevich, A. B. Fisher, and R. F. Colman, “Characterization of the complex of glutathione S-transferase pi and 1-cysteine peroxiredoxin,” Archives of Biochemistry and Biophysics, vol. 474, no. 1, pp. 109–118, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. J. W. Baty, M. B. Hampton, and C. C. Winterbourn, “Proteomic detection of hydrogen peroxide-sensitive thiol proteins in Jurkat cells,” Biochemical Journal, vol. 389, part 3, pp. 785–795, 2005. View at Google Scholar
  107. A. G. Cox and M. B. Hampton, “Bcl-2 over-expression promotes genomic instability by inhibiting apoptosis of cells exposed to hydrogen peroxide,” Carcinogenesis, vol. 28, no. 10, pp. 2166–2171, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. F. M. Low, M. B. Hampton, A. V. Peskin, and C. C. Winterbourn, “Peroxiredoxin 2 functions as a noncatalytic scavenger of low-level hydrogen peroxide in the erythrocyte,” Blood, vol. 109, no. 6, pp. 2611–2617, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. A. V. Peskin, F. M. Low, L. N. Paton, G. J. Maghzal, M. B. Hampton, and C. C. Winterbourn, “The high reactivity of peroxiredoxin 2 with H2O2 is not reflected in its reaction with other oxidants and thiol reagents,” Journal of Biological Chemistry, vol. 282, no. 16, pp. 11885–11892, 2007. View at Publisher · View at Google Scholar · View at Scopus
  110. C. O'Flaherty and A. R. De Souza, “Hydrogen peroxide modifies human sperm peroxiredoxins in a dose-dependent manner,” Biology of Reproduction, vol. 84, no. 2, pp. 238–247, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. S. G. Rhee, S. W. Kang, W. Jeong, T. S. Chang, K. S. Yang, and H. A. Woo, “Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 183–189, 2005. View at Google Scholar
  112. S. G. Rhee, “H2O2, a necessary evil for cell signaling,” Science, vol. 312, no. 5782, pp. 1882–1883, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. I. Banmeyer, C. Marchand, C. Verhaeghe, B. Vucic, J. Rees, and B. Knoops, “Overexpression of human peroxiredoxin 5 in subcellular compartments of Chinese hamster ovary cells: effects on cytotoxicity and DNA damage caused by peroxides,” Free Radical Biology and Medicine, vol. 36, no. 1, pp. 65–77, 2004. View at Publisher · View at Google Scholar · View at Scopus
  114. S. Immenschuh, E. Baumgart-Vogt, M. Tan, S. Iwahara, G. Ramadori, and H. D. Fahimi, “Differential cellular and subcellular localization of heme-binding protein 23/peroxiredoxin I and heme oxygenase-1 in rat liver,” Journal of Histochemistry & Cytochemistry, vol. 51, no. 12, pp. 1621–1631, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. M. S. Seo, S. W. Kang, K. Kim, I. C. Baines, T. H. Lee, and S. G. Rhee, “Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate,” Journal of Biological Chemistry, vol. 275, no. 27, pp. 20346–20354, 2000. View at Publisher · View at Google Scholar · View at Scopus
  116. V. J. Thannickal and B. L. Fanburg, “Reactive oxygen species in cell signaling,” American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 279, no. 6, pp. L1005–L1028, 2000. View at Google Scholar · View at Scopus
  117. T. D. Oberley, E. Verwiebe, W. Zhong, S. W. Kang, and S. G. Rhee, “Localization of the thioredoxin system in normal rat kidney,” Free Radical Biology and Medicine, vol. 30, no. 4, pp. 412–424, 2001. View at Publisher · View at Google Scholar · View at Scopus
