Sperm DNA methylation mediates the association of male age on reproductive outcomes among couples undergoing infertility treatment.
Sperm DNA methylation mediates the association of male age on reproductive outcomes among couples undergoing infertility treatment.
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精子DNA甲基化介导男性年龄对接受不育治疗夫妇生殖结果的相关性
DOI：
10.1038/s41598-020-80857-2
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发表时间：
2021-02-05
影响因子：
4.6
通讯作者：
Pilsner JR
中科院分区：
文献类型：
--
作者：
Oluwayiose OA;Wu H;Saddiki H;Whitcomb BW;Balzer LB;Brandon N;Suvorov A;Tayyab R;Sites CK;Hill L;Marcho C;Pilsner JR
在发达国家，生育子女时的父母年龄正在增加。男性高龄与生育成功率降低和后代神经发育不良的风险增加有关。这些男性年龄效应的机制尚不清楚，但精子DNA甲基化随时间的变化是一个潜在的解释。我们评估了从寻求不育症治疗的夫妇的男性参与者那里收集的47个精液样本的精子DNA全基因组甲基化。我们报告，男性年龄越高，受精和活产的可能性越低，胚胎发育不良(p <； 0.05)。此外，我们的多变量线性模型显示，男性年龄与精子1698CPGS和1146个区域(Q <； 0.05)的甲基化变化有关，这些区域与胚胎发育、行为和神经发育等丰富的 >； 750基因相关。高维中介分析发现4个基因(DEFB126、TPI1P3、PLCH2和DLGAP2)存在与年龄相关的精子差异甲基化，它们解释了(95%CI 0.42~0.86%；p <； 0.05)男性年龄对低受精率的影响。我们在这个适度的试管受精人群中的发现为精子甲基化提供了证据，证明精子甲基化是年龄导致生殖不良结果的一种机制，并确定了可能的候选基因来调节这些影响。
Parental age at time of offspring conception is increasing in developed countries. Advanced male age is associated with decreased reproductive success and increased risk of adverse neurodevelopmental outcomes in offspring. Mechanisms for these male age effects remain unclear, but changes in sperm DNA methylation over time is one potential explanation. We assessed genome-wide methylation of sperm DNA from 47 semen samples collected from male participants of couples seeking infertility treatment. We report that higher male age was associated with lower likelihood of fertilization and live birth, and poor embryo development (p < 0.05). Furthermore, our multivariable linear models showed male age was associated with alterations in sperm methylation at 1698 CpGs and 1146 regions (q < 0.05), which were associated with > 750 genes enriched in embryonic development, behavior and neurodevelopment among others. High dimensional mediation analyses identified four genes (DEFB126, TPI1P3, PLCH2 and DLGAP2) with age-related sperm differential methylation that accounted for 64% (95% CI 0.42–0.86%; p < 0.05) of the effect of male age on lower fertilization rate. Our findings from this modest IVF population provide evidence for sperm methylation as a mechanism of age-induced poor reproductive outcomes and identifies possible candidate genes for mediating these effects.
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