OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: The impact of oxidative stress on reproduction: a focus on gametogenesis and fertilization

in Reproduction
Authors:
R John AitkenPriority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia

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Elizabeth G BromfieldPriority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia

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Zamira GibbPriority Research Centre for Reproductive Science, Discipline of Biological Sciences, School of Environmental and Life Sciences, College of Engineering Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia

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Correspondence should be addressed to R J Aitken; Email: john.aitken@newcastle.edu.au

This paper forms part of a special issue on Oxidative Stress and Reproductive Function. The guest editor for this section was Professor John Aitken, University of Newcastle, New South Wales, Australia

Free access

In brief

Many aspects of the reproductive process are impacted by oxidative stress. This article summarizes the chemical nature of reactive oxygen species and their role in both the physiological regulation of reproductive processes and the pathophysiology of infertility.

Abstract

This article lays out the fundamental principles of oxidative stress. It describes the nature of reactive oxygen species (ROS), the way in which these potentially toxic metabolites interact with cells and how they impact both cellular function and genetic integrity. The mechanisms by which ROS generation is enhanced to the point that the cells’ antioxidant defence mechanisms are overwhelmed are also reviewed taking examples from both the male and female reproductive system, with a focus on gametogenesis and fertilization. The important role of external factors in exacerbating oxidative stress and impairing reproductive competence is also examined in terms of their ability to disrupt the physiological redox regulation of reproductive processes. Developing diagnostic and therapeutic strategies to cope with oxidative stress within the reproductive system will depend on the development of a deeper understanding of the nature, source, magnitude, and location of such stress in order to fashion personalized treatments that meet a given patient’s clinical needs.

Abstract

In brief

Many aspects of the reproductive process are impacted by oxidative stress. This article summarizes the chemical nature of reactive oxygen species and their role in both the physiological regulation of reproductive processes and the pathophysiology of infertility.

Abstract

This article lays out the fundamental principles of oxidative stress. It describes the nature of reactive oxygen species (ROS), the way in which these potentially toxic metabolites interact with cells and how they impact both cellular function and genetic integrity. The mechanisms by which ROS generation is enhanced to the point that the cells’ antioxidant defence mechanisms are overwhelmed are also reviewed taking examples from both the male and female reproductive system, with a focus on gametogenesis and fertilization. The important role of external factors in exacerbating oxidative stress and impairing reproductive competence is also examined in terms of their ability to disrupt the physiological redox regulation of reproductive processes. Developing diagnostic and therapeutic strategies to cope with oxidative stress within the reproductive system will depend on the development of a deeper understanding of the nature, source, magnitude, and location of such stress in order to fashion personalized treatments that meet a given patient’s clinical needs.

Introduction

Physiologically, reactive oxygen species (ROS) are known to play an important role in signal transduction, particularly in mediating the impact of growth factors on cell metabolism via the activation of important biomolecules such as tyrosine kinases, mitogen-activated protein kinases, or Ras proteins. However, ROS are also known to, directly or indirectly, attack all the basic building blocks of life including proteins, carbohydrates, lipids, and nucleic acids, inducing a loss of cell viability and functionality in the process. Thus, when the production of ROS becomes enhanced, and/or antioxidant defences become compromised, a state of oxidative stress arises generating pathological outcomes. These pathologies include cardiovascular disease (including atherosclerosis, ischemia–reperfusion injury, diabetic vascular disease, arrhythmia, myocardial infarction, hypertrophy, cardiomyopathy, and heart failure), neurodegenerative conditions (Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease), digestive disorders (inflammatory bowel diseases, gastroduodenal ulcers, and irritable bowel syndrome), type 2 diabetes, atherosclerosis, cancer, and several disorders of reproduction (Kaneto et al. 2010, Chen et al. 2012, Brown & Griendling 2015, Aitken 2020, Aitken & Drevet 2020, Sarmiento-Salinas et al. 2021).

Clinically, we have understood the role of oxidative stress in the suppression of male fertility since the 1920s when the importance of vitamin E in the regulation of testicular function was first recognized (Mason 1926). Subsequently, the roles of ROS in both the signal transduction pathways that control sperm capacitation and the aetiology of male infertility have become increasingly apparent (Aitken 2017, Baskaran et al. 2021, Mannucci et al. 2021). It is also becoming very evident that oxidative stress plays a major role in the regulation of female reproduction. While ROS are positively involved in processes such as ovulation (Shkolnik et al. 2011), menstruation (Evans & Salamonsen 2012), and luteolysis (Minegishi et al. 2002), they play a deleterious role in the aetiology of endometriosis (Cacciottola et al. 2021), polycystic ovarian disease (Mohammadi 2019), oocyte ageing (Lord & Aitken 2013, Wang et al. 2021), arrested preimplantation development (Nasr-Esfahani et al. 1990, Hardy et al. 2021), and several disorders of pregnancy including preeclampsia, fetal growth restriction, gestational diabetes mellitus, preterm birth, and, ultimately, fetal death (Maiti et al. 2017, Cindrova-Davies et al. 2018, Joo et al. 2021).

Given the pervasive importance of oxidative stress in reproductive biology, this article sets out to present the fundamental nature of this process in terms of the specific ROS involved, the mechanisms by which they create oxidative (or reductive) stress and their ultimate impact on the functionality of the male and female reproductive systems. While this review will focus on the human, the relevance of oxidative stress to reproduction in livestock species will also be highlighted where it serves to illuminate an important principle.

What are reactive oxygen species?

