{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:05:39Z","timestamp":1790373939868,"version":"4.1.0"},"reference-count":103,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Advanced paternal age is associated with increased sperm reactive oxygen species (ROS) and decreased fertilization and pregnancy rates. Sperm washing during infertility treatment provides an opportunity to reduce high sperm ROS concentrations associated with advanced paternal age through the addition of idebenone. Sperm from men aged &gt;40 years and older CBAF1 mice (12\u201318 months), were treated with 5 \u00b5M and 50 \u00b5M of idebenone and intracellular and superoxide ROS concentrations assessed. Following in vitro fertilization (IVF), embryo development, blastocyst differentiation, DNA damage and cryosurvival, pregnancy and implantation rates and fetal and placental weights were assessed. Five \u00b5M of idebenone given to aged human and mouse sperm reduced superoxide concentrations ~20% (p &lt; 0.05), while both 5 and 50 \u00b5M reduced sperm intracellular ROS concentrations in mice ~30% (p &lt; 0.05). Following IVF, 5 \u00b5M of idebenone to aged sperm increased fertilization rates (65% vs. 60%, p &lt; 0.05), blastocyst total, trophectoderm and inner cell mass cell numbers (73 vs. 66, 53 vs. 47 and 27 vs. 24, respectively, p &lt; 0.01). Treatment with idebenone also increased blastocyst cryosurvival rates (96% vs. 78%, p &lt; 0.01) and implantation rates following embryo transfer (35% vs. 18%, p &lt; 0.01). Placental weights were smaller (107 mg vs. 138 mg, p &lt; 0.05), resulting in a larger fetal to placental weight ratio (8.3 vs. 6.3, p = 0.07) after sperm idebenone treatment. Increased sperm ROS concentrations associated with advanced paternal age are reduced with the addition of idebenone in vitro, and are associated with improved fertilization rates, embryo quality and implantation rates after IVF.<\/jats:p>","DOI":"10.3390\/antiox10071079","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T22:02:04Z","timestamp":1625522524000},"page":"1079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Improving Sperm Oxidative Stress and Embryo Quality in Advanced Paternal Age Using Idebenone In Vitro\u2014A Proof-of-Concept Study"],"prefix":"10.3390","volume":"10","author":[{"given":"Victoria","family":"Nikitaras","sequence":"first","affiliation":[{"name":"Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Adelaide Health and Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre","family":"Zander-Fox","sequence":"additional","affiliation":[{"name":"Adelaide Health and Medical School, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Repromed, Dulwich, SA 5065, Australia"},{"name":"Department of Bioengineering, University of South Australia, Adelaide, SA 5072, Australia"},{"name":"Monash University, Clayton, VIC 3800, Australia"},{"name":"Monash IVF Group, Richmond, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-9403","authenticated-orcid":false,"given":"Nicole O.","family":"McPherson","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Adelaide Health and Medical School, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.fertnstert.2013.04.015","article-title":"Effects of combined antioxidant supplementation on human sperm motility and morphology during sperm manipulation in vitro","volume":"100","author":"Yun","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S0967199419000030","article-title":"What are the effects of vitamin c on sperm functional properties during direct swim-up procedure?","volume":"27","author":"Raad","year":"2019","journal-title":"Zygote"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E521","DOI":"10.1208\/aapsj080362","article-title":"Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents","volume":"8","author":"Szeto","year":"2006","journal-title":"AAPS J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1093\/humrep\/dex330","article-title":"Antioxidants improve ivf outcome and subsequent embryo development in the mouse","volume":"32","author":"Truong","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.redox.2015.01.009","article-title":"Border between natural product and drug: Comparison of the related benzoquinones idebenone and coenzyme q10","volume":"4","author":"Gueven","year":"2015","journal-title":"Redox Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101812","DOI":"10.1016\/j.redox.2020.101812","article-title":"Idebenone: When an antioxidant is not an antioxidant","volume":"38","author":"Gueven","year":"2021","journal-title":"Redox Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1021\/tx970136j","article-title":"Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone)","volume":"11","author":"Mordente","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1159\/000381726","article-title":"Idebenone prevents oxidative stress, cell death and senescence of retinal pigment epithelium cells by stabilizing bax\/bcl-2 ratio","volume":"234","author":"Arend","year":"2015","journal-title":"Ophthalmologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.bbrc.2015.08.058","article-title":"Idebenone protects against oxidized low density lipoprotein induced mitochondrial dysfunction in vascular endothelial cells via gsk3\u03b2\/\u03b2-catenin signalling pathways","volume":"465","author":"Lin","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1006\/bbrc.1998.8563","article-title":"The protective effect of vitamin e, idebenone and reduced glutathione on free radical mediated injury in rat brain synaptosomes","volume":"246","author":"Cardoso","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1093\/humrep\/deaa159","article-title":"DNA fragmentation of sperm: A radical examination of the contribution of oxidative stress and age in 16 945 semen samples","volume":"35","author":"Vaughan","year":"2020","journal-title":"Hum. Reprod."