{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:06:04Z","timestamp":1787313964444,"version":"build-2736575974"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T00:00:00Z","timestamp":1595808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Scho 503\/15-2"],"award-info":[{"award-number":["Scho 503\/15-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Ste 892\/14-2"],"award-info":[{"award-number":["Ste 892\/14-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Protamine-2 (Prm2)-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm\u2019s antioxidant capacity, indicated by downregulation of key proteins like Superoxide dismutase type 1 (SOD1) and Peroxiredoxin 5 (PRDX5), ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.<\/jats:p>","DOI":"10.3390\/cells9081789","type":"journal-article","created":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T03:36:38Z","timestamp":1596080198000},"page":"1789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Protamine-2 Deficiency Initiates a Reactive Oxygen Species (ROS)-Mediated Destruction Cascade during Epididymal Sperm Maturation in Mice"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9894-5608","authenticated-orcid":false,"given":"Simon","family":"Schneider","sequence":"first","affiliation":[{"name":"Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhad","family":"Shakeri","sequence":"additional","affiliation":[{"name":"Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany"},{"name":"Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Tr\u00f6tschel","sequence":"additional","affiliation":[{"name":"Department of Plant Biochemistry, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Ar\u00e9valo","sequence":"additional","affiliation":[{"name":"Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-9347","authenticated-orcid":false,"given":"Alexander","family":"Kruse","sequence":"additional","affiliation":[{"name":"Department of Urology, Pediatric Urology and Andrology, Section Molecular Andrology, Biomedical Research Center of the Justus-Liebig University Gie\u00dfen, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1889-8632","authenticated-orcid":false,"given":"Andreas","family":"Buness","sequence":"additional","affiliation":[{"name":"Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany"},{"name":"Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7540-3475","authenticated-orcid":false,"given":"Ansgar","family":"Poetsch","sequence":"additional","affiliation":[{"name":"Department of Plant Biochemistry, Ruhr-University Bochum, 44801 Bochum, Germany"},{"name":"Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China"},{"name":"College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Steger","sequence":"additional","affiliation":[{"name":"Department of Urology, Pediatric Urology and Andrology, Section Molecular Andrology, Biomedical Research Center of the Justus-Liebig University Gie\u00dfen, 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Schorle","sequence":"additional","affiliation":[{"name":"Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.molcel.2017.02.025","article-title":"Histone Variant H2A.L.2 Guides Transition Protein-Dependent Protamine Assembly in Male Germ Cells","volume":"66","author":"Barral","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1006\/bbrc.1993.1773","article-title":"Identification of the Elemental Packing Unit of DNA in Mammalian Sperm Cells by Atomic Force Microscopy","volume":"193","author":"Hud","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1093\/molehr\/gap080","article-title":"Function of sperm chromatin structural elements in fertilization and development","volume":"16","author":"Ward","year":"2009","journal-title":"Mol. Hum. Reprod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.bbagrm.2013.08.004","article-title":"Chromatin dynamics during spermiogenesis","volume":"1839","author":"Rathke","year":"2014","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1083\/jcb.93.2.298","article-title":"A model for the structure of chromatin in mammalian sperm","volume":"93","author":"Balhorn","year":"1982","journal-title":"J. Cell Boil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/gb-2007-8-9-227","article-title":"The protamine family of sperm nuclear proteins","volume":"8","author":"Balhorn","year":"2007","journal-title":"Genome Boil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/mrd.10105","article-title":"Protamine 1: Protamine 2 stoichiometry in the sperm of eutherian mammals","volume":"61","author":"Corzett","year":"2002","journal-title":"Mol. Reprod. Dev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/BF01960243","article-title":"Aberrant protamine 1\/protamine 2 ratios in sperm of infertile human males","volume":"44","author":"Balhorn","year":"1988","journal-title":"Experientia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10553","DOI":"10.1016\/S0021-9258(18)82234-7","article-title":"Complete selective absence of protamine P2 in humans","volume":"268","author":"Vanrell","year":"1993","journal-title":"J. Boil. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/mrd.1080340109","article-title":"Human male infertility may be due to a decrease of the protamine P2 content in sperm chromatin","volume":"34","author":"Belokopytova","year":"1993","journal-title":"Mol. Reprod. Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/BF02765830","article-title":"Human protamines and male infertility","volume":"14","author":"Khara","year":"1997","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/molehr\/gag041","article-title":"Decreased protamine-1 transcript levels in testes from infertile men","volume":"9","author":"Steger","year":"2003","journal-title":"Mol. Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1093\/humrep\/deh798","article-title":"Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males","volume":"20","author":"Aoki","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/humupd\/dml009","article-title":"Protamines and male infertility","volume":"12","author":"Oliva","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1111\/andr.12216","article-title":"The impact of sperm protamine deficiency and sperm DNA damage on human male fertility: A systematic review and meta-analysis","volume":"4","author":"Ni","year":"2016","journal-title":"J. Androl."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e142","DOI":"10.1016\/j.fertnstert.2017.07.427","article-title":"Protamines ratio (P1\/P2) in spermatozoa as biomarker for male infertility","volume":"108","author":"Amor","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1093\/humrep\/del114","article-title":"Protamine 2 precursors, protamine 1\/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients","volume":"21","author":"Torregrosa","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.rbmo.2011.08.010","article-title":"Relationships between human sperm protamines, DNA damage and assisted reproduction outcomes","volume":"23","author":"Simon","year":"2011","journal-title":"Reprod. Biomed. Online"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.fertnstert.2010.06.053","article-title":"Protamine 1 to protamine 2 ratio correlates with dynamic aspects of DNA fragmentation in human sperm","volume":"95","author":"Abad","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2164\/jandrol.05063","article-title":"DNA Integrity Is Compromised in Protamine-Deficient Human Sperm","volume":"26","author":"Aoki","year":"2005","journal-title":"J. Androl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"890","DOI":"10.2164\/jandrol.106.000703","article-title":"Protamine Levels Vary Between Individual Sperm Cells of Infertile Human Males and Correlate with Viability and DNA Integrity","volume":"27","author":"Aoki","year":"2006","journal-title":"J. Androl."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.4103\/2277-9175.124666","article-title":"The effects of protamine deficiency on ultrastructure of human sperm nucleus","volume":"3","author":"Iranpour","year":"2014","journal-title":"Adv. Biomed. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/S1472-6483(10)61776-2","article-title":"Effect of protamine-2 deficiency on ICSI outcome","volume":"9","author":"Salehi","year":"2004","journal-title":"Reprod. Biomed. Online"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.fertnstert.2006.04.024","article-title":"Sperm protamine 1\/protamine 2 ratios are related to in vitro fertilization pregnancy rates and predictive of fertilization ability","volume":"86","author":"Aoki","year":"2006","journal-title":"Fertil. Steril."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1093\/humrep\/des471","article-title":"The sperm protamine mRNA ratio as a clinical parameter to estimate the fertilizing potential of men taking part in an ART programme","volume":"28","author":"Rogenhofer","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/ng0501-82","article-title":"Haploinsufficiency of protamine-1 or -2 causes infertility in mice","volume":"28","author":"Cho","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1038\/srep03355","article-title":"Generation of mutant mice by pronuclear injection of circular plasmid expressing Cas9 and single guided RNA","volume":"3","author":"Mashiko","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27409","DOI":"10.1038\/srep27409","article-title":"Viable offspring obtained from Prm1-deficient sperm in mice","volume":"6","author":"Takeda","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep36764","article-title":"Re-visiting the Protamine-2 locus: Deletion, but not haploinsufficiency, renders male mice infertile","volume":"6","author":"Schneider","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13068-019-1522-8","article-title":"Secretomic analyses of Ruminiclostridium papyrosolvens reveal its enzymatic basis for lignocellulose degradation","volume":"12","author":"Ren","year":"2019","journal-title":"Biotechnol. Biofuels"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nmeth.2557","article-title":"The CRAPome: A contaminant repository for affinity purification\u2013mass spectrometry data","volume":"10","author":"Mellacheruvu","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1007\/s13361-016-1460-7","article-title":"Fast and Accurate Protein False Discovery Rates on Large-Scale Proteomics Data Sets with Percolator 3.0","volume":"27","author":"The","year":"2016","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_33","first-page":"D442","article-title":"The PRIDE database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Csordas","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_34","unstructured":"(2012, February 13). The R Project for Statistical Computing. Available online: http:\/\/www.r-project.org\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v025.i01","article-title":"FactoMineR: An RPackage for Multivariate Analysis","volume":"25","author":"Le","year":"2008","journal-title":"J. Stat. Softw."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis, Springer.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nettersheim, D., Heukamp, L.C., Fronhoffs, F., Grewe, M.J., Haas, N., Waha, A., Honecker, F., Waha, A., Kristiansen, G., and Schorle, H. (2013). Analysis of TET Expression\/Activity and 5mC Oxidation during Normal and Malignant Germ Cell Development. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082881"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Weyrich, A. (2012). Preparation of Genomic DNA from Mammalian Sperm. Curr. Protoc. Mol. Boil., 98.","DOI":"10.1002\/0471142727.mb0213s98"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-1-62703-038-0_2","article-title":"Methods of sperm vitality assessment","volume":"927","author":"Moskovtsev","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Skinner, B.M., Rathje, C.C., Bacon, J., Johnson, E.E.P., Larson, E.L., Kopania, E.E.K., Good, J.M., Yousafzai, G., Affara, N.A., and Ellis, P.J. (2018). A high-throughput method for unbiased quantitation and categorisation of nuclear morphology. Biol. Reprod., 312470.","DOI":"10.1101\/312470"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_46","first-page":"002832","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol. BioMed Cent."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1093\/bioinformatics\/bti525","article-title":"BioMart and Bioconductor: A powerful link between biological databases and microarray data analysis","volume":"21","author":"Durinck","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E175","DOI":"10.1073\/pnas.1011698107","article-title":"Reply to Talloen et al.: Independent filtering is a generic approach that needs domain specific adaptation","volume":"107","author":"Bourgon","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D183","DOI":"10.1093\/nar\/gkw1138","article-title":"PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements","volume":"45","author":"Mi","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D649","DOI":"10.1093\/nar\/gkx1132","article-title":"The Reactome Pathway Knowledgebase","volume":"46","author":"Fabregat","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1242\/dev.121.8.2397","article-title":"Mouse oocytes injected with testicular spermatozoa or round spermatids can develop into normal offspring","volume":"121","author":"Kimura","year":"1995","journal-title":"Development"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/nprot.2007.7","article-title":"Piezo-actuated mouse intracytoplasmic sperm injection (ICSI)","volume":"2","author":"Yoshida","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s11248-015-9897-1","article-title":"Blastocyst genotyping for quality control of mouse mutant archives: An ethical and economical approach","volume":"24","author":"Scavizzi","year":"2015","journal-title":"Transgenic Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3533","DOI":"10.1002\/pmic.200500845","article-title":"Proteomic analysis of sperm regions that mediate sperm-egg interactions","volume":"6","author":"Stein","year":"2006","journal-title":"Proteomics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1074\/mcp.M500322-MCP200","article-title":"Proteomic Profiling of Accessory Structures from the Mouse Sperm Flagellum","volume":"5","author":"Cao","year":"2006","journal-title":"Mol. Cell. Proteom."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1002\/pmic.200701020","article-title":"The mouse sperm proteome characterized via IPG strip prefractionation and LC-MS\/MS identification","volume":"8","author":"Baker","year":"2008","journal-title":"Proteomics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/molbev\/msq007","article-title":"Sperm Proteomics Reveals Intensified Selection on Mouse Sperm Membrane and Acrosome Genes","volume":"27","author":"Dorus","year":"2010","journal-title":"Mol. Boil. Evol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1093\/humupd\/dmy017","article-title":"The contribution of human sperm proteins to the development and epigenome of the preimplantation embryo","volume":"24","author":"Castillo","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1095\/biolreprod.108.068882","article-title":"Sorbitol can fuel mouse sperm motility and protein tyrosine phosphorylation via sorbitol dehydrogenase","volume":"80","author":"Cao","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_62","first-page":"635","article-title":"Acrosin, the peculiar sperm-specific serine protease","volume":"87","author":"Klemm","year":"1991","journal-title":"Qual. Life Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17174","DOI":"10.1038\/s41598-017-17488-7","article-title":"Peroxiredoxin activity is a major landmark of male fertility","volume":"7","author":"Ryu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1530\/REP-13-0229","article-title":"Copper-zinc superoxide dismutase deficiency impairs sperm motility and in vivo fertility","volume":"146","author":"Garratt","year":"2013","journal-title":"Reproduction"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.freeradbiomed.2015.02.032","article-title":"Antioxidant cytoprotection by peroxisomal peroxiredoxin-5","volume":"84","author":"Walbrecq","year":"2015","journal-title":"Free Radic. Boil. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1093\/humupd\/dml057","article-title":"Altered protamine expression and diminished spermatogenesis: What is the link?","volume":"13","author":"Carrell","year":"2007","journal-title":"Hum. Reprod. Update"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/humupd\/dmn004","article-title":"Oxidative stress and male infertility\u2014A clinical perspective","volume":"14","author":"Tremellen","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1071\/RD9950659","article-title":"Free radicals, lipid peroxidation and sperm function","volume":"7","author":"Aitken","year":"1995","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.2164\/jandrol.112.016535","article-title":"Reactive Oxygen Species and Sperm Function--In Sickness and In Health","volume":"33","author":"Aitken","year":"2012","journal-title":"J. Androl."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/j.1939-4640.1987.tb00973.x","article-title":"Spontaneous Lipid Peroxidation and Production of Hydrogen Peroxide and Superoxide in Human Spermatozoa Superoxide Dismutase as Major Enzyme Protectant Against Oxygen Toxicity","volume":"8","author":"Alvarez","year":"1987","journal-title":"J. Androl."