{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:12:39Z","timestamp":1760148759635,"version":"build-2065373602"},"reference-count":70,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T00:00:00Z","timestamp":1685145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PHS","award":["NIH\/NIEHS2SO6GMO8037-28 &-32","NIH\/NIMHD G12RRO3032","NIH\/R01 HD020419-19S1"],"award-info":[{"award-number":["NIH\/NIEHS2SO6GMO8037-28 &-32","NIH\/NIMHD G12RRO3032","NIH\/R01 HD020419-19S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anemia, induces hypogonadism in males. However, the impact of HU on testicular architecture and function, as well as its effects on the resumption of male fertility following treatment withdrawal, remain poorly understood. We used adult male mice to determine whether HU-induced hypogonadism is reversible. Fertility indices of mice treated with HU daily for ~1 sperm cycle (2 months) were compared with those of their control counterparts. All indices of fertility were significantly reduced among mice treated with HU compared to controls. Interestingly, significant improvements in fertility indices were apparent after a 4-month withdrawal from HU treatment (testis weight: month 1 post-HU withdrawal (M1): HU, 0.09 \u00b1 0.01 vs. control, 0.33 \u00b1 0.03; M4: HU, 0.26 \u00b1 0.03 vs. control, 0.37 \u00b1 0.04 g); sperm motility (M1: HU,12 vs. 59; M4: HU, 45 vs. control, 61%; sperm density (M1: HU, 1.3 \u00b1 0.3 vs. control, 15.7 \u00b1 0.9; M4: HU, 8.1 \u00b1 2.5 vs. control, 16.8 \u00b1 1.9 million). Further, circulating testosterone increased in the 4th month following HU withdrawal and was comparable to that of controls. When a mating experiment was conducted, recovering males sired viable offspring with untreated females albeit at a lower rate than control males (p &lt; 0.05); therefore, qualifying HU as a potential candidate for male contraception.<\/jats:p>","DOI":"10.3390\/ijms24119374","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T16:19:37Z","timestamp":1685204377000},"page":"9374","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Resumption of Spermatogenesis and Fertility Post Withdrawal of Hydroxyurea Treatment"],"prefix":"10.3390","volume":"24","author":[{"given":"Carlos","family":"Virgous","sequence":"first","affiliation":[{"name":"Animal Care Facility, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37209, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Letitia","family":"Lyons","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-794X","authenticated-orcid":false,"given":"Amos","family":"Sakwe","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tultul","family":"Nayyar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shawn","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Hildreth","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Physiology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Osteen","sequence":"additional","affiliation":[{"name":"Women\u2019s Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaylon","family":"Bruner-Tran","sequence":"additional","affiliation":[{"name":"Women\u2019s Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oluwatobi","family":"Alawode","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phillip","family":"Bourne","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward Richard","family":"Hills","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony E.","family":"Archibong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"},{"name":"Department of Microbiology, Immunology and Physiology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,27]]},"reference":[{"key":"ref_1","first-page":"172","article-title":"Hydroxyurea: An overview","volume":"13","author":"Stevens","year":"1999","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1534\/genetics.116.191536","article-title":"Hydroxyurea Induces Cytokinesis Arrest in Cells Expressing a Mutated Sterol-14alpha-Demethylase in the Ergosterol Biosynthesis Pathway","volume":"204","author":"Xu","year":"2016","journal-title":"Genetics"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Singh, A., and Xu, Y.J. (2016). The Cell Killing Mechanisms of Hydroxyurea. Genes, 7.","DOI":"10.3390\/genes7110099"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fcimb.2014.00052","article-title":"Ribonucleotide reductases: Essential enzymes for bacterial life","volume":"4","author":"Torrents","year":"2014","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJM199505183322001","article-title":"Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia","volume":"332","author":"Charache","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/bdrb.20123","article-title":"NTP-CERHR expert panel report on the reproductive and developmental toxicity of hydroxyurea","volume":"80","author":"Liebelt","year":"2007","journal-title":"Birth. Defects. Res. B Dev. Reprod. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1590\/S0100-879X2003000100009","article-title":"Effect of hydroxyurea on the intracellular multiplication of Toxoplasma gondii, Leishmania amazonensis and Trypanosoma cruzi","volume":"36","author":"Melo","year":"2003","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1016\/S0021-9258(19)45166-1","article-title":"Electron spin resonance of the iron-containing protein B2 from ribonucleotide reductase","volume":"247","author":"Ehrenberg","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_9","first-page":"1559","article-title":"Inhibition of ribonucleoside diphosphate reductase by hydroxyurea","volume":"28","author":"Krakoff","year":"1968","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1146\/annurev.biochem.75.103004.142443","article-title":"Ribonucleotide reductases","volume":"75","author":"Nordlund","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e0017121","DOI":"10.1128\/JB.00171-21","article-title":"Hydroxyurea Induces a Stress Response That Alters DNA Replication and Nucleotide Metabolism in Bacillus subtilis","volume":"203","author":"Wozniak","year":"2021","journal-title":"J. Bacteriol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.mehy.2010.08.023","article-title":"Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications","volume":"76","author":"Kovacic","year":"2011","journal-title":"Med. Hypotheses"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7753857","DOI":"10.1155\/2021\/7753857","article-title":"Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?","volume":"2021","author":"Kapor","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1111\/j.1349-7006.1997.tb00349.x","article-title":"Nitric oxide generation from hydroxyurea via copper-catalyzed peroxidation and implications for pharmacological actions of hydroxyurea","volume":"88","author":"Sato","year":"1997","journal-title":"Jpn J. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/asheducation-2006.1.58","article-title":"Induction of fetal hemoglobin in the treatment of sickle cell disease","volume":"2006","author":"Fathallah","year":"2006","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3390\/ijerph6031124","article-title":"Adverse effects of a clinically relevant dose of hydroxyurea used for the treatment of sickle cell disease on male fertility endpoints","volume":"6","author":"Jones","year":"2009","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.3390\/ijerph7052033","article-title":"Perturbation of the developmental potential of preimplantation mouse embryos by hydroxyurea","volume":"7","author":"Sampson","year":"2010","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1006\/taap.1998.8593","article-title":"Involvement of germ cell apoptosis in the induction of testicular toxicity following hydroxyurea treatment","volume":"155","author":"Shin","year":"1999","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1182\/blood-2017-03-771857","article-title":"Adverse effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after 6 months of treatment","volume":"130","author":"Berthaut","year":"2017","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"988","DOI":"10.3324\/haematol.11515","article-title":"Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males","volume":"93","author":"Berthaut","year":"2008","journal-title":"Haematologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1445-5994.2006.01290.x","article-title":"Effect of hydroxyurea on sperm count, motility and morphology in adult men with sickle cell or myeloproliferative disease","volume":"37","author":"Grigg","year":"2007","journal-title":"Intern. Med. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/aja.2013.73","article-title":"Cistanche deserticola decoction alleviates the testicular toxicity induced by hydroxyurea in male mice","volume":"15","author":"Gu","year":"2013","journal-title":"Asian J. Androl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0890-6238(94)00052-X","article-title":"Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice","volume":"9","author":"Wiger","year":"1995","journal-title":"Reprod. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1172\/JCI200316672","article-title":"Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase","volume":"111","author":"Cokic","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1038\/s41598-022-06700-y","article-title":"Expression of genes and localization of enzymes involved in polyunsaturated fatty acid synthesis in rabbit testis and epididymis","volume":"12","author":"Castellini","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1093\/humrep\/der132","article-title":"The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy","volume":"26","author":"Gharagozloo","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3583684","DOI":"10.1155\/2016\/3583684","article-title":"In Vitro Anti-Inflammatory Effects of Three Fatty Acids from Royal Jelly","volume":"2016","author":"Chen","year":"2016","journal-title":"Mediators Inflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"425261","DOI":"10.1155\/2015\/425261","article-title":"10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling","volume":"2015","author":"Honda","year":"2015","journal-title":"J. Aging Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21524","DOI":"10.1007\/s11356-019-05521-3","article-title":"Attenuation potentials of royal jelly against hydroxyurea-induced infertility through inhibiting oxidation and release of pro-inflammatory cytokines in male rats","volume":"26","author":"Tohamy","year":"2019","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1042\/cs0920481","article-title":"Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia","volume":"92","author":"Hackney","year":"1997","journal-title":"Clin. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.scr.2018.04.009","article-title":"Spermatogonial stem cells and spermatogenesis in mice, monkeys and men","volume":"29","author":"Fayomi","year":"2018","journal-title":"Stem. Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.5487\/TR.2017.33.2.107","article-title":"Development of a Test Method for the Evaluation of DNA Damage in Mouse Spermatogonial Stem Cells","volume":"33","author":"Jeon","year":"2017","journal-title":"Toxicol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1046\/j.1464-410X.1998.00503.x","article-title":"Leydig cell hyperplasia","volume":"81","author":"Naughton","year":"1998","journal-title":"Br. J. Urol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0090-4295(96)00222-1","article-title":"Leydig cell hyperplasia mimicking testicular neoplasm","volume":"48","author":"Olumi","year":"1996","journal-title":"Urology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1067\/mpd.2001.114477","article-title":"Nodular Leydig cell hyperplasia in a boy with familial male-limited precocious puberty","volume":"138","author":"Leschek","year":"2001","journal-title":"J. Pediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111432","DOI":"10.1016\/j.ecoenv.2020.111432","article-title":"Exposure to di-n-octyl phthalate during puberty induces hypergonadotropic hypogonadism caused by Leydig cell hyperplasia but reduced steroidogenic function in male rats","volume":"208","author":"Zhu","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.reprotox.2004.11.011","article-title":"The inhibitory effects of polychlorinated biphenyl Aroclor 1254 on Leydig cell LH receptors, steroidogenic enzymes and antioxidant enzymes in adult rats","volume":"20","author":"Murugesan","year":"2005","journal-title":"Reprod. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1210\/jcem.86.11.8031","article-title":"Importance of inhibin B in the regulation of FSH secretion in the human male","volume":"86","author":"Hayes","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2174\/1874091X01812010103","article-title":"Testosterone Retention Mechanism in Sertoli Cells: A Biochemical Perspective","volume":"12","year":"2018","journal-title":"Open Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1210\/mend-4-2-349","article-title":"Follicle-stimulating hormone regulation of androgen-binding protein messenger RNA in sertoli cell cultures","volume":"4","author":"Hall","year":"1990","journal-title":"Mol. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fendo.2019.00224","article-title":"Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation","volume":"10","author":"Meroni","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s12288-013-0261-4","article-title":"Hydroxyurea in sickle cell disease: Drug review","volume":"30","author":"Agrawal","year":"2014","journal-title":"Indian J. Hematol. Blood Transfus."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1477-7827-12-33","article-title":"Characterizing semen parameters and their association with reactive oxygen species in infertile men","volume":"12","author":"Agarwal","year":"2014","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3390\/ijerph5010032","article-title":"Effects of benzo(a)pyrene on intra-testicular function in F-344 rats","volume":"5","author":"Archibong","year":"2008","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1677\/JOE-06-0136","article-title":"The effect of testosterone, dihydrotestosterone and oestradiol on the re-initiation of spermatogenesis in the adult photoinhibited Djungarian hamster","volume":"192","author":"Meachem","year":"2007","journal-title":"J. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1006\/scdb.1998.0253","article-title":"Spermatogenesis: Its regulation by testosterone and FSH","volume":"9","author":"Zirkin","year":"1998","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"bqaa092","DOI":"10.1210\/endocr\/bqaa092","article-title":"Testosterone Supplementation Rescues Spermatogenesis and In Vitro Fertilizing Ability of Sperm in Kiss1 Knockout Mice","volume":"161","author":"Goto","year":"2020","journal-title":"Endocrinology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1210\/edrv-9-1-3","article-title":"Contemporary aspects of discrete peak-detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men","volume":"9","author":"Urban","year":"1988","journal-title":"Endocr. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/humupd\/dmn004","article-title":"Oxidative stress and male infertility--a clinical perspective","volume":"14","author":"Tremellen","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.4103\/iju.IJU_15_17","article-title":"Antioxidant therapy in idiopathic oligoasthenoteratozoospermia","volume":"33","author":"Majzoub","year":"2017","journal-title":"Indian J. Urol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/j.1439-0531.2006.00785.x","article-title":"Multivariate cluster analysis regression procedures as tools to identify motile sperm subpopulations in rabbit semen and to predict semen fertility and litter size","volume":"42","author":"Rigau","year":"2007","journal-title":"Reprod. Domest. Anim."