},{"key":"ref_12","unstructured":"WHO (2010). Who Laboratory Manual for the Examination and Processing of Human Semen, Cambridge University Press. [5th ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0021-5198(19)38088-6","article-title":"Inhibition of lipid peroxidation by a novel compound, idebenone (cv-2619)","volume":"35","author":"Suno","year":"1984","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0167-4943(89)90011-3","article-title":"Inhibition of brain mitochondrial swelling by idebenone","volume":"8","author":"Suno","year":"1989","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1111\/j.1365-2605.2010.01092.x","article-title":"The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model","volume":"34","author":"Bakos","year":"2011","journal-title":"Int. J. Androl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.freeradbiomed.2009.10.033","article-title":"Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa","volume":"48","author":"Koppers","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gardner, D.K., Lane, M., and Watson, A.J. (2004). A Laboratory Guide to the Mammalian Embryo, Oxford University Press USA\u2014OSO.","DOI":"10.1093\/oso\/9780195142266.001.0001"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/pd.5402","article-title":"Advanced paternal age, infertility, and reproductive risks: A review of the literature","volume":"39","author":"Brandt","year":"2019","journal-title":"Prenat. Diagn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s10815-017-1054-8","article-title":"Combined advanced parental age has an additive negative effect on live birth rates-data from 4057 first ivf\/icsi cycles","volume":"35","author":"McPherson","year":"2018","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.repbio.2018.11.002","article-title":"The relationship between sperm DNA fragmentation, free radicals and antioxidant capacity with idiopathic repeated pregnancy loss","volume":"18","author":"Kamkar","year":"2018","journal-title":"Reprod. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cissen, M., Wely, M.V., Scholten, I., Mansell, S., Bruin, J.P., Mol, B.W., Braat, D., Repping, S., and Hamer, G. (2016). Measuring sperm DNA fragmentation and clinical outcomes of medically assisted reproduction: A systematic review and meta-analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165125"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Montenegro, L., Turnaturi, R., Parenti, C., and Pasquinucci, L. (2018). Idebenone: Novel strategies to improve its systemic and local efficacy. Nanomaterials, 8.","DOI":"10.3390\/nano8020087"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.bbrc.2005.11.035","article-title":"Inhibition of glycerophosphate-dependent h2o2 generation in brown fat mitochondria by idebenone","volume":"339","author":"Bergamini","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/0006-291X(84)91389-5","article-title":"Inhibition of lipid peroxidation by a novel compound (cv-2619) in brain mitochondria and mode of action of the inhibition","volume":"125","author":"Suno","year":"1984","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12958-020-00668-y","article-title":"Advanced paternal age: Effects on sperm parameters, assisted reproduction outcomes and offspring health","volume":"18","author":"Halvaei","year":"2020","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.freeradbiomed.2016.11.032","article-title":"4-hydroxynonenal-mediated signaling and aging","volume":"111","author":"Zhang","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","first-page":"91","article-title":"Proteolytic degradation of heat shock protein a2 occurs in response to oxidative stress in male germ cells of the mouse","volume":"23","author":"Bromfield","year":"2017","journal-title":"Mol. Hum. Reprod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1093\/humrep\/dev214","article-title":"The impact of oxidative stress on chaperone-mediated human sperm-egg interaction","volume":"30","author":"Bromfield","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1439-0272.2012.01315.x","article-title":"Evaluation of hspa2 in fertile and infertile individuals","volume":"45","author":"Motiei","year":"2012","journal-title":"Andrologia"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Haefeli, R.H., Erb, M., Gemperli, A.C., Robay, D., Courdier Fruh, I., Anklin, C., Dallmann, R., and Gueven, N. (2011). Nqo1-dependent redox cycling of idebenone: Effects on cellular redox potential and energy levels. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017963"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3109\/01485019208987691","article-title":"Nadh-dependent oxidoreductase (diaphorase) activity and isozyme pattern of sperm in infertile men","volume":"28","author":"Gavella","year":"1992","journal-title":"Arch. Androl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/1479-7364-2-5-329","article-title":"Update of the nad(p)h:Quinone oxidoreductase (nqo) gene family","volume":"2","author":"Vasiliou","year":"2006","journal-title":"Hum. Genom."