{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:41:32Z","timestamp":1781509292042,"version":"3.54.1"},"reference-count":106,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Genome instability may play a role in severe cases of male infertility, with disrupted spermatogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed \u201cidiopathic oligo-astheno-teratozoospermia.\u201d We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI\/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, environmental aspects, and lifestyle factors.<\/jats:p>","DOI":"10.3390\/life11070628","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:31:07Z","timestamp":1624941067000},"page":"628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Idiopathic Infertility as a Feature of Genome Instability"],"prefix":"10.3390","volume":"11","author":[{"given":"Agrita","family":"Puzuka","sequence":"first","affiliation":[{"name":"Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"Department of Biology and Microbiology, Riga Stradins University, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiba","family":"Alksere","sequence":"additional","affiliation":[{"name":"Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"EAA Andrology Centre, Clinic IVF-Riga, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-1294","authenticated-orcid":false,"given":"Linda","family":"Gailite","sequence":"additional","affiliation":[{"name":"Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juris","family":"Erenpreiss","sequence":"additional","affiliation":[{"name":"Scientific Laboratory of Molecular Genetics, Riga Stradins University, LV-1007 Riga, Latvia"},{"name":"EAA Andrology Centre, Clinic IVF-Riga, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nieschlag, E., and Behre, H.M. (2001). Scope and Goals of Andrology. Andrology: Male Reproductive Health and Dysfunction, Springer.","DOI":"10.1007\/978-3-662-04491-9"},{"key":"ref_2","first-page":"18","article-title":"Causes of male infertility: A 9-year prospective monocentre study on 1737 patients with reduced total sperm counts","volume":"32","author":"Punab","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1136\/bmj.305.6854.609","article-title":"Evidence for decreasing quality of semen during past 50 years","volume":"305","author":"Carlsen","year":"1992","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1177\/0960327117703690","article-title":"Decline in sperm count in European men during the past 50 years","volume":"37","author":"Sengupta","year":"2017","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1056\/NEJMoa003005","article-title":"Sperm Morphology, Motility, and Concentration in Fertile and Infertile Men","volume":"345","author":"Guzick","year":"2001","journal-title":"New Engl. J. Med."},{"key":"ref_6","first-page":"1059","article-title":"A review of WHO Laboratory Manual for the Examination and Processing of Human Semen (5th edition)]","volume":"17","author":"Cao","year":"2011","journal-title":"Zhonghua Nan Ke Xue"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.fertnstert.2014.09.036","article-title":"Status of sperm morphology assessment: An evaluation of methodology and clinical value","volume":"103","author":"Hendriks","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1007\/s10815-018-1270-x","article-title":"A treatment algorithm for couples with unexplained infertility based on sperm chromatin assessment","volume":"35","author":"Parrella","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1093\/humrep\/14.4.1039","article-title":"Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic","volume":"14","author":"Evenson","year":"1999","journal-title":"Hum. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1093\/humrep\/del326","article-title":"Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome","volume":"22","author":"Bungum","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1093\/humrep\/deh417","article-title":"Toluidine blue cytometry test for sperm DNA conformation: Comparison with the flow cytometric sperm chromatin structure and TUNEL assays","volume":"19","author":"Erenpreiss","year":"2004","journal-title":"Hum. Reprod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1093\/humrep\/dep068","article-title":"Evaluation of male fertility potential by Toluidine Blue test for sperm chromatin structure assessment","volume":"24","author":"Tsarev","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.5653\/cerm.2013.40.1.23","article-title":"The utility of sperm DNA damage assay using toluidine blue and aniline blue staining in routine semen analysis","volume":"40","author":"Kim","year":"2013","journal-title":"Clin. Exp. Reprod. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/j.1939-4640.2001.tb02152.x","article-title":"Comparative study of cytochemical tests for sperm chromatin integrity","volume":"22","author":"Erenpreiss","year":"2001","journal-title":"J. Androl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1745-7262.2006.00112.x","article-title":"Sperm chromatin structure and male fertility: Biological and clinical aspects","volume":"8","author":"Erenpreiss","year":"2006","journal-title":"Asian J. Androl."