Kaltsas Aris, Markou Eleftheria, Kyrgiafini Maria-Anna, Zikopoulos Athanasios, Symeonidis Evangelos N, Dimitriadis Fotios, Zachariou Athanasios, Sofikitis Nikolaos, Chrisofos Michael
Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.
Department of Microbiology, University Hospital of Ioannina, 45500 Ioannina, Greece.
Genes (Basel). 2025 Jan 17;16(1):93. doi: 10.3390/genes16010093.
Male reproductive health is governed by an intricate interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms-encompassing DNA methylation, histone modifications, and non-coding RNA activity-are crucial both for spermatogenesis and sperm maturation. However, oxidative stress, driven by excessive reactive oxygen species, disrupts these processes, leading to impaired sperm function and male infertility. This disruption extends to epigenetic modifications, resulting in abnormal gene expression and chromatin remodeling that compromise genomic integrity and fertilization potential. Importantly, oxidative-stress-induced epigenetic alterations can be inherited, affecting the health and fertility of offspring and future generations. This review investigates how oxidative stress influences epigenetic regulation in male reproduction by modifying DNA methylation, histone modifications, and non-coding RNAs, ultimately compromising spermatogenesis. Additionally, it discusses the transgenerational implications of these epigenetic disruptions and their potential role in hereditary infertility and disease predisposition. Understanding these mechanisms is vital for developing therapeutic strategies that mitigate oxidative damage and restore epigenetic homeostasis in the male germline. By integrating insights from molecular, clinical, and transgenerational research, this work emphasizes the need for targeted interventions to enhance male reproductive health and prevent adverse outcomes in progeny. Furthermore, elucidating the dose-response relationships between oxidative stress and epigenetic changes remains a critical research priority, informing personalized diagnostics and therapeutic interventions. In this context, future studies should adopt standardized markers of oxidative damage, robust clinical trials, and multi-omic approaches to capture the complexity of epigenetic regulation in spermatogenesis. Such rigorous investigations will ultimately reduce the risk of transgenerational disorders and optimize reproductive health outcomes.
男性生殖健康受遗传、表观遗传和环境因素的复杂相互作用所支配。表观遗传机制，包括DNA甲基化、组蛋白修饰和非编码RNA活性，对于精子发生和精子成熟都至关重要。然而，由过量活性氧驱动的氧化应激会破坏这些过程，导致精子功能受损和男性不育。这种破坏还会延伸到表观遗传修饰，导致基因表达异常和染色质重塑，从而损害基因组完整性和受精潜力。重要的是，氧化应激诱导的表观遗传改变可以遗传，影响后代和子孙后代的健康和生育能力。本综述研究了氧化应激如何通过修饰DNA甲基化、组蛋白修饰和非编码RNA影响男性生殖中的表观遗传调控，最终损害精子发生。此外，它还讨论了这些表观遗传破坏的跨代影响及其在遗传性不育和疾病易感性中的潜在作用。了解这些机制对于制定减轻氧化损伤和恢复雄性生殖系表观遗传稳态的治疗策略至关重要。通过整合分子、临床和跨代研究的见解，这项工作强调了有针对性干预的必要性，以增强男性生殖健康并预防后代的不良后果。此外，阐明氧化应激与表观遗传变化之间的剂量反应关系仍然是一个关键的研究重点，为个性化诊断和治疗干预提供依据。在这种背景下，未来的研究应采用氧化损伤的标准化标志物、强有力的临床试验和多组学方法来捕捉精子发生中表观遗传调控的复杂性。这种严谨的研究最终将降低跨代疾病的风险并优化生殖健康结果。