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1126\/science.3851","article-title":"Sperm diaphorase: Genetic polymorphism of a sperm-specific enzyme in man","volume":"191","author":"Caldwell","year":"1976","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Heitz, F.D., Erb, M., Anklin, C., Robay, D., Pernet, V., and Gueven, N. (2012). Idebenone protects against retinal damage and loss of vision in a mouse model of leber\u2019s hereditary optic neuropathy. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045182"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.molcel.2016.01.028","article-title":"The mitochondrial basis of aging","volume":"61","author":"Sun","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jevs.2016.10.015","article-title":"Sperm mitochondrial function is affected by stallion age and predicts post-thaw motility","volume":"50","author":"Darr","year":"2017","journal-title":"J. Equine Vet. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2174\/1874609810902030165","article-title":"Aging, mitochondria and male reproductive function","volume":"2","author":"Amaral","year":"2009","journal-title":"Curr. Aging Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1530\/jrf.0.1090153","article-title":"Differential regulation of mouse embryo development and viability by amino acids","volume":"109","author":"Lane","year":"1997","journal-title":"J. Reprod. Fertil."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.2337\/diab.45.11.1463","article-title":"Disturbed development of the preimplantation embryo in the insulin-dependent diabetic bb\/e rat","volume":"45","author":"Lea","year":"1996","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"423","DOI":"10.21451\/1984-3143-AR2019-0072","article-title":"Embryo competence and cryosurvival: Molecular and cellular features","volume":"16","author":"Marsico","year":"2019","journal-title":"Anim. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13072-018-0224-y","article-title":"Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development","volume":"11","author":"Wyck","year":"2018","journal-title":"Epigenetics Chromatin"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"181560","DOI":"10.1155\/2012\/181560","article-title":"Protein-tyrosine kinase signaling in the biological functions associated with sperm","volume":"2012","author":"Ijiri","year":"2012","journal-title":"J. Signal. Transduct."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"367","DOI":"10.14336\/AD.2018.0324","article-title":"Redefining chronic inflammation in aging and age-related diseases: Proposal of the senoinflammation concept","volume":"10","author":"Chung","year":"2019","journal-title":"Aging Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1515\/REVNEURO.2009.20.1.23","article-title":"The endoplasmic reticulum stress response and aging","volume":"20","author":"Naidoo","year":"2009","journal-title":"Rev. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1093\/humrep\/deq214","article-title":"Analysis of the relationships between oxidative stress, DNA damage and sperm vitality in a patient population: Development of diagnostic criteria","volume":"25","author":"Aitken","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1071\/RD15325","article-title":"Causes and consequences of oxidative stress in spermatozoa","volume":"28","author":"Aitken","year":"2016","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00441-005-1097-5","article-title":"DNA damage to spermatozoa has impacts on fertilization and pregnancy","volume":"322","author":"Lewis","year":"2005","journal-title":"Cell Tissue Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S1472-6483(10)60676-1","article-title":"Origins and consequences of DNA damage in male germ cells","volume":"14","author":"Aitken","year":"2007","journal-title":"Reprod. Biomed. Online"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1093\/humrep\/den321","article-title":"Sperm DNA damage is associated with an increased risk of pregnancy loss after ivf and icsi: Systematic review and meta-analysis","volume":"23","author":"Zini","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/humrep\/deq103","article-title":"Clinical significance of sperm DNA damage in assisted reproduction outcome","volume":"25","author":"Simon","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.3390\/md12041939","article-title":"The marine fungal metabolite, dicitrinone b, induces a375 cell apoptosis through the ros-related caspase pathway","volume":"12","author":"Chen","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1530\/rep.0.1240353","article-title":"Caspase activity and expression of cell death genes during development of human preimplantation embryos","volume":"124","author":"Spanos","year":"2002","journal-title":"J. Reprod."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Fadda, L.M., Hagar, H., Mohamed, A.M., and Ali, H.M. (2018). Quercetin and idebenone ameliorate oxidative stress, inflammation, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in rat liver. Dose Response, 16.","DOI":"10.1177\/1559325818812188"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ydbio.2015.07.024","article-title":"Fertilization stimulates 8-hydroxy-2\u2032-deoxyguanosine repair and antioxidant activity to prevent mutagenesis in the embryo","volume":"406","author":"Lord","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"k4372","DOI":"10.1136\/bmj.k4372","article-title":"Association of paternal age with perinatal outcomes between 2007 and 2016 in the united states: Population based cohort study","volume":"363","author":"Khandwala","year":"2018","journal-title":"BMJ"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fphys.2016.00028","article-title":"Placental adaptation: What can we learn from birthweight:Placental weight ratio?","volume":"7","author":"Hayward","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.ajog.2015.08.030","article-title":"The placenta is the center of the chronic disease universe","volume":"213","author":"Thornburg","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00404-013-2801-4","article-title":"Influence of reactive oxygen species on human sperm functions and fertilizing capacity including therapeutical approaches","volume":"288","author":"Chen","year":"2013","journal-title":"Arch. Gynecol. Obs."