The term ‘ROS’ is a catch-all phase that covers free radicals with unpaired electrons in their outer orbitals such as the one-electron reduction product of molecular oxygen, the superoxide anion radical (O2·−) and its pernicious three-electron reduction relative, the hydroxyl radical (OH·). This term also covers highly reactive free radicals generated during the lipid peroxidation process including peroxyl (ROO·) and alkoxyl (RO·) radicals as well as other radical species commonly encountered in biological systems such as nitric oxide (·NO), nitrogen dioxide (·NO2), and the carbonate radical (CO3·−). In biology, the term ‘ROS’ also encompasses non-radical oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). In addition, when ground state O2 is excited to a higher energy state, singlet O2 (1O2) is formed, which can also be harmful to biological systems. It is important to note that the cellular behaviour of different ROS will be profoundly influenced by their polarity. Nonpolar metabolites such as H2O2 can move freely across cell and organelle membranes, whereas highly polar ROS such as O2·− do not have this facility and, as a result their distribution remains highly compartmentalized unless, that is, their transport is facilitated by specialized anion channels or, in the case of mitochondria, the mitochondrial permeability transition pore (Weidinger & Kozlov 2015).

So, in complex biological situations, there are many different forms of ROS, the fundamental reactivity of which ensures that they have a very short half-life, approximating to 106 s in the case of O2·− or RO· and 109 s for OH·, for example (Fig. 1). They are ephemeral mediators of physiological signalling and pathological change that interact with a wide range of target molecules – as well as each other. For example, O2·−, a relatively inert free radical, will combine with itself in a dismutation reaction to generate H2O2 through the catalytic activity of superoxide dismutase (SOD), in one of the fastest enzymatic reactions known to man, occurring at almost the diffusion-limited rate (∼2 × 109 M−1·s−1), which is ~104 times the rate constant for spontaneous dismutation (Fridovich 1975). This enzyme, originally christened haemocuprein by Thaddeus Mann and David Keilin in view of its high copper content (Bannister 1988), has a clear dependence on pH, as indicated in the following equation:

Figure 1
Figure 1

The nature of some of the reactive oxygen species (ROS) commonly involved in biological processes. Starting with ground state oxygen (O2), the input of energy can generate singlet oxygen (1O2), a highly excited form of ROS which is extremely reactive and toxic. The one electron reduction of O2 generates the superoxide anion (O2·−) which can dismutate (react with itself) under the influence of superoxide dismutase (SOD) to generate hydrogen peroxide (H2O2). O2·− can also become protonated under conditions of low pH to generate the hydroperoxyl radical (HOO·) or react with nitric oxide (·NO) to generate the peroxynitrite anion (ONOO-). Furthermore, O2·− can react with H2O2 in a Haber–Weiss reaction to generate the pernicious hydroxyl radical (OH·). All of these chemical reactions are extremely dynamic ensuring that a range of ROS are available at any point in time, ready to promote physiological redox reactions within the cell or, when present in excess, induce oxidative damage.

Citation: Reproduction 164, 6; 10.1530/REP-22-0126

Another form of SOD also exists in mitochondria, which has manganese at its active site rather than copper (MnSOD). This enzyme is extremely important in the localized processing of O2·− that is constantly being generated by these organelles as a by-product of the oxidative phosphorylation process (Wallace 2001).

Although many authorities have claimed a protective role for SOD in a reproductive context (Alvarez et al. 1987, Kobayashi et al. 1991) in light of the above equation, this may seem paradoxical. SOD takes a relatively unreactive, non-membrane permeant oxygen free radical (O2·−) and converts it into a powerful membrane permeant oxidant (H2O2). Thus, when acting in isolation, SOD may actually ‘increase’ oxidative stress. Indeed, negative relationships have previously been reported between SOD activity in human spermatozoa and both their movement characteristics and their capacity for sperm-oocyte fusion (Aitken et al. 1996). Furthermore, both the cellular content of this enzyme and its biochemical activity are increased in poor quality spermatozoa, emphasizing just how potentially harmful this enzyme can be (Aitken et al. 1996, Calamera et al. 2003).

For the dismutation of O2·− to H2O2 to be protective, this reaction must be coupled to another enzyme system that ensures the H2O2 is removed as rapidly as it is generated. There are two major ways in which this might be achieved. Firstly, catalase directly catalyses the decomposition of H2O2 to water and ground state oxygen according to the equation:

Under the influence of catalase, one molecule of H2O2 is reduced to water and the other is oxidized to O2; a single molecule of catalase can transform millions of molecules of H2O2 into water and oxygen per second. Follicular fluid and semen certainly seem to contain catalase (Pasqualotto et al. 2009) as do spermatozoa (Jeulin et al. 1989) and oocytes (Park et al. 2016), and there is abundant evidence to indicate that catalase is important for both male and female reproduction (Rubio-Riquelme et al. 2020). Thus, overexpression of catalase in transgenic male mice leads to a significant reduction in age-dependent oxidative stress, reducing the levels of oxidative DNA damage observed in spermatozoa and sustaining high levels of fertility into old age (Selvaratnam & Robaire 2016).

A second major pathway for eliminating H2O2 is via glutathione peroxidase (GPx). In this case, the peroxide (H2O2 or its lipid peroxide equivalent, LOOH) is reduced to water or the corresponding lipid alcohol (LOH) at the expense of glutathione (GSH) which becomes oxidized to GSSG, as indicated below:

Glutathione peroxidase is certainly present in human spermatozoa and the inhibition of this enzyme with mercaptosuccinate leads to rapid motility loss (Alvarez & Storey 1989). A key enzyme supporting GPx is phospholipase A2 (PLA2) which actively cleaves the lipid peroxide from its parent phospholipid so that it can be processed by GPx (Alvarez & Storey 1995). The sustained activity of GPx also depends on the recycling of GSSG back to GSH by glutathione reductase using NADPH as a source of reducing equivalents. An important rate-limiting step in this entire process is the activity of glucose-6-phosphate dehydrogenase which controls the generation of NADPH via the hexose monophosphate shunt. As long as the latter is active, sufficient NADPH is generated to fuel the glutathione cycle and maintain a low level of peroxidative damage to the cell (Ford et al. 1997, Storey 1997).