  118. R. A. van Gestel, I. A. Brewis, P. R. Ashton, J. F. Brouwers, and B. M. Gadella, “Multiple proteins present in purified porcine sperm apical plasma membranes interact with the zona pellucida of the oocyte,” Molecular Human Reproduction, vol. 13, no. 7, pp. 445–454, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. K. Park, S. Jeon, Y. Song, and L. S. H. Yi, “Proteomic analysis of boar spermatozoa and quantity changes of superoxide dismutase 1, glutathione peroxidase, and peroxiredoxin 5 during epididymal maturation,” Animal Reproduction Science, vol. 135, no. 1–4, pp. 53–61, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. S. Gong, M. C. S. Gabriel, A. Zini, P. Chan, and C. O'flaherty, “Low amounts and high thiol oxidation of peroxiredoxins in spermatozoa from infertile men,” Journal of Andrology, vol. 33, no. 6, pp. 1342–1351, 2012. View at Publisher · View at Google Scholar · View at Scopus
  121. Y. Iuchi, F. Okada, S. Tsunoda et al., “Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress,” Biochemical Journal, vol. 419, no. 1, pp. 149–158, 2009. View at Publisher · View at Google Scholar · View at Scopus
  122. B. Ozkosem and C. O'Flaherty, “Detrimental effects of oxidative stress on spermatozoa lacking peroxiredoxin 6,” Free Radical Biology and Medicine, vol. 53, supplement 2, p. S86, 2012. View at Publisher · View at Google Scholar
  123. C. A. Neumann, D. S. Krause, C. V. Carman et al., “Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression,” Nature, vol. 424, no. 6948, pp. 561–565, 2003. View at Publisher · View at Google Scholar · View at Scopus
  124. R. A. Egler, E. Fernandes, K. Rothermund et al., “Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1,” Oncogene, vol. 24, no. 54, pp. 8038–8050, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. Y. Han, H. Kim, J. Kim, S. Kim, D. Yu, and E. Moon, “Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence,” FEBS Letters, vol. 579, no. 21, pp. 4897–4902, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. G. Manandhar, A. Miranda-Vizuete, J. R. Pedrajas et al., “Peroxiredoxin 2 and peroxidase enzymatic activity of mammalian spermatozoa,” Biology of Reproduction, vol. 80, no. 6, pp. 1168–1177, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. A. G. Cox, C. C. Winterbourn, and M. B. Hampton, “Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling,” Biochemical Journal, vol. 425, no. 2, pp. 313–325, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. A. J. Koppers, M. L. Garg, and R. J. Aitken, “Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa,” Free Radical Biology and Medicine, vol. 48, no. 1, pp. 112–119, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. R. J. Aitken and G. N. De Iuliis, “On the possible origins of DNA damage in human spermatozoa,” Molecular Human Reproduction, vol. 16, no. 1, pp. 3–13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. E. S. J. Arnér and A. Holmgren, “Physiological functions of thioredoxin and thioredoxin reductase,” European Journal of Biochemistry, vol. 267, no. 20, pp. 6102–6109, 2000. View at Publisher · View at Google Scholar · View at Scopus
  131. Y. Meyer, W. Siala, T. Bashandy, C. Riondet, F. Vignols, and J. P. Reichheld, “Glutaredoxins and thioredoxins in plants,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1783, no. 4, pp. 589–600, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. E. M. Hanschmann, J. R. Godoy, C. Berndt, C. Hudemann, and C. H. Lillig, “Thioredoxins, glutaredoxins, and peroxiredoxins-molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling,” Antioxidants & Redox Signaling, vol. 19, pp. 1539–1605, 2013. View at Google Scholar
  133. M. Lukosz, S. Jakob, N. Büchner, T. Zschauer, J. Altschmied, and J. Haendeler, “Nuclear redox signaling,” Antioxidants and Redox Signaling, vol. 12, no. 6, pp. 713–742, 2010. View at Publisher · View at Google Scholar · View at Scopus
