全世界估计有10%到15%的夫妇受不孕症影响,大约一半的案件归因于男性相关问题。大多数被诊断患有不孕症的男性表现出诸如少精子症的症状,弱精子症,无精子症,精子质量受损。精子发生是生殖细胞分化的一个复杂而紧密协调的过程,精确调节转录,转录后,和翻译水平,以确保在生精细胞发育和正常生精过程中阶段特异性基因表达。N6-甲基腺苷(m6A)是真核mRNA上最普遍的修饰,在各种生物过程中发挥关键作用,包括mRNA剪接,交通运输,和翻译。RNA甲基化修饰是一个动态的可逆过程,主要由“作者”介导被“橡皮擦”删除,并被“读者”认可。在哺乳动物中,mRNA上m6A的异常甲基化修饰与多种疾病相关,包括男性不育.然而,m6A修饰在人类男性不育症发病机制中的确切参与仍未解决。有趣的是,已发现睾丸中m6A调节剂的表达水平与精子浓度的严重程度之间存在显着相关性,运动性,和形态学。在异常的人精液样本中检测到m6A调节蛋白的异常表达模式,包括少精子症,弱精子症,和无精子症.此外,对精子样本和睾丸组织的检查均显示m6AmRNA的异常修饰,导致不育男性精子活力和浓度降低。因此,据推测,m6A修饰的失调可能是男性不育机制中不可或缺的环节。本文对睾丸组织中m6A调节子的时空表达动力学以及m6A调节子与人类男性不育之间的相关性的最新发现进行了全面回顾。以前的研究主要使用组成型或条件敲除动物模型进行睾丸表型研究。然而,其他组织中的基因抑制可能会影响组成型敲除模型中的睾丸。此外,考虑到在组成型动物中观察到的精子发生受损,区分基因耗竭对睾丸发育的间接影响及其对生精过程的直接影响具有挑战性,由于他们错综复杂的关系。这些混杂因素可能会损害研究结果的有效性。为了应对这一挑战,诱导型和条件性基因敲除模型可能是一种更好的方法。迄今为止,几乎所有报道的研究都只集中在生殖细胞中m6A及其调节剂的水平变化上,而对m6A修饰在睾丸体细胞中的功能的理解仍然有限。睾丸体细胞,包括肾小管周围的肌样细胞,支持细胞,和Leydig细胞,在精子发生过程中起着不可或缺的作用。因此,有必要全面探索这些细胞内的m6A修饰作为额外的关键调节机制。此外,探索睾丸内独特的甲基化机制或m6A调节因子的存在是必要的.为了阐明m6A修饰在生殖细胞和睾丸体细胞中的作用,需要实施详细的实验策略。其中,操纵参与m6A甲基化和去甲基化的关键酶的水平可能是最有效的方法。此外,综合分析涉及各种信号通路的基因表达谱,如Wnt/β-catenin,Ras/MAPK,和河马,在m6A修饰的生殖细胞和睾丸体细胞中可以更深入地了解其在精子发生过程中的调节作用。该领域的进一步研究可以为制定治疗男性不育的创新策略提供有价值的见解。最后,考虑到M6A失衡调节对疾病的缓解影响,关于恢复m6A修饰调节的平衡是否可以恢复正常的精子发生功能的研究至关重要,可能阐明m6A调制在男性不育中的关键临床意义。
Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with infertility exhibit symptoms such as oligospermia, asthenospermia, azoospermia, and compromised sperm quality. Spermatogenesis is a complex and tightly coordinated process of germ cell differentiation, precisely regulated at transcriptional, posttranscriptional, and translational levels to ensure stage-specific gene expression during the development of spermatogenic cells and normal spermiogenesis. N6-methyladenosine (m6A) stands out as the most prevalent modification on eukaryotic mRNA, playing pivotal roles in various biological processes, including mRNA splicing, transportation, and translation. RNA methylation modification is a dynamic and reversible process primarily mediated by \"writers\", removed by \"erasers\", and recognized by \"readers\". In mammals, the aberrant methylation modification of m6A on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted m6A modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of m6A regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of m6A regulatory proteins have been detected in anomalous human semen samples, including those of oligospermia, asthenozoospermia, and azoospermia. Furthermore, the examination of both sperm samples and testicular tissues revealed abnormal mRNA m6A modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of m6A modification might serve as an integral link in the mechanism of male infertility. This paper presents a comprehensive review of the recent discoveries regarding the spatial and temporal expression dynamics of m6A regulators in testicular tissues and the correlation between deregulated m6A regulators and human male infertility. Previous studies predominantly utilized constitutive or conditional knockout animal models for testicular phenotypic investigations. However, gene suppression in additional tissues could potentially influence the testis in constitutive knockout models. Furthermore, considering the compromised spermatogenesis observed in constitutive animals, distinguishing between the indirect effects of gene depletion on testicular development and its direct impact on the spermatogenic process is challenging, due to their intricate relationship. Such confounding factors might compromise the validity of the findings. To address this challenge, an inducible and conditional gene knockout model may serve as a superior approach. To date, nearly all reported studies have concentrated solely on the level changes of m6A and its regulators in germs cells, while the understanding of the function of m6A modification in testicular somatic cells remains limited. Testicular somatic cells, including peritubular myoid cells, Sertoli cells, and Leydig cells, play indispensable roles during spermatogenesis. Hence, comprehensive exploration of m6A modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or m6A regulatory factors within the testes is warranted. To elucidate the role of m6A modification in germ cells and testicular somatic cells, detailed experimental strategies need to be implemented. Among them, manipulation of the levels of key enzymes involved in m6A methylation and demethylation might be the most effective approach. Moreover, comprehensive analysis of the gene expression profiles involved in various signaling pathways, such as Wnt/β-catenin, Ras/MAPK, and Hippo, in m6A-modified germ cells and testicular somatic cells can provide more insight into its regulatory role in the spermatogenesis process. Further research in this area could provide valuable insights for developing innovative strategies to treat male infertility. Finally, considering the mitigation impact of m6A imbalance regulation on disease, investigation concerning whether restoring the equilibrium of m6A modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of m6A modulation in male infertility.