In addition, spermatozoa possess a form of phospholipid hydroperoxide glutathione peroxidase (GPx4) that can detoxify membrane lipid peroxides in situ, without the need for prior PLA2 action (Puglisi et al. 2005). Moreover, GPx4 activity is deficient in the spermatozoa of infertile men (Imai et al. 2001), and male mice heterozygous for a mutant form of this enzyme exhibits subfertility (Ingold et al. 2015). This multipurpose enzyme not only protects spermatozoa from oxidative stress but is also important in facilitating the cross-linking of nuclear protamines during epididymal transit, thereby contributing to sperm chromatin condensation and stability (Conrad et al. 2007).

Another extremely important enzyme involved in peroxide removal within the male reproductive system is peroxiredoxin (PRDX). This class of enzyme traditionally uses thioredoxin to recycle the oxidized enzyme. Thioredoxin itself then becomes oxidized and has to be reduced by thioredoxin reductase using NAD(P)H as a source of electrons in a similar manner to glutathione reductase. Although there are many isoforms of this enzyme, PRDX6 is the major peroxiredoxin in human spermatozoa (Fernandez & O’Flaherty 2018). This enzyme is versatile; in addition to its peroxidase activity, PRDX6 also removes and replaces damaged fatty acids via its inherent PLA2 and lysophospholipid acyltransferase activities (Fisher 2017). PRDX6 therefore possesses the full range of enzymatic activities needed to effect phospholipid repair in damaged sperm plasma membranes. To illustrate this point, PRDX6 has been observed to translocate from a cytoplasmic position to the plasma membrane in response to the oxidative damage associated with cryopreservation and asthenozoospermia (Xin et al. 2021). Inhibition of this enzyme system leads to ROS generation, lipid peroxidation, a loss of mitochondrial membrane potential, oxidative DNA damage, and, ultimately, cell death (Fernandez & O’Flaherty 2018).

The downstream effects of unchecked O2·− and H2O2 production is the generation of cytotoxic secondary metabolites. In the case of O2·−, rapid removal from the cellular environment is thought to be important to circumvent its potential to become protonated and thereby generate the pernicious hydroperoxyl radical (HO2·), a powerful oxidant capable of initiating damaging lipid peroxidation cascades. The pKa for this protonation reaction is 4.8, with the result that at pH 7 only 0.6% of O2·− exists as HO2·. Nevertheless, it has been tentatively suggested that there may be microenvironments within the cell where the pH may be low enough to support HO2· formation (Storey 1997, Salvador et al. 2001). A related reason to rapidly remove O2·− is to prevent it reacting with H2O2 to generate the hydroxyl radical, another potent initiator of lipoperoxidative chain reactions.

This reaction, known as the Haber–Weiss reaction or superoxide-driven Fenton reaction, is catalysed by trace amounts of Fe2+ and Cu+. Since there are no enzymes capable of detoxifying OH·, it is an extremely dangerous radical species. The pernicious nature of this radical explains the lengths that biological systems go to, in order to control the availability of catalytic metals, such as iron and copper, through the complex interaction of metal binding proteins such as ferritin, lactoferrin, ceruloplasmin, and metallothionein (Collins et al. 2010).

Along similar lines, spermatozoa are active generators of the reactive nitrogen radical species, nitric oxide (·NO) via enzymatic (nitic oxide synthase) and non-enzymatic means (Herrero et al. 1996, Aitken et al. 2004, Kadlec et al. 2020). ·NO may react rapidly with O2·− to generate the powerful oxidant, peroxynitrite (ONOO-). This oxidant is thought to play an important role in the redox regulation of sperm capacitation (Herrero et al. 2001) although sustained production of ONOO- may overwhelm the cells’ antioxidant defences and ultimately trigger senescence and cell death via the intrinsic apoptotic pathway and opening of the mitochondrial permeability transition pore (Aitken et al. 2015b , Uribe et al. 2018). Indeed, the induction of capacitation and the emergence of sperm senescence have been portrayed as a continuum mediated by ROS such as ONOO- (Aitken et al. 2015b ).

The reactivity of ONOO- is enhanced in biological systems through its reaction with carbon dioxide to form nitrosoperoxycarbonate, which can then undergo homolytic fission to generate nitrogen dioxide and carbonate radicals, both of which are reactive and can cause damage to biomolecules. For example, they can react with tyrosine residues or tyrosyl radicals on proteins, resulting in 3-nitrotyrosine adducts which cause a broad range of pathologies including poor sperm motility in infertile males (Cassina et al. 2015). As is often the case with ROS, ONOO- is therefore a two-edged sword; low levels supporting sperm function, while excessive exposure results in tyrosine nitration and a loss of sperm function (Cruz & Fardilha 2016).

Thus overall, ROS appear to be important for normal cellular function when generated in small physiological amounts. However, the intrinsic reactivity of these molecules and their tendency to combine to generate potentially damaging metabolites such as ONOO-, OH·, and HO2· mean that the availability of the primary ROS, such as ·NO, O2·−, and H2O2, has to be very carefully controlled.

While we have exemplified these principal features of ROS generation by reference to spermatozoa, exactly the same reactive oxygen metabolites are generated in the female germ line, which also presents a similar pattern of O2·− and H2O2 scavenging enzymes including SOD, catalase, GPx, and peroxiredoxins (Cetica et al. 2001, Leyens et al. 2004). Furthermore, oocytes possess exactly the same functional vulnerability to oxidative stress as we see in their male counterparts (Lord & Aitken 2013, Lord et al. 2015, Mihalas et al. 2018).

How do ROS damage cells?

Lipid peroxidation

One of the most intensely studied aspects of oxidative stress is lipid peroxidation. In the non-enzymatic version of this process, ROS attack the unsaturated fatty acids at position 2 of membrane glycerophospholipids, initiating a lipid peroxidation chain reaction by abstracting hydrogen from an unsaturated fatty acid to create a carbon centred lipid radical (L·). The latter then combines with molecular oxygen (the universal electron acceptor) to generate an unstable lipid peroxyl radical (LOO·) which then abstracts a hydrogen atom from another unsaturated fatty acid to stabilize as the lipid hydroperoxide (LOOH). This process invariably creates another lipid radical that will again combine with oxygen thereby propagating the chain reaction (Fig. 2). Lipid peroxides can also be created enzymatically by lipoxygenases (generating hydroperoxyeicosatetraenoic acids, lipoxins, leukotrienes, or hepoxilins), cyclooxygenases (generating prostaglandins), and cytochrome P450 (generating epoxyeicosatrienoic acids, leukotoxins, thromboxane, or prostacyclin). In general, these products of lipid peroxidation are produced in a tightly controlled manner and serve as important biological signalling molecules that use receptor activation and second messenger generation to influence a wide variety of cellular processes.

