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      Update on the proteomics of male infertility: A systematic review

      research-article
      , *
      Arab Journal of Urology
      Elsevier
      Sperm proteomics, Male infertility, Spermatozoa, Varicocele, Biomarkers

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          Abstract

          Objective

          To assess the role of differentially expressed proteins as a resource for potential biomarker identification of infertility, as male infertility is of rising concern in reproductive medicine and evidence pertaining to its aetiology at a molecular level particularly proteomic as spermatozoa lack transcription and translation. Proteomics is considered as a major field in molecular biology to validate the target proteins in a pathophysiological state. Differential expression analysis of sperm proteins in infertile men and bioinformatics analysis offer information about their involvement in biological pathways.

          Materials and methods

          Literature search was performed on PubMed, Medline, and Science Direct databases using the keywords ‘sperm proteomics’ and ‘male infertility’. We also reviewed the relevant cross references of retrieved articles and included them in the review process. Articles written in any language other than English were excluded.

          Results

          Of 575 articles identified, preliminary screening for relevant studies eliminated 293 articles. At the next level of selection, from 282 studies only 80 articles related to male infertility condition met the selection criteria and were included in this review.

          Conclusion

          In this molecular era, sperm proteomics has created a platform for enhanced understanding of male reproductive physiology as a potential tool for identification of novel protein biomarkers related to sperm function in infertile men. Therefore, it is believed that proteomic biomarkers can overcome the gaps in information from conventional semen analysis that are of limited clinical utility.

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          Most cited references72

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          Proteomic analysis of post-translational modifications.

          Post-translational modifications modulate the activity of most eukaryote proteins. Analysis of these modifications presents formidable challenges but their determination generates indispensable insight into biological function. Strategies developed to characterize individual proteins are now systematically applied to protein populations. The combination of function- or structure-based purification of modified 'subproteomes', such as phosphorylated proteins or modified membrane proteins, with mass spectrometry is proving particularly successful. To map modification sites in molecular detail, novel mass spectrometric peptide sequencing and analysis technologies hold tremendous potential. Finally, stable isotope labeling strategies in combination with mass spectrometry have been applied successfully to study the dynamics of modifications.
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            On the possible origins of DNA damage in human spermatozoa.

            DNA damage in the male germ line has been linked with a variety of adverse clinical outcomes including impaired fertility, an increased incidence of miscarriage and an enhanced risk of disease in the offspring. The origins of this DNA damage could, in principle, involve: (i) abortive apoptosis initiated post meiotically when the ability to drive this process to completion is in decline (ii) unresolved strand breaks created during spermiogenesis to relieve the torsional stresses associated with chromatin remodelling and (iii) oxidative stress. In this article, we present a two-step hypothesis for the origins of DNA damage in human spermatozoa that highlights the significance of oxidative stress acting on vulnerable, poorly protaminated cells generated as a result of defective spermiogenesis. We further propose that these defective cells are characterized by several hallmarks of 'dysmaturity' including the retention of excess residual cytoplasm, persistent nuclear histones, poor zona binding and disrupted chaperone content. The oxidative stress experienced by these cells may originate from infiltrating leukocytes or, possibly, the entry of spermatozoa into an apoptosis-like cascade characterized by the mitochondrial generation of reactive oxygen species. This oxidative stress may be exacerbated by a decline in local antioxidant protection, particularly during epididymal maturation. Finally, if oxidative stress is a major cause of sperm DNA damage then antioxidants should have an important therapeutic role to play in the clinical management of male infertility. Carefully controlled studies are now needed to critically examine this possibility.
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              Role of reactive oxygen species in male infertility.

              Human spermatozoa exhibit a capacity to generate ROS and initiate peroxidation of the unsaturated fatty acids in the sperm plasma membrane, which plays a key role in the etiology of male infertility. The short half-life and limited diffusion of these molecules is consistent with their physiologic role in key biological events such as acrosome reaction and hyperactivation. The intrinsic reactivity of these metabolites in peroxidative damage induced by ROS, particularly H2O2 and the superoxide anion, has been proposed as a major cause of defective sperm function in cases of male infertility. The number of antioxidants known to attack different stages of peroxidative damage is growing, and it will be of interest to compare alpha-tocopherol and ascorbic acid with these for their therapeutic potential in vitro and in vivo. Both spermatozoa and leukocytes generate ROS, although leukocytes produce much higher levels. The clinical significance of leukocyte presence in semen is controversial. Seminal plasma confers some protection against ROS damage because it contains enzymes that scavenge ROS, such as catalase and superoxide dismutase. A variety of defense mechanisms comprising a number of anti-oxidants can be employed to reduce or overcome oxidative stress caused by excessive ROS. Determination of male infertility etiology is important, as it will help us develop effective therapies to overcome excessive ROS generation. ROS can have both beneficial and detrimental effects on the spermatozoa and the balancing between the amounts of ROS produced and the amounts scavenged at any moment will determine whether a given sperm function will be promoted or jeopardized. Accurate assessment of ROS levels and, subsequently, OS is vital, as this will help clinicians both elucidate the fertility status and identify the subgroups of patients that respond or do not respond to these therapeutic strategies. The overt commercial claims of antioxidant benefits and supplements for fertility purposes must be cautiously looked into, until proper multicentered clinical trials are studied. From the current data it appears that no single adjuvant will be able to enhance the fertilizing capacity of sperm in infertile men, and a combination of the possible strategies that are not toxic at the dosage used would be a feasible approach.
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                Author and article information

                Contributors
                Journal
                Arab J Urol
                Arab J Urol
                Arab Journal of Urology
                Elsevier
                2090-598X
                2090-5998
                29 December 2017
                March 2018
                29 December 2017
                : 16
                : 1
                : 103-112
                Affiliations
                American Centre for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA
                Author notes
                [* ]Corresponding author at: Lerner College of Medicine, Andrology Center and American Center for Reproductive Medicine, 10681 Carnegie Avenue, Desk X11, Cleveland, OH 44195, USA. Fax: +1 216 445 6049. agarwaa@ 123456ccf.org
                Article
                S2090-598X(17)30150-X
                10.1016/j.aju.2017.11.016
                5922221
                29713541
                5c69f767-5cd8-4e4a-89a7-3e431f7cb198
                © 2017 Production and hosting by Elsevier B.V. on behalf of Arab Association of Urology.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 October 2017
                : 17 November 2017
                : 19 November 2017
                Categories
                Diagnosis

                sperm proteomics,male infertility,spermatozoa,varicocele,biomarkers

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