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1590\/S1677-55382007000500002","article-title":"Clinical relevance of oxidative stress and sperm chromatin damage in male infertility: An evidence based analysis","volume":"33","author":"Cocuzza","year":"2007","journal-title":"Int. Braz. J. Urol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/humrep\/10.suppl_1.15","article-title":"Impact of reactive oxygen species on spermatozoa: A balancing act between beneficial and detrimental effects","volume":"10","author":"Gagnon","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1530\/jrf.0.1030017","article-title":"Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa","volume":"103","author":"Griveau","year":"1995","journal-title":"J. Reprod. Fertil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.theriogenology.2012.05.002","article-title":"Effects of reactive oxygen species on sperm function","volume":"78","author":"Guthrie","year":"2012","journal-title":"Theriogenology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.aju.2017.11.001","article-title":"Role of reactive oxygen species in male infertility: An updated review of literature","volume":"16","author":"Wagner","year":"2018","journal-title":"Arab. J. Urol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/bdrc.20040","article-title":"Mechanisms and consequences of paternally-transmitted chromosomal abnormalities","volume":"75","author":"Marchetti","year":"2005","journal-title":"Birth. Defects. Res. C Embryo. Today"},{"key":"ref_58","first-page":"75","article-title":"The Possibility of Increasing Oocyte Capacity to Repair Sperm DNA Fragmentation","volume":"22","author":"Sadeghi","year":"2021","journal-title":"J. Reprod. Infertil."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"263","DOI":"10.59566\/IJBS.2011.7263","article-title":"Mutagenic and genotoxic effect of hydroxyurea","volume":"7","author":"Santos","year":"2011","journal-title":"Int. J. Biomed. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/35002510","article-title":"Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA","volume":"403","author":"Bruner","year":"2000","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4689","DOI":"10.1038\/srep04689","article-title":"8-oxoguanine causes spontaneous de novo germline mutations in mice","volume":"4","author":"Ohno","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/j.1601-5223.2009.02131.x","article-title":"A mutation in the Kit gene leads to novel gonadal phenotypes in both heterozygous and homozygous mice","volume":"147","author":"Wu","year":"2010","journal-title":"Hereditas"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Lane, M., McPherson, N.O., Fullston, T., Spillane, M., Sandeman, L., Kang, W.X., and Zander-Fox, D.L. (2014). Oxidative stress in mouse sperm impairs embryo development, fetal growth and alters adiposity and glucose regulation in female offspring. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100832"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1262\/jrd.11-138N","article-title":"Oxidative stress and redox regulation on in vitro development of mammalian embryos","volume":"58","author":"Takahashi","year":"2012","journal-title":"J. Reprod. Dev."},{"key":"ref_65","first-page":"2074","article-title":"Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice","volume":"119","author":"Chabory","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.yfrne.2007.09.001","article-title":"Reflexive testosterone release: A model system for studying the nongenomic effects of testosterone upon male behavior","volume":"29","author":"Nyby","year":"2008","journal-title":"Front. Neuroendocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1006\/faat.1993.1102","article-title":"Optimization of the Hamilton-Thorn computerized sperm motility analysis system for use with rat spermatozoa in toxicological studies","volume":"21","author":"Slott","year":"1993","journal-title":"Fundam. Appl. Toxicol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/S0015-0282(01)02890-4","article-title":"Male partner screening before in vitro fertilization: Preselecting patients who require intracytoplasmic sperm injection with the sperm penetration assay","volume":"76","author":"Freeman","year":"2001","journal-title":"Fertil. Steril."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0890-6238(92)90183-T","article-title":"Methods for assessing rat sperm motility","volume":"6","author":"Chapin","year":"1992","journal-title":"Reprod. Toxicol."},{"key":"ref_70","first-page":"663","article-title":"Timing of induced ovulation in C.B-17\/Icr-scid\/scid and B6SJLF1 mice","volume":"46","author":"Masters","year":"1996","journal-title":"Lab. Anim. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9374\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:43:34Z","timestamp":1760125414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,27]]},"references-count":70,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119374"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119374","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,5,27]]}}}