Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health
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′-deoxyguanosine (8-OHdG) has em...
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MDPI AG
2025-05-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/5/570 |
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| author | Aron Moazamian Fabrice Saez Joël R. Drevet Robert John Aitken Parviz Gharagozloo |
| author_facet | Aron Moazamian Fabrice Saez Joël R. Drevet Robert John Aitken Parviz Gharagozloo |
| author_sort | Aron Moazamian |
| collection | DOAJ |
| description | 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′-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 “perfect storm” 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. |
| format | Article |
| id | doaj-art-46f3ebcd02534df4ac64ac9520dc6ed9 |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-46f3ebcd02534df4ac64ac9520dc6ed92025-08-20T02:33:39ZengMDPI AGAntioxidants2076-39212025-05-0114557010.3390/antiox14050570Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational HealthAron Moazamian0Fabrice Saez1Joël R. Drevet2Robert John Aitken3Parviz Gharagozloo4EVALSEM, GReD Institute, CRBC, Faculté de Médecine, Université Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, FranceEVALSEM, GReD Institute, CRBC, Faculté de Médecine, Université Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, FranceEVALSEM, GReD Institute, CRBC, Faculté de Médecine, Université Clermont Auvergne, 28 Place Henri Dunant, 6300 Clermont-Ferrand, FrancePriority Research Centre for Reproductive Science, University of Newcastle, Newcastle 2308, AustraliaCellOxess Biotechnology, Research & Development, Ewing, NJ 08638, USAMale-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′-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 “perfect storm” 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.https://www.mdpi.com/2076-3921/14/5/570male infertilityoxidative stresssperm DNA damageepigenetics8-hydroxy-2′-deoxyguanosine (8-OHdG)embryo development |
| spellingShingle | Aron Moazamian Fabrice Saez Joël R. Drevet Robert John Aitken Parviz Gharagozloo Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health Antioxidants male infertility oxidative stress sperm DNA damage epigenetics 8-hydroxy-2′-deoxyguanosine (8-OHdG) embryo development |
| title | Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health |
| title_full | Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health |
| title_fullStr | Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health |
| title_full_unstemmed | Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health |
| title_short | Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health |
| title_sort | redox driven epigenetic modifications in sperm unraveling paternal influences on embryo development and transgenerational health |
| topic | male infertility oxidative stress sperm DNA damage epigenetics 8-hydroxy-2′-deoxyguanosine (8-OHdG) embryo development |
| url | https://www.mdpi.com/2076-3921/14/5/570 |
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