摘要
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.
摘要译文
男性因素不育几乎占所有不育病例的一半，而安装证据表明氧化应激是精子功能障碍，遗传不稳定性和表观遗传失调的关键驱动因素。特别是，在DNA损伤和表观遗传调节的界面上，氧化性DNA病变8-羟基-2'-脱氧鸟苷（8-OHDG）已成为中央介体。我们讨论这种病变如何破坏关键的表观遗传机制，例如DNA甲基化，组蛋白修饰和小型非编码RNA，从而影响受精结果，胚胎发育和后代健康。我们建议，氧化性DNA损伤与表观遗传重编程之间的相互作用会因父亲和母体种系的老化而进一步加剧，从而产生了“完美的风暴”，从而增加了可遗传（EPI）突变的风险。因此，未解决的氧化病变的后果可能会持续超越受精，从而导致转世健康风险。最后，我们探讨了抗氧化剂疗法的希望和潜在陷阱，以减轻精子氧化损伤的策略。虽然补充抗氧化剂可能对具有差异较高的氧化压力的男性具有显着的治疗价值，但谨慎的个性化方法对于避免减轻压力和意外表观遗传破坏至关重要。认识到氧化应激在塑造基因组和表观基因组中的双重作用强调了将氧化还原生物学纳入生殖医学的必要性，目的是改善生育能力并维护后代的健康。
Aron Moazamian (https://orcid.org/0000-0002-1291-4390) [1];Fabrice Saez (https://orcid.org/0000-0001-9570-3777) [2];Joël R. Drevet (https://orcid.org/0000-0003-3077-6558) [3];Robert John Aitken (https://orcid.org/0000-0002-9152-156X) [4];Parviz Gharagozloo (https://orcid.org/0000-0003-3955-3297) [5];. Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health[J]. Antioxidants, 2025,14(5): 570