Figure 2
Figure 2

The lipid peroxidation process. Lipid peroxidation cascades are initiated by the abstraction of a hydrogen atom from an unsaturated fatty acid generating a lipid radical (L·) which then reacts with oxygen to form a lipid peroxyl radical (LOO·). In order to stabilize, this radical then abstracts another hydrogen atom from an unsaturated fatty acid in the immediate vicinity, to generate the corresponding lipid hydroperoxide (LOOH), thereby propagating the lipid peroxidation chain reaction. In the presence of transition metals such as iron, these lipid hydroperoxides can be induced to breakdown, generating a series of highly electrophilic toxic lipid aldehydes such as acrolein, 4-hydroxynonenal, 4-oxo-2-nonenal, and malondiadehyde, which by binding to the nucleophilic centres of proteins and DNA can cause significant cellular damage.

Citation: Reproduction 164, 6; 10.1530/REP-22-0126

However, it is also clear that the generation of lipid peroxides via these mechanisms can become dysregulated and cause oxidative stress. In the case of male fertility, particular attention has focused on the lipoxygenase, arachidonate 15-lipoxygenase (ALOX 15). This enzyme is located in the cytoplasmic droplet of mammalian spermatozoa (Fischer et al. 2005, Moore et al. 2010) and catalyzes an oxygenation reaction whereby O2 is incorporated as a peroxy residue in polyunsaturated fatty acids (PUFA). Human and rodent ALOX15 enzymes are thought to act on linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid when presented not only as free acids but also when incorporated as esters in phospholipids, glycerides, or cholesteryl esters. A role for this enzyme in the induction of oxidative stress was first suggested by Brütsch et al. (2016) when they discovered the subfertility experienced by heterozygous catalytically inactive glutathione peroxidase 4 (GPx4) transgenic mice could be rescued if ALOX15 was simultaneously deleted. This result suggested that the antioxidant properties of GPx4 and the prooxidant properties of ALOX15 exist in a state of dynamic tension and, as a result, excessive lipoxygenase activity might well be associated with oxidative stress and male subfertility. In keeping with this suggestion, the pharmacological suppression of ALOX15 activity has been found to reduce ROS generation and inhibit the generation of 4-hydroxynonenal (4HNE; a marker of lipid peroxidation) in precursor male germ cells and the GC-2 cell line (Bromfield et al. 2017). In addition, inhibition of ALOX15 suppressed ROS generation and 4-HNE generation in human spermatozoa and, in the process, preserved the functional competence of these cells in terms of both acrosomal exocytosis and zona binding (Walters et al. 2018). The clinical significance of this work is suggested by the observation that the spermatozoa of infertile patients possess significantly elevated levels of ALOX15 protein, in concert with an increase in the appearance of proteins adducted by 4HNE (Walters et al. 2020). In light of the above, it is clear that in the male germ line, lipid peroxidation is a key factor in the aetiology of defective sperm function and that both enzymatic and non-enzymatic pathways are probably involved in the mediation of this process.

In the presence of transition metals such as iron and copper, lipid hydroperoxides can be induced to break down, creating a series of highly cytotoxic lipid aldehydes such as acrolein, 4-HNE, and malondialdehyde (Aitken et al. 1993). These aldehydes are powerful electrophiles and will bind to the nucleophilic centres of proteins, phospholipids, and nucleic acids in the immediate vicinity, causing significant damage and, particularly in the case of acrolein and 4-HNE, damaging cell function and promoting inflammation (Guo et al. 2012, Moazamian et al. 2015). The lipid aldehydes generated as a consequence of lipid peroxidation may bind directly to proteins involved in the regulation of sperm function such as the dynein heavy chain component of the axoneme that drives motility (Baker et al. 2015), as well as A-kinase anchoring protein 4 (AKAP4), one of the key regulators of sperm capacitation (Nixon et al. 2019, Griffin et al. 2020). In addition, the ability of this aldehyde to bind heat shock protein A2 (HSPA2) is known to disrupt the ability of spermatozoa to bind to the zona pellucida (Bromfield et al. 2015). Importantly, several of the proteins adducted by 4-HNE are components of the mitochondrial electron transport chain such as ATP synthase subunit β (ATP5B), succinate dehydrogenase [ubiquinone] flavoprotein subunit (SDHA), and NADH dehydrogenase [ubiquinone] iron–sulphur protein 2 (NDUFS2) (Aitken et al. 2012b , Zhao et al. 2014). One of the consequences of this adductive behaviour is that 4-HNE disrupts the flow of electrons along the mitochondrial electron transport chain leading to electron leakage and the formation of O2·−, which rapidly dismutates to H2O2 creating yet more oxidative stress, lipid peroxidation, and 4-HNE generation in a self-perpetuating cycle (Aitken et al. 2012b ). Mitochondria therefore play a key role in the perpetuation of oxidative stress and the propagation of damage throughout affected cells (Aitken et al. 2012a, b ). Importantly, this pathological mechanism is not only relevant to defective sperm function but also applies to the pathophysiology of oocytes (Lord & Aitken 2013, Lord et al. 2015, Jeelani et al. 2017) and possibly other cell types as well (Raza & John 2006). Given the particular importance of oxidative phosphorylation in the metabolism of oocytes and the spermatozoa of ungulate species, damage to the mitochondria will have a major impact on energy generation in these cells, compromising their viability and function (Lord et al. 2015, Gallo et al. 2021, Giaretta et al. 2022).