  134. P. A. Mitozo, L. F. de Souza, G. Loch-Neckel et al., “A study of the relative importance of the peroxiredoxin-, catalase-, and glutathione-dependent systems in neural peroxide metabolism,” Free Radical Biology and Medicine, vol. 51, no. 1, pp. 69–77, 2011. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Miranda-Vizuete, J. Ljung, A. E. Damdimopoulos et al., “Characterization of Sptrx, a novel member of the thioredoxin family specifically expressed in human spermatozoa,” The Journal of Biological Chemistry, vol. 276, no. 34, pp. 31567–31574, 2001. View at Publisher · View at Google Scholar · View at Scopus
  136. A. Miranda-Vizuete, K. Tsang, Y. Yu et al., “Cloning and developmental analysis of murid spermatid-specific thioredoxin-2 (SPTRX-2), a novel sperm fibrous sheath protein and autoantigen,” The Journal of Biological Chemistry, vol. 278, no. 45, pp. 44874–44885, 2003. View at Publisher · View at Google Scholar · View at Scopus
  137. A. Jiménez, C. Johansson, J. Ljung et al., “Human spermatid-specific thioredoxin-1 (Sptrx-1) is a two-domain protein with oxidizing activity,” FEBS Letters, vol. 530, no. 1–3, pp. 79–84, 2002. View at Publisher · View at Google Scholar · View at Scopus
  138. Y. Yu, R. Oko, and A. Miranda-Vizuete, “Developmental expression of spermatid-specific thioredoxin-1 protein: transient association to the longitudinal columns of the fibrous sheath during sperm tail formation,” Biology of Reproduction, vol. 67, no. 5, pp. 1546–1554, 2002. View at Publisher · View at Google Scholar · View at Scopus
  139. A. Miranda-Vizuete, C. M. Sadek, A. Jiménez, W. J. Krause, P. Sutovsky, and R. Oko, “The mammalian testis-specific thioredoxin system,” Antioxidants and Redox Signaling, vol. 6, no. 1, pp. 25–40, 2004. View at Publisher · View at Google Scholar · View at Scopus
  140. C. Buckman, C. Ozanon, J. Qiu et al., “Semen levels of spermatid-specific thioredoxin-3 correlate with pregnancy rates in ART couples,” PLoS ONE, vol. 8, no. 5, Article ID e61000, 2013. View at Publisher · View at Google Scholar · View at Scopus
  141. C. M. Sadek, A. Jiménez, A. E. Damdimopoulos et al., “Characterization of human thioredoxin-like 2: a novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme,” The Journal of Biological Chemistry, vol. 278, no. 15, pp. 13133–13142, 2003. View at Publisher · View at Google Scholar · View at Scopus
  142. T. B. Smith, M. A. Baker, H. S. Connaughton, U. Habenicht, and R. J. Aitken, “Functional deletion of Txndc2 and Txndc3 increases the susceptibility of spermatozoa to age-related oxidative stress,” Free Radical Biology & Medicine, vol. 65, pp. 872–881, 2013. View at Google Scholar
  143. H. H. Jang, K. O. Lee, Y. H. Chi et al., “Two enzymes in one: two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function,” Cell, vol. 117, no. 5, pp. 625–635, 2004. View at Publisher · View at Google Scholar · View at Scopus
  144. J. C. Moon, Y. Hah, W. Y. Kim et al., “Oxidative stress-dependent structural and functional switching of a human 2-Cys peroxiredoxin isotype II that enhances HeLa cell resistance to H2O2-induced cell death,” Journal of Biological Chemistry, vol. 280, no. 31, pp. 28775–28784, 2005. View at Publisher · View at Google Scholar · View at Scopus
  145. C. A. Neumann, J. Cao, and Y. Manevich, “Peroxiredoxin 1 and its role in cell signaling,” Cell Cycle, vol. 8, no. 24, pp. 4072–4078, 2009. View at Publisher · View at Google Scholar · View at Scopus