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.rbmo.2014.10.018","article-title":"The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: A systematic review and meta-analysis","volume":"30","author":"Osman","year":"2015","journal-title":"Reprod. Biomed. Online"},{"key":"ref_17","first-page":"95","article-title":"Evaluation of Sperm Chromatin Integrity Using Aniline Blue and Toluidine Blue Staining in Infertile and Normozoospermic Men","volume":"20","author":"Pourmasumi","year":"2019","journal-title":"J. Reprod. Infertil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1093\/humrep\/del251","article-title":"Sperm DNA fragmentation: Paternal effect on early post-implantation embryo development in ART","volume":"21","author":"Borini","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.fertnstert.2007.04.055","article-title":"Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?","volume":"89","author":"Collins","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.rbmo.2013.06.014","article-title":"The impact of sperm DNA damage in assisted conception and beyond: Recent advances in diagnosis and treatment","volume":"27","author":"Lewis","year":"2013","journal-title":"Reprod. Biomed. Online"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nrg2268","article-title":"Genome instability: A mechanistic view of its causes and consequences","volume":"9","author":"Aguilera","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.tma.2017.09.003","article-title":"Genome instability and aging: Cause or effect?","volume":"1","author":"Vijg","year":"2017","journal-title":"Transl. Med. Aging"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Iourov, I.Y., Vorsanova, S.G., Yurov, Y.B., and Kutsev, S.I. (2019). Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism. Genes, 10.","DOI":"10.3390\/genes10050379"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/aje\/kwp168","article-title":"Good Semen Quality and Life Expectancy: A Cohort Study of 43,277 Men","volume":"170","author":"Jensen","year":"2009","journal-title":"Am. J. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.eururo.2009.03.001","article-title":"Are Infertile Men Less Healthy than Fertile Men? Results of a Prospective Case-Control Survey","volume":"56","author":"Salonia","year":"2009","journal-title":"Eur. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/19396368.2011.635751","article-title":"Emerging evidence for the role of genomic instability in male factor infertility","volume":"58","author":"Aston","year":"2011","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cheung, S., Parrella, A., Rosenwaks, Z., and Palermo, G.D. (2019). Genetic and epigenetic profiling of the infertile male. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214275"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/sj.ejhg.5201956","article-title":"Is the prevalence of Klinefelter syndrome increasing?","volume":"16","author":"Morris","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1159\/000086902","article-title":"Segregation of chromosomes in sperm of Robertsonian translocation carriers","volume":"111","author":"Roux","year":"2005","journal-title":"Cytogenet. Genome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1159\/000086901","article-title":"Segregation of chromosomes in sperm of reciprocal translocation carriers: A review","volume":"111","author":"Benet","year":"2005","journal-title":"Cytogenet. Genome Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1093\/humrep\/dez022","article-title":"A systematic review and standardized clinical validity assessment of male infertility genes","volume":"34","author":"Oud","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1159\/000184715","article-title":"Copy number variation on the human Y chromosome","volume":"123","author":"Jobling","year":"2008","journal-title":"Cytogenet. Genome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/BF03347463","article-title":"The Y chromosome-linked copy number variations and male fertility","volume":"34","author":"Krausz","year":"2011","journal-title":"J. Endocrinol. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/nature01722","article-title":"The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes","volume":"423","author":"Skaletsky","year":"2003","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrg1124","article-title":"The human Y chromosome: An evolutionary marker comes of age","volume":"4","author":"Jobling","year":"2003","journal-title":"Nat. Rev. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2004.06.008","article-title":"Genomic heterogeneity and instability of the AZF locus on the human Y chromosome","volume":"224","author":"Vogt","year":"2004","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.2741\/2032","article-title":"Y chromosome and male infertility: Update, 2006","volume":"11","author":"Krausz","year":"2006","journal-title":"Front. Biosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1046\/j.1365-2605.2003.00402.x","article-title":"The Y chromosome and male fertility and infertility1","volume":"26","author":"Krausz","year":"2003","journal-title":"Int. J. Androl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12958-018-0330-5","article-title":"Genetics of the human Y chromosome and its association with male infertility","volume":"16","author":"Colaco","year":"2018","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrclinonc.2009.237","article-title":"Microsatellite instability in colorectal cancer\u2014The stable evidence","volume":"7","author":"Vilar","year":"2010","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1093\/humrep\/det294","article-title":"Alterations in the frequency of trinucleotide repeat dynamic mutations in offspring conceived through assisted reproductive technology","volume":"28","author":"Zheng","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1365-2605.2007.00791.x","article-title":"The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia","volume":"31","author":"Erenpreiss","year":"2008","journal-title":"Int. J. Androl."