Effect of Antioxidant Supplementation on the Sperm Proteome of Idiopathic Infertile Men

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Abstract

Antioxidant supplementation in idiopathic male infertility has a beneficial effect on semen parameters. However, the molecular mechanism behind this effect has not been reported. The objective of this study was to evaluate the sperm proteome of idiopathic infertile men pre- and post-antioxidant supplementation. Idiopathic infertile men were provided with oral antioxidant supplementation once daily for a period of 6 months. Of the 379 differentially expressed proteins (DEPs) between pre- and post-antioxidant treatment patients, the majority of the proteins ( n = 274) were overexpressed following antioxidant treatment. Bioinformatic analysis revealed the activation of oxidative phosphorylation pathway and upregulation of key proteins involved in spermatogenesis, sperm maturation, binding of sperm, fertilization and normal reproductive function. In addition, the transcriptional factors associated with antioxidant defense system (PPARGC1A) and free radical scavenging (NFE2L2) were predicted to be functionally activated post-treatment. Key DEPs, namely, NDUFS1, CCT3, PRKARA1 and SPA17 validated by Western blot showed significant overexpression post-treatment. Our novel proteomic findings suggest that antioxidant supplementation in idiopathic infertile men improves sperm function at the molecular level by modulating proteins involved in CREM signaling, mitochondrial function and protein oxidation. Further, activation of TRiC complex helped in nuclear compaction, maintenance of telomere length, flagella function, and expression of zona pellucida receptors for sperm–oocyte interaction.

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Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Ashok Agarwal, Neel Parekh, Manesh Panner Selvam … (2019)

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

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Oxidative stress and sperm function: A systematic review on evaluation and management

Sulagna Dutta, Ahmad A. Majzoub, Ashok Agarwal (2019)

ABSTRACT Objective: To review and present the most distinct concepts on the association of reactive oxygen species (ROS) with male reproduction. Methods: The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines were used to search PubMed, Medline, EMBASE, and the Cochrane electronic databases for studies investigating the role of oxidative stress (OS) on sperm function. Results: The literature search yielded 1857 studies, of which 1791 articles were excluded because of irrelevance of data, non-English language, non-human nature or because they were case reports or commentaries. All included studies were reviews (46), meta-analyses (one), original research studies (18) and guideline articles (one). The studies were published between 1984 and 2018. Under normal physiological conditions, ROS are vital for sperm maturation, hyperactivation, capacitation, acrosome reaction, as well as fertilisation. However, a number of endogenous and exogenous causes may induce supra-physiological levels of ROS resulting in lipid peroxidation, sperm DNA fragmentation and apoptosis, and consequently infertility. Several laboratory testing methods can be used in infertile men to diagnose OS. Treatment usually involves antioxidant supplementation and, when possible, elimination of the causative factor. Conclusion: OS is an important cause of male factor infertility. Its assessment provides essential information that can guide treatment strategies aimed at improving the male’s reproductive potential. Abbreviations: bp: base-pair; CAT: catalase; LPO: lipid peroxidation; MDA: malondialdehyde; MiOXSYS: Male Infertility Oxidative System; mtDNA: mitochondrial DNA; NAD(PH): nicotinamide adenine dinucleotide (phosphate); NO: nitric oxide; 8-OHdG: 8-hydroxy-2’-deoxyguanosine; ORP: oxidation–reduction potential; OS: oxidative stress; PKA: protein kinase A; PLA2: phospholipase A2; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PUFA: poly-unsaturated fatty acid; ROS: reactive oxygen species; SOD: superoxide dismutase; TAC: total antioxidant capacity; TBA: thiobarbituric acid

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Apoptosis and DNA damage in human spermatozoa.

R. Alan Aitken, Adam J Koppers (2010)

DNA damage is frequently encountered in spermatozoa of subfertile males and is correlated with a range of adverse clinical outcomes including impaired fertilization, disrupted preimplantation embryonic development, increased rates of miscarriage and an enhanced risk of disease in the progeny. The etiology of DNA fragmentation in human spermatozoa is closely correlated with the appearance of oxidative base adducts and evidence of impaired spermiogenesis. We hypothesize that oxidative stress impedes spermiogenesis, resulting in the generation of spermatozoa with poorly remodelled chromatin. These defective cells have a tendency to default to an apoptotic pathway associated with motility loss, caspase activation, phosphatidylserine exteriorization and the activation of free radical generation by the mitochondria. The latter induces lipid peroxidation and oxidative DNA damage, which then leads to DNA fragmentation and cell death. The physical architecture of spermatozoa prevents any nucleases activated as a result of this apoptotic process from gaining access to the nuclear DNA and inducing its fragmentation. It is for this reason that a majority of the DNA damage encountered in human spermatozoa seems to be oxidative. Given the important role that oxidative stress seems to have in the etiology of DNA damage, there should be an important role for antioxidants in the treatment of this condition. If oxidative DNA damage in spermatozoa is providing a sensitive readout of systemic oxidative stress, the implications of these findings could stretch beyond our immediate goal of trying to minimize DNA damage in spermatozoa as a prelude to assisted conception therapy.

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Journal

Journal ID (nlm-ta): Antioxidants (Basel)

Journal ID (iso-abbrev): Antioxidants (Basel)

Journal ID (publisher-id): antioxidants

Title: Antioxidants

Publisher: MDPI

ISSN (Electronic): 2076-3921

Publication date (Electronic): 16 October 2019

Publication date Collection: October 2019

Volume: 8

Issue: 10

Electronic Location Identifier: 488

Affiliations

[1 ]American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; pannerm@ 123456ccf.org (M.K.P.S.); lsamanta@ 123456ravenshawuniversity.ac.in (L.S.); sharmar@ 123456ccf.org (R.S.)

[2 ]Department of Urology, Cleveland Clinic, Cleveland, OH 44195, USA; VIJS@ 123456ccf.org (S.C.V.); PAREKHN3@ 123456ccf.org (N.P.); SABANEE@ 123456ccf.org (E.S.)

[3 ]Redox Biology Laboratory, Department of Zoology, Ravenshaw University, Cuttack 753003, India

[4 ]Division of Urology, Southern Illinois University School of Medicine, Springfield, IL 62769, USA; nicktadros@ 123456gmail.com

[5 ]Department of Urology, Hamad Medical Corporation, Doha 00974, Qatar; mohamedmostafaarafa@ 123456gmail.com

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[* ]Correspondence: agarwaa@ 123456ccf.org ; Tel.: +1-216-444-9485

Author information

Ashok Agarwal https://orcid.org/0000-0003-0585-1026

Luna Samanta https://orcid.org/0000-0002-2969-0071

Neel Parekh https://orcid.org/0000-0002-6218-9254

Nicholas N. Tadros https://orcid.org/0000-0002-2272-235X

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Publisher ID: antioxidants-08-00488

DOI: 10.3390/antiox8100488

PMC ID: 6827009

PubMed ID: 31623114

SO-VID: 1cbc7d62-e866-4a0f-b89b-47c3964d279e

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Effect of Antioxidant Supplementation on the Sperm Proteome of Idiopathic Infertile Men

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Most cited references 66

Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Oxidative stress and sperm function: A systematic review on evaluation and management

Apoptosis and DNA damage in human spermatozoa.

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