Given the importance of lipid peroxidation as a pathological mechanism, sophisticated mechanisms have evolved to limit the initiation and propagation of peroxidative damage in biological systems. The enzymatic defences against peroxidative damage have been discussed earlier and include the superoxide dismutatases, catalase, peroxidases, and peroxiredoxins. In addition, there are a range of small molecular mass antioxidant molecules that are capable of suppressing the peroxidative process. This is achieved by interfering with the initiation or the propagation of the lipid peroxidation chain reaction. Various radical-scavenging antioxidants are known that may be either hydrophilic or lipophilic. Ascorbic acid (vitamin C), uric acid, bilirubin, albumin, carotenoids, and thiols such as glutathione are examples of hydrophilic, radical-scavenging antioxidants. Vitamin E and ubiquinol are representative of lipophilic free radical scavengers, with the former regarded as nature’s most potent radical-scavenging lipophilic antioxidant, particularly when working in synergy with vitamin C, which serves to recycle the vitamin E within lipid membranes (Niki 1987).

Protein oxidation and adduction

Another major mechanism by which ROS can influence cell function is via the modification of proteins. We have already discussed how aldehydes, (e.g. 4-HNE or acrolein) generated as a result of lipid peroxidation can adduct to proteins, severely disrupting the intricate biochemical mechanisms responsible for maintaining cell homeostasis. These electrophilic aldehydes preferentially bind to cysteine, lysine, and histidine residues in proteins and via this mechanism are known to have a major impact on male and female gametes, influencing a variety of functions from the completion of meiosis to the induction of sperm capacitation (Windsor et al. 1993, Aitken et al. 2012b , Baker et al. 2015, Hall et al. 2017, Mihalas et al. 2017, Nixon et al. 2019, Ortega-Ferrusola et al. 2019, Griffin et al. 2020).

In addition to electrophilic aldehyde adduction (referred to as ‘secondary protein carbonylation’), ROS can also directly modify protein structure and function by attacking lysine, arginine, proline, and threonine residues (among other amino acids) in a process known as ‘primary protein carbonylation’ (Suzuki et al. 2010). Protein carbonyl expression in human semen is negatively correlated with sperm motility, fertility rate, and subsequent embryo quality in human intracytoplasmic sperm injection (ICSI) cycles (Al Smadi et al. 2021). On the female side, protein oxidative stress markers are increased in peritoneal fluids from women with deep infiltrating endometriosis, when compared with endometriosis-free controls (Santulli et al. 2015). In addition, reproductive ageing appears to be accompanied by an increase in maternal uterine carbonylated albumin that, in turn, disrupts extravillous trophoblast function and placentation (Mendes et al. 2020).

Another form of oxidative protein damage occurs when reactive nitrogen species (including ONOO-) attack proteins leading to their nitration. Several amino acids are particularly vulnerable to nitration including tyrosine, tryptophan, cysteine, and methionine such that protein 3-nitrotyrosine (3-NT) has become established as a biomarker of cell, tissue, and systemic ‘nitroxidative stress. As with oxidative stress, protein nitration is probably a two-edged sword as far as sperm function is concerned. At low doses, nitration may well be helpful, reflecting the impact of powerful oxidants such as ONOO- on sperm capacitation (Herrero et al. 2001). This positive association between protein nitration and sperm function is also supported by the observation that seminal 3-NT levels are significantly reduced in cases of male infertility (Kalezic et al. 2018). However, if the nitroxidative stress is sustained, it ultimately overwhelms the antioxidative defence capacity of these cells and precipitates a loss of sperm function. It may be for this reason that we see negative correlations between ONOO- and sperm movement and why 3-NT expression is elevated in the spermatozoa of asthenozoospermic patients (Vignini et al. 2006). Nitrosylation of tyrosine residues interferes with the phosphorylation and activation of tyrosine kinases, thereby disrupting cell signalling pathways associated with critical reproductive processes such as sperm movement and capacitation (Morielli & O’Flaherty 2015). Similarly in the ovary, repeated induction of ovulation leads to significantly decreased ovarian function and oocyte quality and increased oxidative stress reflected by the increased expression of both 4-HNE and 3-NT (Nie et al. 2018). Increased protein nitration has also been observed in the granulosa cells recovered from women exhibiting poor oocyte quality in association with endometriosis (Goud et al. 2014).

Oxidative DNA damage

DNA is notoriously vulnerable to oxidative attack. The guanine residues are particularly vulnerable because they possess the lowest redox potential of the four DNA bases. An ROS attack on DNA therefore generates the oxidative base adduct, 8-hydroxy-2′-deoxyguanosine (8OHdG), which is highly correlated with DNA fragmentation (De Iuliis et al. 2009b , Santiso et al. 2010).

The adverse developmental consequences of oxidative DNA damage in the male germ line have been demonstrated using the glutathione peroxidase 5 (Gpx5) knockout mouse. Gpx5 is the major antioxidant enzyme in the epididymis; as a result, knocking out this gene leads to the generation of oxidatively stressed male mice with high levels of 8OHdG in their epididymal spermatozoa. Interestingly, this modification did not have an ‘immediate’ impact on the fertility of these animals, but as they aged, a significant increase in miscarriages and developmental defects was observed in their offspring (Chabory et al. 2009, Aitken 2009). Following from this research, a high incidence of 8OHdG lesions in the spermatozoa of male infertility patients (Vorilhon et al. 2018) has raised awareness about the potential clinical importance of oxidative DNA damage, in defining the genetic and epigenetic mutational load carried by children (Aitken et al. 2020, Aitken & Gibb 2022). However, the fact that the DNA damage precipitated by GPx5 inactivation can be ameliorated using antioxidant therapy suggests a possible means of resolving this problem in a clinical context (Gharagozloo et al. 2016).

