Mass Spectrometry Reveals New Insights into the Production of Superoxide Anions and 4‐Hydroxynonenal Adducted Proteins in Human Sperm

Netherton, Jacob; Hetherington, Louise; Ogle, Rachel A; Gavgani, Marum Mazloumi; Velkov, Tony; Villaverde, Ana Izabel Bilbin; Tanphaichitr, Nuch; Baker, Mark

doi:10.1002/pmic.202070024

Cited by 4 publications

(9 citation statements)

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“…To the best of our knowledge, this methodology has only been used to analyse menadione-treated spermatozoa [33] and has never been used to compare the level of ROS spontaneously generated by normal and pathological sperm cells. Recently, we have used the LC-MS/MS approach to investigate sperm O 2 • − generation during in vitro incubation [141]. As previously reported, we also observed an increase in DHE over time.…”

Section: Discussionsupporting

confidence: 81%

“…Finally, although sperm are susceptible to in vitro induced and exogenous sources of ROS and its by-products, the in vivo relevance of these compounds needs further clarity. Of interest, considering only the ROS produced by sperm, our laboratory has recently found that neither O 2 • − nor other free radicals, which lead to 4-HNE production, are responsible for motility loss during incubation [141]. In addition, a clear distinction must be made between the physiological versus the pathological roles of ROS in sperm.…”

Section: Discussionmentioning

confidence: 99%

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

Villaverde¹,

Netherton

Baker

2019

Antioxidants

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

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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

Villaverde¹,

Netherton

Baker

2019

Antioxidants

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“…It should also be recognized that a vast majority of the probes used with flow cytometry are redox active agents that do not measure ROS directly but rather, oxidative activity. Nevertheless, by using dihydroethidium as a probe and separating out the reaction product specifically generated by superoxide anion, 2-hydroxyethidium, it has been possible to generate evidence of superoxide production by mammalian spermatozoa ( 102 , 103 ). Moreover, these data have been confirmed with definitive techniques such as electron paramagnetic resonance spectroscopy ( 104 – 106 ).…”

Section: Oxidative Stressmentioning

confidence: 99%

“…However, there is still some conjecture as to how many other factors are involved in sperm motility loss in vitro . In a recent study of human spermatozoa incubated over a 5 day period, the loss of virtually all motility was not accompanied by a corresponding increase in 4-HNE levels by Western blot ( 102 ). In light of these data, we have to conclude that there may be multiple reasons why spermatozoa become senescent in vitro and we are yet to resolve the full complexities of this process.…”

Section: Oxidative Stressmentioning

confidence: 99%

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

Aitken

Baker

2020

Front. Endocrinol.

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Despite the high prevalence of male infertility, very little is known about its etiology. In recent years however, advances in gene sequencing technology have enabled us to identify a large number of rare single point mutations responsible for impeding all aspects of male reproduction from its embryonic origins, through the endocrine regulation of spermatogenesis to germ cell differentiation and sperm function. Such monogenic mutations aside, the most common genetic causes of male infertility are aneuploidies such as Klinefelter syndrome and Y-chromosome mutations which together account for around 20-25% of all cases of non-obstructive azoospermia. Oxidative stress has also emerged as a major cause of male fertility with at least 40% of patients exhibiting some evidence of redox attack, resulting in high levels of lipid peroxidation and oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8OHdG). The latter is highly mutagenic and may contribute to de novo mutations in our species, 75% of which are known to occur in the male germ line. An examination of 8OHdG lesions in the human sperm genome has revealed ∼9,000 genomic regions vulnerable to oxidative attack in spermatozoa. While these oxidized bases are generally spread widely across the genome, a particular region on chromosome 15 appears to be a hot spot for oxidative attack. This locus maps to a genetic location which has linkages to male infertility, cancer, imprinting disorders and a variety of behavioral conditions (autism, bipolar disease, spontaneous schizophrenia) which have been linked to the age of the father at the moment of conception. We present a hypothesis whereby a number of environmental, lifestyle and clinical factors conspire to induce oxidative DNA damage in the male germ line which then triggers the formation de novo mutations which can have a major impact on the health of the offspring including their subsequent fertility.

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“…have re‐visited the question of oxidative stress, because there are many flaws with the techniques widely used to characterize reactive oxygen species activity or by‐products of their effects, which arguably puts into question most of the accumulated data . It is quite interesting that there are a number of anomalies in the literature, to use Kuhn's definition, regarding semen oxidative stress, in which some articles report that oxidative stress is strongly associated to male infertility, while others fail to find any effect at all, as reviewed in the current study . Moreover, studies that have approached sample and/or patient supplementation with antioxidants for improved semen quality have very antagonistic results, so that no consensus may be achieved (reviewed in ref.…”

mentioning

confidence: 91%

Mechanisms of Sperm Oxidation: Breaking Down the Origins of Oxidative Activity

Bertolla

2020

Proteomics

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Oxidative stress has been long considered an important cause of male infertility, and sperm-derived reactive oxygen species (ROS) have been considered one of the major sources. In article number 1900205, Issue 2, Netherton et al. have improved upon current technologies for detection of true ROS-derived oxidative events from those originated by mitochondrial compounds. Moreover, the authors have isolated proteins that bear lipid aldehyde adducts, in order to verify their origin. In their paper, Netherton et al. demonstrate that sperm-derived ROS do not contribute to sperm oxidative stress, which is an important finding, given that most studies consider altered sperm a major source of seminal ROS. Moreover, adducted proteins are mostly of prostatic origin, which leads to questions regarding how and where the oxidative events occur. Under the light of this study and the methodological improvements it has brought, it may be important to revisit some foundation studies in semen and sperm oxidative stress.

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Mass Spectrometry Reveals New Insights into the Production of Superoxide Anions and 4‐Hydroxynonenal Adducted Proteins in Human Sperm

Cited by 4 publications

References 0 publications

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

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

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

Mechanisms of Sperm Oxidation: Breaking Down the Origins of Oxidative Activity

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