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"420","DOI":"10.2741\/s495","article-title":"Oxidative stress: Major executioner in disease pathology, role in sperm DNA damage and preventive strategies","volume":"9","author":"Bisht","year":"2017","journal-title":"Front. Biosci. (Sch. Ed.)"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10863-014-9571-y","article-title":"Idebenone and neuroprotection: Antioxidant, pro-oxidant, or electron carrier?","volume":"47","author":"Jaber","year":"2015","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0014-5793(01)02850-2","article-title":"The site of production of superoxide radical in mitochondrial complex i is not a bound ubisemiquinone but presumably iron\u2013sulfur cluster n2","volume":"505","author":"Genova","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s12640-011-9245-z","article-title":"Idebenone induces apoptotic cell death in the human dopaminergic neuroblastoma shsy-5y cells","volume":"20","author":"Tai","year":"2011","journal-title":"Neurotox. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1387\/ijdb.130146ja","article-title":"Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development","volume":"57","author":"Aitken","year":"2013","journal-title":"Int. J. Dev. Biol."},{"key":"ref_67","unstructured":"ABS (2010). Births, Australia, 2010."},{"key":"ref_68","unstructured":"AIHW (2012). Australian Insitute of Health and Welfare."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.maturitas.2014.02.011","article-title":"How to overcome male infertility after 40: Influence of paternal age on fertility","volume":"78","author":"Belloc","year":"2014","journal-title":"Maturitas"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/humrep\/15.8.1703","article-title":"Increasing paternal age is associated with delayed conception in a large population of fertile couples: Evidence for declining fecundity in older men. The alspac study team (avon longitudinal study of pregnancy and childhood)","volume":"15","author":"Ford","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1093\/oxfordjournals.humrep.a136100","article-title":"Cumulative conception rate following intrauterine artificial insemination with husband\u2019s spermatozoa: Influence of husband\u2019s age","volume":"10","author":"Mathieu","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S1472-6483(10)60223-4","article-title":"Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination","volume":"17","author":"Belloc","year":"2008","journal-title":"Reprod. Biomed. Online"},{"key":"ref_73","unstructured":"Newman, J., Paul, R., and Chambers, G.M. (2020). Assisted Reproductive Technology in Australia and New Zealand 2018, The University of New South Wales."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.fertnstert.2015.03.004","article-title":"Reproduction at an advanced maternal age and maternal health","volume":"103","author":"Sauer","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0015-0282(00)01679-4","article-title":"Effects of male age on semen quality and fertility: A review of the literature","volume":"75","author":"Kidd","year":"2001","journal-title":"Fertil. Steril."},{"key":"ref_76","unstructured":"Feingold, K.R., Anawalt, B., Boyce, A., Chrousos, G., de Herder, W.W., Dhatariya, K., Dungan, K., Grossman, A., Hershman, J.M., and Hofland, J. (2000). Age-related changes in the male reproductive system. Endotext, South Dartmouth."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.18632\/aging.102120","article-title":"Age-related changes in human sperm DNA integrity","volume":"11","author":"Gill","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"ref_78","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_79","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.urology.2007.11.041","article-title":"Age-related increase of reactive oxygen species in neat semen in healthy fertile men","volume":"71","author":"Cocuzza","year":"2008","journal-title":"Urology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"233","DOI":"10.4111\/icu.20200066","article-title":"Aging increases oxidative stress in semen","volume":"62","author":"Nago","year":"2021","journal-title":"Investig. Clin. Urol."},{"key":"ref_81","first-page":"60","article-title":"The role of oxidative stress and antioxidants in male fertility","volume":"66","author":"Wolski","year":"2013","journal-title":"Cent. Eur. J. Urol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1016\/j.fertnstert.2014.10.020","article-title":"Male infertility testing: Reactive oxygen species and antioxidant capacity","volume":"102","author":"Ko","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Redgrove, K.A., Nixon, B., Baker, M.A., Hetherington, L., Baker, G., Liu, D.Y., and Aitken, R.J. (2012). The molecular chaperone hspa2 plays a key role in regulating the expression of sperm surface receptors that mediate sperm-egg recognition. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050851"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0100832","article-title":"Oxidative stress in mouse sperm impairs embryo development, fetal growth and alters adiposity and glucose regulation in female offspring.(research article)","volume":"9","author":"Lane","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/bies.950160409","article-title":"Reactive oxygen species generation and human spermatozoa: The balance of benefit and risk","volume":"16","author":"Aitken","year":"1994","journal-title":"BioEssays News Rev. Mol. Cell. Dev. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1089\/ars.2010.3186","article-title":"Redox regulation of human sperm function: From the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line","volume":"14","author":"Aitken","year":"2011","journal-title":"Antioxid Redox Signal."},{"key":"ref_87","first-page":"1849","article-title":"Gpx5 protects the family jewels","volume":"119","author":"Aitken","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/j.1939-4640.2000.tb03422.x","article-title":"Quantification of the nonenzymatic fast and slow trap in a postaddition assay in human seminal plasma and the antioxidant contributions of various seminal compounds","volume":"21","author":"Rhemrev","year":"2000","journal-title":"J. Androl."},{"key":"ref_89","first-page":"693","article-title":"Characterization of recombinant precursor proteins of the human seminal plasma sperm motility inhibitor synthesized in insect cells","volume":"2","author":"Murakami","year":"1998","journal-title":"Int. J. Mol. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/j.1939-4640.2003.tb03139.x","article-title":"Quantification of seminal plasma motility inhibitor\/semenogelin in human seminal plasma","volume":"24","author":"Yoshida","year":"2003","journal-title":"J. Androl."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0891-5849(96)00119-0","article-title":"Superoxide dismutase in human sperm suspensions: Relationship with cellular composition, oxidative stress, and sperm function","volume":"21","author":"Aitken","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1095\/biolreprod.104.028407","article-title":"Functional significance of the pentose phosphate pathway and glutathione reductase in the antioxidant defenses of human sperm","volume":"71","author":"Williams","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0531-5565(98)00066-7","article-title":"Reactive oxygen species and biological aging: A mechanistic approach","volume":"34","author":"Schoneich","year":"1999","journal-title":"Exp. Gerontol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.rbmo.2010.03.008","article-title":"A systematic review of the effect of oral antioxidants on male infertility","volume":"20","author":"Ross","year":"2010","journal-title":"Reprod. Biomed. Online"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Showell, M.G., Mackenzie-Proctor, R., Brown, J., Yazdani, A., Stankiewicz, M.T., and Hart, R.J. (2014). Antioxidants for male subfertility. Cochrane Database Syst. Rev., 12.","DOI":"10.1002\/14651858.CD007411.pub3"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"729","DOI":"10.29252\/ijrm.14.12.729","article-title":"Antioxidant supplements and semen parameters: An evidence based review","volume":"14","author":"Ahmadi","year":"2016","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1093\/humrep\/den060","article-title":"Protective effect of antioxidant supplementation in sperm-preparation medium against oxidative stress in human spermatozoa","volume":"23","author":"Chi","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/1477-7827-11-81","article-title":"Protective effects of in vitro treatment with zinc, d-aspartate and coenzyme q10 on human sperm motility, lipid peroxidation and DNA fragmentation","volume":"11","author":"Talevi","year":"2013","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.theriogenology.2014.05.028","article-title":"Treatment with zinc, d-aspartate, and coenzyme q10 protects bull sperm against damage and improves their ability to support embryo development","volume":"82","author":"Gualtieri","year":"2014","journal-title":"Theriogenology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1017\/S0967199416000459","article-title":"Supplementation of sperm media with zinc, d-aspartate and co-enzyme q10 protects bull sperm against exogenous oxidative stress and improves their ability to support embryo development","volume":"25","author":"Barbato","year":"2017","journal-title":"Zygote"},{"key":"ref_101","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_102","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.fertnstert.2012.07.1126","article-title":"Micronutrients intake is associated with improved sperm DNA quality in older men","volume":"98","author":"Schmid","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.fertnstert.2009.04.004","article-title":"Lycopene supplementation in vitro can protect human sperm deoxyribonucleic acid from oxidative damage","volume":"94","author":"Zini","year":"2010","journal-title":"Fertil. Steril."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/7\/1079\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:16Z","timestamp":1760163976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/7\/1079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":103,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["antiox10071079"],"URL":"https:\/\/doi.org\/10.3390\/antiox10071079","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]}}}