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/andr.12344","article-title":"The number of CAG and GGN triplet repeats in the Androgen Receptor gene exert combinatorial effect on hormonal and sperm parameters in young men","volume":"5","author":"Grigorova","year":"2017","journal-title":"Andrology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1101\/gad.1564207","article-title":"Cell- and gene-specific regulation of primary target genes by the androgen receptor","volume":"21","author":"Bolton","year":"2007","journal-title":"Genes Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"40554","DOI":"10.1038\/srep40554","article-title":"Androgen receptor gene polymorphisms and risk of prostate cancer: A meta-analysis","volume":"7","author":"Weng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1056\/NEJMoa1406192","article-title":"X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men","volume":"372","author":"Yatsenko","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.rbmo.2017.12.005","article-title":"A search for molecular mechanisms underlying male idiopathic infertility","volume":"36","author":"Bracke","year":"2018","journal-title":"Reprod. Biomed. Online"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"144778","DOI":"10.1016\/j.gene.2020.144778","article-title":"Multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes: The relationships between genetic variation and litter size in goats","volume":"753","author":"Wang","year":"2020","journal-title":"Gene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/humu.21663","article-title":"Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon","volume":"33","author":"Solyom","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1101\/gr.5826307","article-title":"The evolutionary history of human DNA transposons: Evidence for intense activity in the primate lineage","volume":"17","author":"Pace","year":"2007","journal-title":"Genome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1073\/pnas.93.4.1443","article-title":"Tiggers and DNA transposon fossils in the human genome","volume":"93","author":"Smit","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.mrfmmm.2006.11.021","article-title":"Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity","volume":"616","author":"Hedges","year":"2007","journal-title":"Mutat. Res. Mol. Mech. Mutagen."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-018-1577-z","article-title":"Ten things you should know about transposable elements","volume":"19","author":"Bourque","year":"2018","journal-title":"Genome Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"135","DOI":"10.12688\/f1000research.21018.1","article-title":"Jump around: Transposons in and out of the laboratory","volume":"9","author":"Kumar","year":"2020","journal-title":"F1000Research"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/gm97","article-title":"LINE dancing in the human genome: Transposable elements and disease","volume":"1","author":"Belancio","year":"2009","journal-title":"Genome Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-017-01049-7","article-title":"The emergence of piRNAs against transposon invasion to preserve mammalian genome integrity","volume":"8","author":"Ernst","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-3-030-21664-1_2","article-title":"Age-Dependent De Novo Mutations During Spermatogenesis and Their Consequences","volume":"1166","author":"Cioppi","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Zini, A., and Agarwal, A. (2018). Sperm DNA Damage and Oocyte Repair Capability BT. A Clinician\u2019s Guide to Sperm DNA and Chromatin Damage, Springer International Publishing.","DOI":"10.1007\/978-3-319-71815-6"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Barb\u0103ro\u0219ie, C., Ambar, R., and Finelli, R. (2020). The Impact of Single- and Double-Strand DNA Breaks in Human Spermatozoa on Assisted Reproduction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113882"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1097\/MOU.0b013e32833f1c21","article-title":"DNA mismatch repair and infertility","volume":"20","author":"Mukherjee","year":"2010","journal-title":"Curr. Opin. Urol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e12903","DOI":"10.1111\/and.12903","article-title":"Association between promoter methylation of MLH1 and MSH2 and reactive oxygen species in oligozoospermic men-A pilot study","volume":"50","author":"Gunes","year":"2018","journal-title":"Andrology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/iji.12448","article-title":"The association of four SNPs in DNA mismatch repair genes with idiopathic male infertility in northwest China","volume":"46","author":"Zhao","year":"2019","journal-title":"Int. J. Immunogenet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMra012242","article-title":"Hereditary Colorectal Cancer","volume":"348","author":"Lynch","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0079-6603(06)81005-6","article-title":"Repair of Topoisomerase I-Mediated DNA Damage","volume":"81","author":"Pommier","year":"2006","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3389\/fmolb.2019.00141","article-title":"DNA Double Strand Breaks and Chromosomal Translocations Induced by DNA Topoisomerase II","volume":"6","year":"2019","journal-title":"Front. Mol. Biosci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Mavragani, I.V., Nikitaki, Z., Kalospyros, S.A., and Georgakilas, A.G. (2019). Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance. Cancers, 11.","DOI":"10.3390\/cancers11111789"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"129","DOI":"10.2174\/138920207780368141","article-title":"The Human Pseudoautosomal Region (PAR): Origin, Function and Future","volume":"8","author":"Morris","year":"2007","journal-title":"Curr. Genom."},{"key":"ref_68","first-page":"426","article-title":"Ensuring meiotic DNA break formation in the mouse pseudoautosomal region","volume":"582","author":"Acquaviva","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1038\/s41418-020-0493-4","article-title":"NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis","volume":"27","author":"Zhang","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1080\/0886022X.2016.1274661","article-title":"The SPO11-C631T gene polymorphism and male infertility risk: A meta-analysis","volume":"39","author":"Ren","year":"2017","journal-title":"Ren. Fail."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/biolre\/ioz089","article-title":"A segregating human allele of SPO11 modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve\u2020","volume":"101","author":"Tran","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ribas-Maynou, J., Garc\u00eda-Peir\u00f3, A., Fernandez-Encinas, A., Amengual, M.J., Prada, E., Cort\u00e9s, P., Navarro, J., and Benet, J. (2012). Double Stranded Sperm DNA Breaks, Measured by Comet Assay, Are Associated with Unexplained Recurrent Miscarriage in Couples without a Female Factor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044679"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Zeng, Y., and Chen, T. (2019). DNA Methylation Reprogramming during Mammalian Development. Genes, 10.","DOI":"10.3390\/genes10040257"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nm.1924","article-title":"Chromosome instability is common in human cleavage-stage embryos","volume":"15","author":"Vanneste","year":"2009","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Cav\u00e9, T., Desmarais, R., Lacombe-Burgoyne, C., and Boissonneault, G. (2019). Genetic Instability and Chromatin Remodeling in Spermatids. Genes, 10.","DOI":"10.3390\/genes10010040"},{"key":"ref_76","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 (BBA) Bioenerg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1073\/pnas.0406060102","article-title":"Polar nuclear localization of H1T2, a histone H1 variant, required for spermatid elongation and DNA condensation during spermiogenesis","volume":"102","author":"Martiyanov","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1530\/REP-16-0586","article-title":"Expression patterns of HENMT1 and PIWIL1 in human testis: Implications for transposon expression","volume":"154","author":"Hempfling","year":"2017","journal-title":"Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1093\/humupd\/dmt031","article-title":"The presence, role and clinical use of spermatozoal RNAs","volume":"19","author":"Jodar","year":"2013","journal-title":"Hum. Reprod. Updat."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1080\/19396368.2017.1374488","article-title":"Polymorphisms of DNA repair genes XRCC1 and LIG4 and idiopathic male infertility","volume":"63","author":"Ghasemi","year":"2017","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1083\/jcb.201708092","article-title":"Senescence and aging: Causes, consequences, and therapeutic avenues","volume":"217","author":"McHugh","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.fertnstert.2020.03.028","article-title":"Relationships between the age of 25,445 men attending infertility clinics and sperm chromatin structure assay (SCSA\u00ae) defined sperm DNA and chromatin integrity","volume":"114","author":"Evenson","year":"2020","journal-title":"Fertil. Steril."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/19396368.2018.1557762","article-title":"The relationship among sperm global DNA methylation, telomere length, and DNA fragmentation in varicocele: A cross-sectional study of 20 cases","volume":"65","author":"Santana","year":"2019","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1447-0594.2012.00913.x","article-title":"Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey","volume":"13","author":"Takemoto","year":"2013","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.arr.2016.03.002","article-title":"Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions","volume":"33","author":"Oshima","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Shimamoto, A., Yokote, K., and Tahara, H. (2015). Werner Syndrome-specific induced pluripotent stem cells: Recovery of telomere function by reprogramming. Front. Genet., 6.","DOI":"10.3389\/fgene.2015.00010"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"13785","DOI":"10.1038\/ncomms13785","article-title":"WRN regulates pathway choice between classical and alternative non-homologous