Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, India.
Mutat Res. 2011 May-Jun;727(3):62-71. doi: 10.1016/j.mrrev.2011.04.002. Epub 2011 Apr 16.
Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in a number of biological processes, including spermatogenesis. Several genes in the testes are regulated through epigenetic mechanisms, indicating a direct influence of epigenetic mechanisms on the process of spermatogenesis. In the present article, we have provided a comprehensive review of the epigenetic processes in the testes, correlation of epigenetic aberrations with male infertility, impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations in assisted reproduction. The literature review suggested a significant impact of epigenetic aberrations (epimutations) on spermatogenesis, and this could lead to male infertility. Epimutations (often hypermethylation) in several genes, namely MTHFR, PAX8, NTF3, SFN, HRAS, JHM2DA, IGF2, H19, RASGRF1, GTL2, PLAG1, D1RAS3, MEST, KCNQ1, LIT1, and SNRPN, have been reported in association with poor semen parameters or male infertility. Environmental toxins/drugs may affect fertility via epigenetic modifications. For example, 5-aza-2'-deoxycytidine, an anticancer agent, causes a decrease in global DNA methylation that leads to altered sperm morphology, decreased sperm motility, decreased fertilization capacity, and decreased embryo survival. Similarly, Endocrine disruptors, such as methoxychlor (an estrogenic pesticide) and vinclozolin (an anti-androgenic fungicide) have been found by experiments on animals to affect epigenetic modifications that may cause spermatogenic defects in subsequent generations. Assisted reproduction procedures that have been considered rather safe, are now being implicated in inducing epigenetic changes that could affect fertility in subsequent generations. Techniques such as intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI) may increase the incidence of imprinting disorders and adversely affect embryonic development by using immature spermatozoa that may not have established proper imprints or global methylation. Epigenetic changes, in contrast to genetic aberrations, may be less deleterious because they are potentially reversible. Further research could identify certain drugs capable of reversing epigenetic changes.
表观遗传修饰，如 DNA 甲基化、组蛋白修饰和染色质重塑，是许多生物学过程的重要调控因子，包括精子发生。睾丸中的一些基因受表观遗传机制调控，这表明表观遗传机制对精子发生过程有直接影响。在本文中，我们全面回顾了睾丸中的表观遗传过程、表观遗传异常与男性不育的相关性、环境因素对表观基因组和男性生育力的影响，以及表观遗传变化/异常在辅助生殖中的意义。文献回顾表明，表观遗传异常（表观突变）对精子发生有显著影响，这可能导致男性不育。几种基因的表观突变（常为过度甲基化），如 MTHFR、PAX8、NTF3、SFN、HRAS、JHM2DA、IGF2、H19、RASGRF1、GTL2、PLAG1、D1RAS3、MEST、KCNQ1、LIT1 和 SNRPN，与精液参数差或男性不育有关。环境毒素/药物可能通过表观遗传修饰影响生育能力。例如，5-氮杂-2'-脱氧胞苷是一种抗癌药物，可导致全球 DNA 甲基化减少，导致精子形态改变、精子活力下降、受精能力下降和胚胎存活率下降。同样，实验发现，内分泌干扰物，如甲氧滴滴涕（一种雌激素农药）和杀真菌剂 vinclozolin（一种抗雄激素），可影响表观遗传修饰，可能导致后代的精子发生缺陷。人们认为，辅助生殖技术相当安全，但现在却被牵连到诱导可能影响后代生育能力的表观遗传变化中。卵胞浆内单精子注射（ICSI）和圆形精子注射（ROSI）等技术可能会增加印迹障碍的发生率，并通过使用不成熟的精子，对胚胎发育产生不利影响，这些精子可能尚未建立适当的印迹或全球甲基化。与遗传异常相比，表观遗传变化的潜在危害可能较小，因为它们是潜在可逆的。进一步的研究可以确定某些能够逆转表观遗传变化的药物。
