Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, 173A Goessmann, 686 North Pleasant Street, Amherst, MA, 01003, USA.
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, 722 W 168th St, New York, NY, 10032, USA.
Sci Rep. 2021 Feb 5;11(1):3216. doi: 10.1038/s41598-020-80857-2.
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.
在发达国家，后代受孕时父母的年龄正在增加。男性年龄的增长与生殖成功率下降以及后代出现不良神经发育结果的风险增加有关。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。我们评估了来自寻求不孕治疗的夫妇中 47 名男性参与者的精液样本中的精子 DNA 全基因组甲基化。我们报告说，男性年龄越高，受精和活产的可能性越低，胚胎发育越差（p<0.05）。此外，我们的多变量线性模型显示，男性年龄与 1698 个 CpG 和 1146 个区域的精子甲基化改变有关（q<0.05），这些区域与胚胎发育、行为和神经发育等多种基因有关。高维中介分析确定了四个与年龄相关的精子差异甲基化的基因（DEFB126、TPI1P3、PLCH2 和 DLGAP2），它们解释了男性年龄对受精率降低的 64%（95%CI 0.42-0.86%；p<0.05）的影响。我们从这个适度的 IVF 人群中获得的发现为精子甲基化作为年龄引起的生殖不良结果的机制提供了证据，并确定了可能介导这些影响的候选基因。