end joining","volume":"7","author":"Shamanna","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1093\/carcin\/bgg034","article-title":"Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process","volume":"24","author":"Opresko","year":"2003","journal-title":"Carcinogenesis"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8302","DOI":"10.1073\/pnas.88.19.8302","article-title":"Physical map of human Xq27-qter: Localizing the region of the fragile X mutation","volume":"88","author":"Poustka","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10333","DOI":"10.1093\/nar\/gkx780","article-title":"Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis","volume":"45","author":"Tashiro","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molmet.2018.02.006","article-title":"Sperm epigenetics and influence of environmental factors","volume":"14","author":"Donkin","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Kumar, D., Salian, S.R., Kalthur, G., Uppangala, S., Kumari, S., Challapalli, S., Chandraguthi, S.G., Krishnamurthy, H., Jain, N., and Kumar, P. (2013). Semen Abnormalities, Sperm DNA Damage and Global Hypermethylation in Health Workers Occupationally Exposed to Ionizing Radiation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069927"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zhang, W., Li, M., Sun, F., Xu, X., Zhang, Z., Liu, J., Sun, X., Zhang, A., Shen, Y., and Xu, J. (2019). Association of Sperm Methylation at LINE-1, Four Candidate Genes, and Nicotine\/Alcohol Exposure With the Risk of Infertility. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.01001"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e12818","DOI":"10.1111\/and.12818","article-title":"Cigarette smoking induces only marginal changes in sperm DNA methylation levels of patients undergoing intracytoplasmic sperm injection treatment","volume":"50","author":"Tierling","year":"2018","journal-title":"Andrology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/j.molp.2016.04.015","article-title":"DNA Damage-Induced Transcription of Transposable Elements and Long Non-coding RNAs in Arabidopsis Is Rare and ATM-Dependent","volume":"9","author":"Wang","year":"2016","journal-title":"Mol. Plant"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.fertnstert.2016.12.027","article-title":"Retrotransposon expression and incorporation of cloned human and mouse retroelements in human spermatozoa","volume":"107","author":"Lazaros","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1534\/g3.119.400613","article-title":"Restriction Enzyme Based Enriched L1Hs Sequencing (REBELseq): A Scalable Technique for Detection of Ta Subfamily L1Hs in the Human Genome","volume":"10","author":"Reiner","year":"2020","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/tpj.14546","article-title":"\u00c1vila; Nov\u00e1k, P.; Kobl\u00ed\u017ekov\u00e1, A.; Neumann, P.; Macas, J. Characterization of repeat arrays in ultra-long nanopore reads reveals frequent origin of satellite DNA from retrotransposon-derived tandem repeats","volume":"101","author":"Vondrak","year":"2019","journal-title":"Plant J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"163","DOI":"10.21037\/tp.2020.03.06","article-title":"The third generation sequencing: The advanced approach to genetic diseases","volume":"9","author":"Xiao","year":"2020","journal-title":"Transl. Pediatr."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ygeno.2015.11.003","article-title":"The sequence of sequencers: The history of sequencing DNA","volume":"107","author":"Heather","year":"2016","journal-title":"Genomics"},{"key":"ref_101","first-page":"1","article-title":"Microsatellite instability testing in colorectal cancer using the QiaXcel advanced platform","volume":"18","author":"Brockmann","year":"2018","journal-title":"BMC Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1373\/clinchem.2014.223677","article-title":"Microsatellite Instability Detection by Next Generation Sequencing","volume":"60","author":"Salipante","year":"2014","journal-title":"Clin. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Cellerino, A., and Sanguanini, M. (2018). Next-generation RNA sequencing. Transcriptome Analysis, Springer.","DOI":"10.1007\/978-88-7642-642-1"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fgene.2013.00131","article-title":"Micronuclei in genotoxicity assessment: From genetics to epigenetics and beyond","volume":"4","author":"Luzhna","year":"2013","journal-title":"Front. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/mutage\/gex010","article-title":"The OECD\u2019s micronucleus test guideline for single exposure to an agent and the genotox-kinetic alternative","volume":"32","year":"2017","journal-title":"Mutagenesis"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/(SICI)1098-2280(2000)35:3<206::AID-EM8>3.0.CO;2-J","article-title":"Single cell gel\/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing","volume":"35","author":"Tice","year":"2000","journal-title":"Environ. Mol. Mutagen."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/628\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:30Z","timestamp":1760163990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":106,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["life11070628"],"URL":"https:\/\/doi.org\/10.3390\/life11070628","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,29]]}}}