BACKGROUND Varicocele is an abnormal dilation and torsion of the pampiniform venous plexus in the scrotum due to venous reflux, primarily affecting the left side. It affects 15% of men and is a prevalent contributor to male infertility. Varicocele is a complex disorder influenced by genetic, epigenetic, and environmental factors. Epigenetic modifications, which regulate genome activity independently of DNA or RNA sequences, may contribute to the development and severity of varicocele. These include DNA methylation, histone modifications, and RNA modifications like N6-methyladenosine (m6A). Irregularities in DNA and m6A-RNA methylation during spermatogenesis can cause gene expression abnormalities, DNA damage, and decreased fertility in varicocele patients. OBJECTIVE AND RATIONALE The review aims to comprehensively understand the underlying mechanisms of varicocele, a condition that can significantly impact male fertility. By exploring the role of methylation modifications, specifically DNA and m6A-RNA methylation, the review aims to synthesize evidence from basic, preclinical, and clinical research to expand the existing knowledge on this subject. The ultimate goal is to identify potential avenues for developing targeted treatments that can effectively improve varicocele and ultimately increase sperm quality in affected individuals. SEARCH METHODS A thorough investigation of the scientific literature was conducted through searches in PubMed, Google Scholar, and Science Direct databases until May 2024. All studies investigating the relationship between DNA and m6A-RNA methylation and male infertility, particularly varicocele were reviewed, and the most pertinent reports were included. Keywords such as varicocele, epigenetics, DNA methylation, m6A-RNA methylation, hypermethylation, hypomethylation, spermatozoa, semen parameters, spermatogenesis, and male infertility were used during the literature search, either individually or in combination. OUTCOMES The sperm has a specialized morphology essential for successful fertilization, and its epigenome is unique, potentially playing a key role in embryogenesis. Sperm DNA and RNA methylation, major epigenetic marks, regulate the expression of testicular genes crucial for normal spermatogenesis. This review explores the role of DNA and m6A-RNA methylation, in responding to oxidative stress and how various nutrients influence their function in varicocele condition. Evidence suggests a potential link between varicocele and aberrant DNA/m6A-RNA methylation patterns, especially hypomethylation, but the body of evidence is still limited. Further studies are needed to understand how abnormal expression of DNA/m6A-RNA methylation regulators affects testicular gene expression. Thus, analyzing sperm DNA 5mC/5hmC levels and m6A-RNA methylation regulators may reveal spermatogenesis defects and predict reproductive outcomes. WIDER IMPLICATIONS Nutri-epigenomics is an emerging field that could enhance the knowledge and management of diseases with unpredictable risks and consequences, even among individuals with similar lifestyles, by elucidating the influence of nutrition on DNA/m6A-RNA methylation through one-carbon metabolism. However, the importance of one-carbon metabolism to varicocele is not well-recognized. Health status and diet influence one-carbon metabolism and its associated DNA/m6A-RNA methylation modification. Future research should identify optimal methylation patterns that promote health and investigate modulating one-carbon metabolism to achieve this. Furthermore, additional studies are necessary to develop personalized dietary strategies through clinical and longitudinal research. However, a research gap exists on dietary interventions utilizing epigenetics as a therapeutic method for treating varicocele. REGISTRATION NUMBER Not applicable.

中文翻译：

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精索静脉曲张的表观遗传学方法：关注精子 DNA 和 m6A-RNA 甲基化


背景 精索静脉曲张是由于静脉反流引起的阴囊海绵状静脉丛异常扩张和扭转，主要影响左侧。它影响 15% 的男性，是导致男性不育的普遍原因。精索静脉曲张是一种受遗传、表观遗传和环境因素影响的复杂疾病。独立于 DNA 或 RNA 序列调节基因组活性的表观遗传修饰可能导致精索静脉曲张的发生和严重程度。这些包括 DNA 甲基化、组蛋白修饰和 RNA 修饰，如 N6-甲基腺苷 （m6A）。精子发生过程中 DNA 和 m6A-RNA 甲基化的不规则会导致精索静脉曲张患者的基因表达异常、DNA 损伤和生育能力下降。客观和基本原理 本综述旨在全面了解精索静脉曲张的潜在机制，精索静脉曲张是一种可显着影响男性生育能力的疾病。通过探索甲基化修饰的作用，特别是 DNA 和 m6A-RNA 甲基化，本综述旨在综合来自基础、临床前和临床研究的证据，以扩展有关该主题的现有知识。最终目标是确定开发靶向治疗的潜在途径，这些治疗方法可以有效改善精索静脉曲张并最终提高受影响个体的精子质量。检索方法 通过在 PubMed、Google Scholar 和 Science Direct 数据库中进行搜索，对科学文献进行了彻底调查，直到 2024 年 5 月。回顾了所有调查 DNA 和 m6A-RNA 甲基化与男性不育症（尤其是精索静脉曲张）之间关系的研究，并纳入了最相关的报告。 在文献检索过程中，单独或组合使用了精索静脉曲张、表观遗传学、DNA 甲基化、m6A-RNA 甲基化、高甲基化、低甲基化、精子、精子、精液参数、精子发生和男性不育等关键词。结果 精子具有成功受精所必需的特殊形态，其表观基因组是独一无二的，可能在胚胎发生中发挥关键作用。精子 DNA 和 RNA 甲基化是主要的表观遗传标记，可调节对正常精子发生至关重要的睾丸基因的表达。本综述探讨了 DNA 和 m6A-RNA 甲基化在响应氧化应激中的作用，以及各种营养素如何影响它们在精索静脉曲张情况下的功能。有证据表明精索静脉曲张与异常 DNA/m6A-RNA 甲基化模式之间存在潜在联系，尤其是低甲基化，但证据主体仍然有限。需要进一步的研究来了解 DNA/m6A-RNA 甲基化调节因子的异常表达如何影响睾丸基因表达。因此，分析精子 DNA 5mC/5hmC 水平和 m6A-RNA 甲基化调节因子可能会揭示精子发生缺陷并预测生殖结果。更广泛的影响 营养表观基因组学是一个新兴领域，它可以通过阐明营养通过一碳代谢对 DNA/m6A-RNA 甲基化的影响，加强对具有不可预测风险和后果的疾病的知识和管理，即使在具有相似生活方式的个体中也是如此。然而，一碳代谢对精索静脉曲张的重要性尚未得到充分认识。健康状况和饮食影响一碳代谢及其相关的 DNA/m6A-RNA 甲基化修饰。 未来的研究应确定促进健康的最佳甲基化模式，并研究调节一碳代谢以实现这一目标。此外，还需要进行额外的研究，以通过临床和纵向研究来制定个性化的饮食策略。然而，利用表观遗传学作为治疗精索静脉曲张的治疗方法的饮食干预存在研究空白。注册号 不适用。