Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy.
Department of Clinical and Experimental Sciences, Unit of Endocrinology, University of Brescia, Brescia, Italy.
Andrology. 2019 Mar;7(2):251-256. doi: 10.1111/andr.12583. Epub 2019 Jan 18.
Copy number variations (CNVs) play an important role in the onset of several diseases, and recently research focused on the relationship between these structural variants and diseases of the reproductive tract, including male infertility and cryptorchidism.
To evaluate the contribution of copy number variations of E2F1 gene to idiopathic male infertility and the factors influencing expression of this gene.
We performed a retrospective study on 540 subjects recruited from September 2014 to February 2015. TaqMan CNV assay was used to analyze E2F1 CNV. Real-time PCR was used to assess E2F1 and HSP70 expression level in heat stressed and transfected cells with three E2F1 copies.
We found a significant difference in the frequency of altered E2F1 copies in patients (12/343, 3.5%) compared with controls (0/197) (p = 0.005). Six patients with E2F1 CNV had history of cryptorchidism, but the prevalence between men with idiopathic infertility (6/243, 2.5%) and infertile men with history of cryptorchidism (6/100, 6.0%) was not statistically different (p = 0.1). E2F1 expression increased under heat stress conditions, especially in cells carrying more copies of gene and this was associated with increased expression of HSP70.
Our data suggest that an abnormal E2F1 expression caused by multiple copies of E2F1 gene predisposes to the onset of infertility and that the risk further increases if subjects with altered E2F1 copies have stressful conditions, such as heat stress or history of cryptorchidism.
This study shows a link between E2F1 CNV and male infertility, suggesting that the increased risk of spermatogenic impairment associated with higher E2F1 copies might be due to higher susceptibility to stressful conditions.
拷贝数变异（CNVs）在多种疾病的发生中起着重要作用，最近的研究集中在这些结构变异与生殖道疾病之间的关系上，包括男性不育和隐睾症。
评估 E2F1 基因拷贝数变异对特发性男性不育的影响，并评估影响该基因表达的因素。
我们对 2014 年 9 月至 2015 年 2 月招募的 540 名受试者进行了回顾性研究。采用 TaqMan CNV 分析技术分析 E2F1 CNV。实时 PCR 用于评估热应激和转染 3 个 E2F1 拷贝细胞中 E2F1 和 HSP70 的表达水平。
我们发现患者 E2F1 拷贝改变的频率与对照组（0/197）相比有显著差异（12/343，3.5%）（p=0.005）。6 例 E2F1 CNV 患者有隐睾症病史，但特发性不育男性（6/243，2.5%）和隐睾症病史不育男性（6/100，6.0%）之间的发生率无统计学差异（p=0.1）。E2F1 基因在热应激条件下表达增加，特别是在携带更多基因拷贝的细胞中，这与 HSP70 表达增加有关。
我们的数据表明，E2F1 基因的多个拷贝导致的异常 E2F1 表达易导致不育症的发生，如果 E2F1 拷贝改变的患者有应激条件，如热应激或隐睾症病史，风险进一步增加。
本研究表明 E2F1 CNV 与男性不育之间存在联系，提示与较高 E2F1 拷贝数相关的精子发生损伤风险增加可能是由于对应激条件的更高易感性所致。