The damage to lipids, proteins, and nucleic acids described earlier occurs because the exposure to ROS has overwhelmed the defensive capacity of antioxidant systems that have evolved to maintain redox homeostasis in reproductive cells and tissues. Oxidative stress may occur when these antioxidant systems are diminished due to such factors as a lack of dietary micronutrients (e.g. vitamin C or selenium), the impaired synthesis of effective antioxidant enzymes, or the excessive consumption of antioxidants in the wake of an oxidative attack. Stress may also arise because of exposure to excessive levels of ROS. In vitro, excessive ROS production may be induced by high oxygen tensions affecting, for example, the developmental potential of embryos in an in vitro fertilization setting (Arias et al. 2012). In vivo, the cellular systems responsible for ROS generation may have become excessively active for a variety of reasons, key examples of which are outlined below.

Why do ROS levels become elevated?

Leukocytic infiltration

The mechanisms responsible for the elevation of ROS generation in human spermatozoa have recently been reviewed in depth (Aitken et al. 2022) and will only be summarized here. One of the key mechanisms by which oxidative stress is created in the human ejaculate is via the infiltration of free radical-generating leukocytes, particularly macrophages and neutrophils, and the consequent development of leukocytospermia (Aitken et al. 1995). Whether the presence of leukocytes in the ejaculate will create a state of oxidative stress that will suppress sperm function depends on the number and type of leukocytes involved, the site of infiltration (epididymis, prostate, seminal vesicles, or urethra), whether the leukocytes are activated, how they were activated, and when they were activated. Although these questions are often difficult to answer, overall, there seems to be good evidence to suggest a causative chain of events involving leukocytic infiltration, oxidative stress, sperm DNA damage, and impaired sperm function (Aitken et al. 2022).

Similarly in the ovary, resident and infiltrating leukocytes represent a source of oxidative stress that can seriously impact ovarian function and oocyte quality. ROS are generated by infiltrating leukocytes during luteolysis, and this response is associated with reversible depletion of ascorbic acid, uncoupling of the luteinizing hormone receptor from adenylate cyclase, and the inhibition of steroidogenesis (Behrman et al. 2001). ROS are also produced within the follicle at ovulation, with both leukocytes and granulosa cells being major sources of these damaging metabolites. In much the same manner as we observe in the male, ROS serve important physiologic roles in biological processes surrounding female fertility, such as the resumption of oocyte maturation and ovulation, but the sustained production of these damaging metabolites by infiltrating leukocytes may lead to an increased cumulative risk of ovarian pathology (Behrman et al. 2001) and a loss of developmental potential on the part of the oocyte (Mihalas et al. 2017).

Mitochondria

A major site of ROS generation in all cells, including germ cells, are the mitochondria. In order to generate ATP, the mitochondria have to split hydrogen atoms into electrons and protons. The former are passaged along a carefully orchestrated series of redox centres culminating in the four electron reduction of oxygen to water by cytochrome oxidase. This process is not fool-proof, and there is a tendency for electrons to leak from the mitochondrial electron transport chain. These leaked electrons are swept up by oxygen thereby generating O2·− and, via SOD-mediated dismutation, H2O2. In some cell types, such as equine spermatozoa, the intense metabolic activity required to maintain rapid sperm velocity means that there is a constant leakage of electrons from the electron transport chain, with the downstream effect being that in this cell type, mitochondrial ROS generation is, somewhat paradoxically, positively correlated with fertility (Gibb et al. 2014). Of course, even equine spermatozoa are not completely immune to oxidative stress and with the passage of time even these cells become overwhelmed, if ROS generation is sustained (Aitken et al. 2012a , Gibb et al. 2016).

Mitochondrial ROS generation can be promoted by a variety of factors that encourage electron leakage from the mitochondria including the above-mentioned lipid aldehydes such as 4-HNE, the male contraceptive agent, gossypol, the vitamin K mimetic, menadione, and the homocysteine cyclic congener, homocysteine thiolactone (Aitken et al. 2022). Defects in proline metabolism have recently been identified as contributing to the aetiology of premature reproductive senescence in males (Yen & Currna 2021). Such metabolic errors might also activate mitochondrial ROS generation and impair sperm function via the generation of glutamic semialdehyde, an electrophile capable of forming adducts with proteins in the mitochondrial electron transport chain and inducing electron leakage in a similar fashion to lipid aldehydes (Nomura & Takagi 2004).

A variety of synthetic, environmental, and natural oestrogens will also trigger mitochondrial ROS generation in spermatozoa. These include compounds such as parabens, catechol oestrogen, bisphenol A, genistein, and pyrogallol, all of which contain the common biochemical feature of a hydroxylated aromatic ring (Aitken et al. 2022). Another group of compounds that are involved in the stimulation of mitochondrial ROS generation by mammalian spermatozoa are PUFA. Exposure of these cells to free, unesterified, unsaturated fatty acids elicits a powerful mitochondrial ROS response in human spermatozoa. The magnitude of this response is correlated with the degree of unsaturation, such that the major naturally occurring PUFAs in spermatozoa (arachidonic and docosahexaenoic acids) are, in their free unesterified form, powerful instigators of mitochondrial ROS generation (Aitken et al. 2006). The observation that defective human spermatozoa contain an abnormally high content of free PUFA and that these levels positively correlate with ROS generation by the mitochondria suggests that this association is causative (Koppers et al. 2010). There may be significant implications here for the impact of fat-rich, Westernized diets on the biochemical composition and function of human spermatozoa.

Putting energy into mitochondria in the form of radiofrequency electromagnetic radiation (De Iuliis et al. 2009a ), heat (De Iuliis et al. 2009a , Houston et al. 2018), and visible light (Shahar et al. 2011) is also known to enhance mitochondrial ROS generation. These observations are important because they suggest a plausible mechanism by which electromagnetic radiation, in all of its various forms, can influence cellular function.

Finally, many different disruptive pathways converge with induction of the intrinsic apoptotic cascade in both spermatozoa and oocytes, and this process is also associated with the activation of mitochondrial ROS generation, thereby accelerating the rate at which affected cells lose their viability (Koppers et al. 2011, Dai et al. 2015, Lord et al. 2015).

