Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China.
PLoS One. 2010 Nov 9;5(11):e13884. doi: 10.1371/journal.pone.0013884.
Abnormal germline DNA methylation in males has been proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. Previous studies have been focused on imprinted genes with DNA methylation in poor quality human sperms. However, recent but limited data have revealed that sperm methylation abnormalities may involve large numbers of genes or shown that genes that are not imprinted are also affected.
METHODOLOGY/PRINCIPAL FINDINGS: Using the methylation-specific polymerase chain reaction and bisulfite sequencing method, we examined methylation patterns of the promoter of methylenetetrahydrofolate reductase (MTHFR) gene (NG_013351: 1538-1719) in sperm DNA obtained from 94 idiopathic infertile men and 54 normal fertile controls. Subjects with idiopathic infertility were further divided into groups of normozoospermia and oligozoospermia. Overall, 45% (41/94) of idiopathic infertile males had MTHFR hypermethylation (both hemimethylation and full methylation), compared with 15% of fertile controls (P<0.05). Subjects with higher methylation level of MTHFR were more likely to have idiopathic male infertility (P-value for trend = 0.0007). Comparing the two groups of idiopathic infertile subjects with different sperm concentrations, a higher methylation pattern was found in the group with oligozoospermia.
Hypermethylation of the promoter of MTHFR gene in sperms is associated with idiopathic male infertility. The functional relevance of hypermathylation of MTHFR to male fertility warrants further investigation.
异常的种系 DNA 甲基化已被提出，可能是导致一些目前被诊断为特发性不育男性精子发生受损的机制。以前的研究主要集中在人类精子质量较差的印迹基因的 DNA 甲基化上。然而，最近但有限的数据表明，精子甲基化异常可能涉及大量基因，或者表明非印迹基因也受到影响。
方法/主要发现：我们使用甲基化特异性聚合酶链反应和亚硫酸氢盐测序方法，检测了来自 94 名特发性不育男性和 54 名正常生育对照组精子 DNA 中亚甲基四氢叶酸还原酶（MTHFR）基因启动子（NG_013351：1538-1719）的甲基化模式。特发性不育患者进一步分为正常精子症和少精子症组。总体而言，45%（41/94）的特发性不育男性存在 MTHFR 过度甲基化（半甲基化和全甲基化），而正常生育对照组为 15%（P<0.05）。MTHFR 甲基化水平较高的患者更有可能患有特发性男性不育（趋势检验 P 值=0.0007）。比较两组精子浓度不同的特发性不育患者，发现少精子症组的甲基化模式更高。
MTHFR 基因启动子的过度甲基化与特发性男性不育有关。MTHFR 过度甲基化对男性生育力的功能相关性值得进一步研究。