  146. H. Z. Chae, H. Oubrahim, J. W. Park, S. G. Rhee, and P. B. Chock, “Protein glutathionylation in the regulation of peroxiredoxins: A family of thiol-specific peroxidases that function as antioxidants, molecular chaperones, and signal modulators,” Antioxidants and Redox Signaling, vol. 16, no. 6, pp. 506–523, 2012. View at Publisher · View at Google Scholar · View at Scopus
  147. S. G. Rhee and H. A. Woo, “Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones,” Antioxidants & Redox Signaling, vol. 15, no. 3, pp. 781–794, 2011. View at Publisher · View at Google Scholar · View at Scopus
  148. T. Chang, W. Jeong, A. W. Hyun, M. L. Sun, S. Park, and G. R. Sue, “Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine,” The Journal of Biological Chemistry, vol. 279, no. 49, pp. 50994–51001, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. T. J. Jönsson and W. T. Lowther, “The peroxiredoxin repair proteins,” Subcellular Biochemistry, vol. 44, pp. 115–141, 2007. View at Publisher · View at Google Scholar · View at Scopus
  150. P. B. Kopnin, L. S. Agapova, B. P. Kopnin, and P. M. Chumakov, “Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability,” Cancer Research, vol. 67, no. 10, pp. 4671–4678, 2007. View at Publisher · View at Google Scholar · View at Scopus
  151. J. Y. Baek, S. H. Han, S. H. Sung et al., “Sulfiredoxin protein is critical for redox balance and survival of cells exposed to low steady-state levels of H2O2,” Journal of Biological Chemistry, vol. 287, no. 1, pp. 81–89, 2012. View at Publisher · View at Google Scholar · View at Scopus
  152. K. Abbas, S. Riquier, and J. Drapier, “Peroxiredoxins and sulfiredoxin at the crossroads of the NO and H2O2 signaling pathways,” Methods in Enzymology, vol. 527, pp. 113–128, 2013. View at Publisher · View at Google Scholar · View at Scopus
  153. Y. Manevich, T. Shuvaeva, C. Dodia, A. Kazi, S. I. Feinstein, and A. B. Fisher, “Binding of peroxiredoxin 6 to substrate determines differential phospholipid hydroperoxide peroxidase and phospholipase A2 activities,” Archives of Biochemistry and Biophysics, vol. 485, no. 2, pp. 139–149, 2009. View at Publisher · View at Google Scholar · View at Scopus
  154. S. Sarkar, A. J. Nelson, and O. W. Jones, “Glucose-6-phosphate dehydrogenase (G6PD) activity of human sperm,” Journal of Medical Genetics, vol. 14, no. 4, pp. 250–255, 1977. View at Publisher · View at Google Scholar · View at Scopus
  155. C. O'Flaherty, N. Beorlegui, and M. T. Beconi, “Heparin- and superoxide anion-dependent capacitation of cryopreserved bovine spermatozoa: Requirement of dehydrogenases and protein kinases,” Free Radical Research, vol. 40, no. 4, pp. 427–432, 2006. View at Publisher · View at Google Scholar · View at Scopus
  156. T. K. Li, “The glutathione and thiol content of mammalian spermatozoa and seminal plasma,” Biology of Reproduction, vol. 12, no. 5, pp. 641–646, 1975. View at Publisher · View at Google Scholar · View at Scopus
  157. B. Halliwell and J. Gutteridge, “Antioxidant defences: endogenous and diet derived,” in Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, Eds., pp. 79–186, Oxford University Press, New York, NY, USA, 2007. View at Google Scholar
  158. S. Zhou, Y. Lien, T. Shuvaeva, K. Debolt, S. I. Feinstein, and A. B. Fisher, “Functional interaction of glutathione S-transferase pi and peroxiredoxin 6 in intact cells,” International Journal of Biochemistry and Cell Biology, vol. 45, no. 2, pp. 401–407, 2013. View at Publisher · View at Google Scholar · View at Scopus
  159. I. S. Kil and J. Park, “Regulation of mitochondrial NADP+-dependent isocitrate dehydrogenase activity by glutathionylation,” Journal of Biological Chemistry, vol. 280, no. 11, pp. 10846–10854, 2005. View at Publisher · View at Google Scholar · View at Scopus