Oxidases

The first enzyme that was ever shown to generate ROS in the germ line was an L-amino acid oxidase in bovine spermatozoa that generated H2O2 when these cells were exposed to cryodiluents containing egg yolk (Tosic & Walton 1950). This oxidase preferentially uses aromatic amino acids such as phenylalanine, tryptophan, and tyrosine as substrate and has been found in the spermatozoa of all mammalian species that have been examined to date including bull, ram, boar stallion, mouse, and man (Shannon & Curson 1982, Aitken et al. 2015a , Houston et al. 2015, Kwon et al. 2015, Zhang et al. 2021). This enzyme only requires the presence of substrate to generate both hydrogen peroxide and ammonia:

Attention initially focused on the pathological consequences of this enzyme’s activity and the notion that it was dead spermatozoa with damaged plasma membranes which responded to the presence of aromatic amino acids with the generation of ROS and an oxidative attack on live cells in the immediate vicinity (Tosic & Walton 1950, Shannon & Curson 1972). While this scenario has been validated for bovine, equine, and ovine spermatozoa, it does not play out in the case of human spermatozoa where this oxidase is lost from non-viable cells. In this cell type, the L-amino acid oxidase has been shown to play a physiological role in the redox regulation of sperm capacitation and acrosomal exocytosis (Houston et al. 2015). This hypothesis has recently been born out in the mouse, where genetic deletion of the −L-amino acid oxidase gene has been shown to impair male fertility, in concert with a reduction in H2O2 generation by the spermatozoa and an impaired capacity of the spermatozoa to acrosome react in response to the calcium ionophore, A23187 (Zhang et al. 2021). Similarly in the boar, the L-amino acid gene has been positively associated with spermatozoa capable of generating high letter sizes (Kwon et al. 2015).

A second group of oxidases in mammalian spermatozoa that are thought to be involved in the regulation of sperm function are the NADPH oxidases (NOX). In this case, particular attention has focused on NOX5, an isoform of this enzyme that possesses EF-hand motifs rendering it is sensitive to calcium (Bánfi et al. 2001).

This enzyme has been demonstrated in man (Musset et al. 2012), ram (Miguel-Jiménez et al. 2021), stallion (Sabeur & Ball 2007), and dog (Aparnak & Saberivand 2017) and is represented in genomic databases in several mammalian species including the bull and grey mouse lemur (Aitken et al. 2022). NOX5 is thought to play a key role in the redox regulation of sperm capacitation, where it controls key elements of this process including intracellular pH, cAMP generation, tyrosine phosphorylation, and cholesterol efflux from the plasma membrane (Aitken et al. 2022). On the other side of the redox coin, elevated NOX5 is implicated in generating the oxidative stress associated with asthenozoospermia, in association with the enhanced generation of both O2·− and H2O2, along with DNA damage (Vatannejad et al. 2019). Interestingly, NOX5 expression is also elevated in cases of teratozoospermia (Ghani et al. 2013). These morphologically abnormal cells retain a larger volume of residual cytoplasm following spermiogenesis and therefore contain more cytoplasmic glucose-6-phosphate dehydrogenase to generate the NADPH needed to fuel NOX5 activity (Gomez et al. 1996). Surprisingly, the NOX5 gene is absent from the genomes of rodent species such as mouse, rat, and hamster despite the fact that sperm capacitation in these species is known to be redox regulated (Bize et al. 1991, Lewis & Aitken 2001, Ecroyd et al. 2003, Aitken et al. 2022). In these species, the redox regulation of sperm capacitation must be controlled by other members of the NOX family such as NOX2 (Shukla et al. 2005, Chandrasekhar et al. 2011) or other ROS-generating enzymes such as the L-amino acid oxidase mentioned earlier.

In the ovary, it is also clear that enzymatic ROS generation via NOX enzymes plays a critical role in the processes of ovulation and oocyte maturation (Chen et al. 2014, Li et al. 2018). Granulosa cells, in particular, are known to contain a rich mixture of NOX-like enzymes (NOX4, NOX5, DUOX1, and DUOX2) that are thought to regulate the redox status of the ovarian follicle, orchestrating both physiological ROS generation (Buck et al. 2019), and potentially contributing to the intra-ovarian oxidative stress that accompanies ageing (Maraldi et al. 2016) and impairs the developmental potential of the oocyte (Terao et al. 2019). The existence of NOX activity in the endometrium also signals the potential importance of these enzymes in the regulation of fundamental processes such as decidualization and implantation that have yet to be extensively explored (Yu et al. 2019).

Development of biomarkers for oxidative stress

If oxidative stress is such an important factor in the promotion and dysregulation of reproductive function, then it is imperative that we develop biomarkers by which such stress can be recognized. The classical markers of oxidative stress focus on assessment of oxidative changes to lipids, proteins, and DNA. In the case of lipids, assays have been developed to measure the three major stages of lipid peroxidation including the initiation of this process as reflected in the formation of conjugated dienes (Recknagel & Glende 1984), the peroxidation process itself, as characterized by lipid peroxide formation (Thomas & Poznansky 1990), and ultimately the breakdown of these peroxides into lipid aldehydes (Dator et al. 2019). Of all these potential assays, the thiobarbituric acid assay for the detection of malondialdehyde or, more accurately, thiobarbituric acid reactive substances, is the most widely used marker of oxidative stress in biological systems. The assay is simple and sensitive and gives results that parallel the outcome of more sophisticated gas chromatography-mass spectrometric assays (Liu et al. 1997). Providing its lack of specificity is recognized, it provides a robust measure of oxidative stress for diagnostic purposes and has been widely used in a reproductive context to measure the stress associated with such conditions as varicocele (Barradas et al. 2021), menopausal insomnia (Semenova et al. 2019), endometriosis (de Lima et al. 2017), assisted reproductive technology (Becatti et al. 2018), hyperprolactinemia (Kolesnikova et al. 2014), and male subfertility (Nakamura et al. 2002). For greater specificity, assays of lipid aldehydes can be conducted using antibodies against specific metabolites such as malondialdhyde, 4HNE, and acrolein in flow cytometry protocols (Moazamian et al. 2015).