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1095\/biolreprod.102.015115","article-title":"Protamine 2 Deficiency Leads to Sperm DNA Damage and Embryo Death in Mice1","volume":"69","author":"Cho","year":"2003","journal-title":"Boil. Reprod."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Champroux, A., Damon-Soubeyrand, C., Goubely, C., Bravard, S., Henry-Berger, J., Guiton, R., Saez, F., Drevet, J.R., and Kocer, A. (2018). Nuclear Integrity but Not Topology of Mouse Sperm Chromosome is Affected by Oxidative DNA Damage. Genes, 9.","DOI":"10.3390\/genes9100501"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7765","DOI":"10.1074\/jbc.273.13.7765","article-title":"Reduced Fertility in Female Mice Lacking Copper-Zinc Superoxide Dismutase","volume":"273","author":"Ho","year":"1998","journal-title":"J. Boil. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1095\/biolreprod.112.102129","article-title":"Impaired Fertilizing Ability of Superoxide Dismutase 1-Deficient Mouse Sperm During In Vitro Fertilization1","volume":"87","author":"Tsunoda","year":"2012","journal-title":"Boil. Reprod."},{"key":"ref_75","first-page":"23","article-title":"Evaluation of superoxide dismutase activity and its impact on semen quality parameters of infertile men","volume":"45","author":"Murawski","year":"2007","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10815-014-0215-2","article-title":"Seminal superoxide dismutase activity and its relationship with semen quality and SOD gene polymorphism","volume":"31","author":"Yan","year":"2014","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0968-0004(02)00003-8","article-title":"Structure, mechanism and regulation of peroxiredoxins","volume":"28","author":"Wood","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"ref_78","first-page":"238","article-title":"Hydrogen peroxide modifies human sperm peroxiredoxins in a dose-dependent manner","volume":"84","year":"2010","journal-title":"Boil. Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.2164\/jandrol.111.016162","article-title":"Low Amounts and High Thiol Oxidation of Peroxiredoxins in Spermatozoa from Infertile Men","volume":"33","author":"Gong","year":"2012","journal-title":"J. Androl."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.theriogenology.2005.10.024","article-title":"Nuclear status of immature and mature stallion spermatozoa","volume":"66","author":"Dias","year":"2006","journal-title":"Theriogenology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"19696","DOI":"10.1073\/pnas.0803266105","article-title":"Dynamical roles of metal ions and the disulfide bond in Cu, Zn superoxide dismutase folding and aggregation","volume":"105","author":"Ding","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.freeradbiomed.2009.05.018","article-title":"Regulation of superoxide dismutase genes: Implications in disease","volume":"47","author":"Miao","year":"2009","journal-title":"Free Radic. Boil. Med."},{"key":"ref_83","first-page":"e13624","article-title":"Total antioxidant capacity-Relevance, methods and clinical implications","volume":"2","author":"Gupta","year":"2020","journal-title":"Andrologia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/2051-4190-23-8","article-title":"The immunobiology of the mammalian epididymis: The black box is now open","volume":"23","author":"Guiton","year":"2013","journal-title":"Basic Clin. Androl."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1024\/0300-9831\/a000136","article-title":"Dietary Supplementation of Antioxidants Improves Semen Quality of IVF Patients in Terms of Motility, Sperm Count, and Nuclear Vacuolization","volume":"82","author":"Wirleitner","year":"2012","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.1073\/pnas.97.9.4683","article-title":"Abnormal spermatogenesis and reduced fertility in transition nuclear protein 1-deficient mice","volume":"97","author":"Yu","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/molehr\/7.6.513","article-title":"Teratozoospermia in mice lacking the transition protein 2 (Tnp2)","volume":"7","author":"Adham","year":"2001","journal-title":"Mol. Hum. Reprod."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1093\/humrep\/dei169","article-title":"Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI","volume":"20","author":"Suganuma","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1093\/humrep\/dex224","article-title":"Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content","volume":"32","author":"Rogenhofer","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sarasa, J., Enciso, M., Garc\u00eda, L., Leza, A., Steger, K., and Aizpurua, J. (2020). Comparison of ART outcomes in men with altered mRNA protamine 1\/protamine 2 ratio undergoing intracytoplasmic sperm injection with ejaculated and testicular spermatozoa. Asian J. Androl.","DOI":"10.4103\/aja.aja_146_19"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1093\/bioinformatics\/btm455","article-title":"Idiographica: A general-purpose web application to build idiograms on-demand for human, mouse and rat","volume":"23","author":"Kin","year":"2007","journal-title":"Bioinformatics"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/8\/1789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:52:05Z","timestamp":1760176325000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/8\/1789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,27]]},"references-count":91,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["cells9081789"],"URL":"https:\/\/doi.org\/10.3390\/cells9081789","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.05.05.075929","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,27]]}}}