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      Investigation on the mechanisms of human sperm DNA damage based on the proteomics analysis by SWATH-MS

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          Abstract

          Background

          Spermatozoa have the task of delivering an intact paternal genome to the oocyte and supporting successful embryo development. The detection of sperm DNA fragmentation (SDF) has been emerging as a complementary test to conventional semen analysis for male infertility evaluation, but the mechanism leading to SDF and its impact on assisted reproduction remain unclear. Therefore, the study identified and analyzed the differentially expressed proteins of sperm with high and low SDF.

          Methods

          Semen samples from men attended the infertility clinic during June 2020 and August 2020 were analyzed, and sperm DNA fragmentation index (DFI) was detected by the sperm chromatin structure assay. Semen samples with low DFI (< 30%, control group) and high DFI (≥ 30%, experimental group) were optimized by density gradient centrifugation (DGC), and the differentially expressed proteins of obtained sperm were identified by the Sequential Window Acquisition of All Theoretical Mass Spectra Mass Spectrometry (SWATH-MS) and performed GO and KEGG analysis.

          Results

          A total of 2186 proteins were identified and 1591 proteins were quantified, of which 252 proteins were identified as differentially expressed proteins, including 124 upregulated and 128 downregulated. These differentially expressed proteins were involved in metabolic pathways, replication/recombination/repair, acrosomal vesicles, kinase regulators, fertilization, tyrosine metabolism, etc. Western blotting results showed that the expression levels of RAD23B and DFFA proteins and the levels of posttranslational ubiquitination and acetylation modifications in the experimental group were significantly higher than those in the control group, which was consistent with the results of proteomics analysis.

          Conclusions

          Proteomic markers of sperm with high DNA fragmentation can be identified by the SWATH-MS and bioinformatic analysis, and new protein markers and posttranslational modifications related to sperm DNA damage are expected to be intensively explored. Our findings may improve our understanding of the basic molecular mechanism of sperm DNA damage.

          Highlights

          • Differentially expressed proteins in sperm could be identified by the SWATH-MS.

          • The validation results of Western blotting were identical to the results of proteomics analysis.

          • Proteomic markers of sperm with high DNA fragmentation could be identified by the bioinformatic analysis.

          • New protein markers and posttranslational modifications related to sperm DNA damage are expected to be intensively explored.

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          Most cited references47

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          Metabolic regulation of gene expression through histone acylations

          In addition to acetylation, eight types of structurally and functionally different short-chain acylations have recently been identified as important histone Lys modifications: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These modifications are regulated by enzymatic and metabolic mechanisms and have physiological functions, which include signal-dependent gene activation and metabolic stress.
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            Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis.

            Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The aim of this study was to examine the influence of sperm DNA damage on the risk of spontaneous pregnancy loss after IVF and ICSI. We conducted a systematic review and meta-analysis of studies on sperm DNA damage and pregnancy loss after an IVF and/or ICSI pregnancy. Two by two tables were constructed and odds ratios (ORs) were derived from 11 estimates of pregnancy loss (five IVF and six ICSI studies from seven reports). These 11 studies involved 1549 cycles of treatment (808 IVF and 741 ICSI cycles) with 640 pregnancies (345 IVF and 295 ICSI) and 122 pregnancy losses. The combined OR of 2.48 (95% CI 1.52, 4.04, P < 0.0001) indicates that sperm DNA damage is predictive of pregnancy loss after IVF and ICSI. In conclusion, sperm DNA damage is associated with a significantly increased risk of pregnancy loss after IVF and ICSI. These data provide a clinical indication for the evaluation of sperm DNA damage prior to IVF or ICSI and a rationale for further investigating the association between sperm DNA damage and pregnancy loss.
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              Sperm DNA fragmentation: paternal effect on early post-implantation embryo development in ART.

              The relationship between early embryo post-implantation development in couples undergoing assisted reproductive techniques (ARTs) and sperm chromatin alterations has not been satisfactorily explained. The aim of this study was to assess the relationship between sperm DNA fragmentation in IVF/ICSI patients, sperm parameters (concentration, motility and morphology) and ART outcome, especially with regard to clinical pregnancy and pregnancy loss (spontaneous miscarriage or biochemical pregnancy). DNA fragmentation was evaluated by TUNEL assay, performed on sperm suspensions after density gradient separation, in 132 men undergoing an ART cycle (82 IVF and 50 ICSI) and correlated with sperm parameters and ART outcome. A highly significant negative correlation was found between DNA fragmentation and sperm parameters. There was a close relationship between DNA fragmentation and post-implantation development in ICSI patients: the clinical pregnancy and pregnancy loss rates significantly differed between patients with high and low sperm DNA fragmentation (P = 0.007 and P = 0.009, respectively). Sperm DNA fragmentation seems to affect embryo post-implantation development in ICSI procedures: high sperm DNA fragmentation can compromise 'embryo viability', resulting in pregnancy loss.
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                Author and article information

                Contributors
                hmcui@yzu.edu.cn
                406646227@qq.com
                Journal
                Clin Proteomics
                Clin Proteomics
                Clinical Proteomics
                BioMed Central (London )
                1542-6416
                1559-0275
                6 January 2023
                6 January 2023
                2023
                : 20
                : 2
                Affiliations
                [1 ]GRID grid.268415.c, Center for Reproductive Medicine, , Northern Jiangsu People’s Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, ; Yangzhou, 225001 Jiangsu China
                [2 ]GRID grid.268415.c, Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, , Yangzhou University, ; 48 Wenhui Road, Yangzhou, 225009 Jiangsu China
                [3 ]GRID grid.452290.8, ISNI 0000 0004 1760 6316, Center for Reproductive Medicine, , Zhongda Hospital, Southeast University, ; 3 Xinmofan Road, Nanjing, 210037 Jiangsu China
                Article
                9391
                10.1186/s12014-022-09391-9
                9817420
                36609216
                8bd279c2-628c-4f2d-8fb1-4ef9613a466f
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 24 August 2022
                : 29 December 2022
                Funding
                Funded by: Jiangsu Postgraduate Training Innovation Project
                Award ID: KYCX17_1888
                Award Recipient :
                Funded by: National Natural Science Foundation of China
                Award ID: 81773013
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2023

                Molecular medicine
                proteomics,sperm dna damage,male infertility,biomarker
                Molecular medicine
                proteomics, sperm dna damage, male infertility, biomarker

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