Oxidative damage to proteins is generally assessed using the dinitrophenylhydrazine method to detect carbonyl groups (Dalle-Donne et al. 2003). This method of monitoring oxidative stress has been successfully used to demonstrate the importance of protein carbonyl formation in several reproductive situations including impaired semen quality in elephants (Satitmanwiwat et al. 2017), myometrial stress during delivery (Khan et al. 2010), the control of blastocyst implantation (Durán-Reyes et al. 1999), and the induction of teratogenesis (Winn & Wells 1997). The use of Western blot techniques to reveal the adduction of proteins by lipid aldehydes such as 4HNE has also been used to monitor oxidative stress in a reproductive context. For example, 4HNE adduction of AKAP4 has been linked with failures of sperm capacitation (Nixon et al. 2019). Similarly, the binding of 4HNE to proteins in the mitochondrial electron transport chain has been associated with the enhanced generation of mitochondrial ROS (Aitken et al. 2012b), while the ability of this aldehyde to adduct tubulin has been linked with the age-dependent increase in aneuploidy rates seen in ageing oocytes (Mihalas et al. 2017).

The development of probes to detect DNA oxidation in the form of 8OHdG has also been used as an oxidative stress biomarker in a reproductive context. For example, the ability of xenobiotics to induce oxidative stress during pregnancy (Lan et al. 2022), to monitor the quality of oocytes used in ICSI cycles (Mukheef et al. 2022), to evaluate oxidative stress in spermatozoa (Vorilhon et al. 2018, Gharagozloo et al. 2022), and as a means of determining the reproductive toxicity associated with a wide variety of pollutants including phthalate esters and insecticides (Brassea-Pérez et al. 2022, Pan et al. 2022).

The measurement of antioxidant levels in biological fluids such as semen, blood, and follicular fluid is another approach to monitoring oxidative stress that has found application in a wide range of reproductive contexts including the potential role of antioxidant deficiency in the aetiology of male infertility (Sharma et al. 1999, Gharagozloo et al. 2016) and the oxidative stress associated with pregnancy (Wagle et al. 2021) or suffered by premature neonates (Miller et al. 1993). Traditionally, antioxidant potential has been determined by assessing the ability of a given biological fluid to scavenge the free radicals generated in vitro by the 2,2’-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical cation, as originally described by Catherine Rice-Evans (Miller et al. 1993, Erel 2004). The development of simple technologies for monitoring the antioxidant potential of reproductive tissues and fluids is both ongoing and essential, if we are to provide clinicians with a rational basis for prescribing antioxidant therapy without running the risk of driving their patients into a state of reductive stress (Gharagozloo & Aitken 2011).

Conclusions

Redox homeostasis is critical for the entire reproductive process. Both male and female germ lines rely on oxidative processes to achieve a wide range of biological functions from capacitation and chromatin cross linking in the spermatozoa to the maturation and ovulation of oocytes, preimplantation embryo development, implantation, fetal development to term and, if conception does not occur, menstruation and luteolysis (Manfredi Romanini et al. 1986, Sugino 2007, Hardy et al. 2021, Aitken et al. 2022). However, if ROS generation becomes dysregulated and exceeds the capacity of the reproductive system to defend itself against these potentially toxic oxygen metabolites then a state of oxidative stress is induced that can compromise the reproductive process at many different points (Fig. 3). To date much attention has focused on the role of oxidative stress in male infertility and placental function during pregnancy (Aitken 2017, Cindrova-Davies et al. 2018). However, in reality, an appropriate redox balance is critical for all aspects of the reproductive process from conception to parturition. A disruption of redox homeostasis is one of the major mechanisms by which age, lifestyle and environmental factors impact the reproductive system (Shahin et al. 2017, Snider & Wood 2019, Nourian et al. 2020, Wang et al. 2021, Yu et al. 2021) and impair not just the fertility of our species (Aitken 2022) but also the genetic and epigenetic status of future generations (Menezo et al. 2021, Aitken & Gibb 2022).

Figure 3
Figure 3

Mechanisms regulating oxidative stress in both male and female reproductive systems. Dysregulation of NADPH oxidase acid and high levels of leucocytic infiltration can cause oxidative stress in both the ovary and the testes. In addition, the mitochondria can make a significant contribution to oxidative stress in the reproductive tract particularly when the free flow of electrons along the electron transport chain in compromised by the ability of electrophilic aldehydes to bind to mitochondrial redox carriers. These pernicious electrophiles may be generated as a result of lipid peroxidation (e.g. 4-HNE or acrolein) or defects in metabolism (e.g. the glutamate semialdehyde generated during proline metabolism). Specifically in spermatozoa, an L-amino acid oxidase can generate sufficient ROS to compromise sperm function particularly in the presence of eye yolk-based cryopreservation media that contain high quantities of the aromatic amino acids, such as phenylalanine, needed to stimulate oxidase activity. All of these various pathways converge at the generation of excessive ROS, particularly H2O2, which can have a devastating impact at all levels of the reproductive process from gametogenesis to parturition as well as impacting the health and wellbeing of any subsequent progeny. Created with BioRender.com.

Citation: Reproduction 164, 6; 10.1530/REP-22-0126

The task that now lies before us is to develop a deeper understanding of this process and acquire more fundamental information on the oxidative stress phenomenon as it relates to reproduction in terms of its existence, location, magnitude and source. Only in the light of such information can appropriate therapies be fashioned that are capable of effectively addressing the redox imbalance that underpins so much pathology relating to the reproductive process (Aitken 2021).

Declaration of interest

R J A is funded by Memphasys Ltd and CellOxess. Robert J Aitken is an Associate Editor of Reproduction. Robert J Aitken was not involved in the review or editorial process for this paper, on which he is listed as an author. The other authors have nothing to disclose.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution statement

R J A prepared the first draft of this manuscript that was then edited and improved by Z G and E B. All authors provided intellectual input and critically edited the paper.

Acknowledgement

We are extremely grateful to the University of Newcastle for its support.

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