{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:16:52Z","timestamp":1792718212202,"version":"4.5.0"},"reference-count":196,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"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>Male-factor infertility accounts for nearly half of all infertility cases, and mounting evidence points to oxidative stress as a pivotal driver of sperm dysfunction, genetic instability, and epigenetic dysregulation. In particular, the oxidative DNA lesion 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG) has emerged as a central mediator at the interface of DNA damage and epigenetic regulation. We discuss how this lesion can disrupt key epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNAs, thereby influencing fertilization outcomes, embryo development, and offspring health. We propose that the interplay between oxidative DNA damage and epigenetic reprogramming is further exacerbated by aging in both the paternal and maternal germlines, creating a \u201cperfect storm\u201d that increases the risk of heritable (epi)mutations. The consequences of unresolved oxidative lesions can thus persist beyond fertilization, contributing to transgenerational health risks. Finally, we explore the promise and potential pitfalls of antioxidant therapy as a strategy to mitigate sperm oxidative damage. While antioxidant supplementation may hold significant therapeutic value for men with subfertility experiencing elevated oxidative stress, a careful, personalized approach is essential to avoid reductive stress and unintended epigenetic disruptions. Recognizing the dual role of oxidative stress in shaping both the genome and the epigenome underscores the need for integrating redox biology into reproductive medicine, with the aim of improving fertility treatments and safeguarding the health of future generations.<\/jats:p>","DOI":"10.3390\/antiox14050570","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T11:25:53Z","timestamp":1746789953000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-4390","authenticated-orcid":false,"given":"Aron","family":"Moazamian","sequence":"first","affiliation":[{"name":"EVALSEM, GReD Institute, CRBC, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, France"},{"name":"CellOxess Biotechnology, Research & Development, Ewing, NJ 08638, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9570-3777","authenticated-orcid":false,"given":"Fabrice","family":"Saez","sequence":"additional","affiliation":[{"name":"EVALSEM, GReD Institute, CRBC, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3077-6558","authenticated-orcid":false,"given":"Jo\u00ebl R.","family":"Drevet","sequence":"additional","affiliation":[{"name":"EVALSEM, GReD Institute, CRBC, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-156X","authenticated-orcid":false,"given":"Robert John","family":"Aitken","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Reproductive Science, University of Newcastle, Newcastle 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3955-3297","authenticated-orcid":false,"given":"Parviz","family":"Gharagozloo","sequence":"additional","affiliation":[{"name":"CellOxess Biotechnology, Research & Development, Ewing, NJ 08638, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Fertility and Forecasting Collaborators (2024). 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