BACKGROUND The impact of aging on the sperm methylome is well understood. However, the direct, subsequent impact on offspring and the role of altered sperm DNA methylation alterations in this process remain poorly understood. The well-defined impact of aging on sperm DNA methylation represents an excellent opportunity to trace the direct, transgenerational transmission of these signals. RESULTS We utilized the Illumina MethylationEPIC array to analyze the sperm of 16 patients with older (> 40 years of age) paternal grandfathers ('old grand paternal age' patients; OGPA) and 16 patients with younger (< 25 years of age) grandfathers ('young grand paternal age' patients; YGPA) identified through the Subfertility Health Assisted Reproduction and the Environment (SHARE) cohort to investigate differences in DNA methylation. No differentially methylated regions were identified between the OGPA and YGPA groups. Further, when assessing only the sites previously shown to be altered by age, no statistically significant differences between OGPA and YGPA were identified. This was true even despite the lower bar for significance after removing multiple comparison correction in a targeted approach. Interestingly though, in an analysis of the 140 loci known to have decreased methylation with age, the majority (~ 72%) had lower methylation in OGPA compared to YGPA though the differences were extremely small (~ 1.5%). CONCLUSIONS This study suggests that the robust and consistent age-associated methylation alterations seen in human sperm are 'reset' during large-scale epigenetic reprograming processes and are not directly inherited trans-generationally (over two generations). An extremely small trend was present between the YGPA and OGPA groups that resemble the aging pattern in older sperm. However, this trend was not significant and was so small that, if real, is almost certainly biologically inert.

中文翻译：

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与年龄相关的精子DNA甲基化模式不会直接持续世代相传。

背景技术衰老对精子甲基化的影响是众所周知的。然而，对后代的直接，后续影响以及精子DNA甲基化改变在此过程中的作用仍知之甚少。衰老对精子DNA甲基化的明确影响代表了追踪这些信号直接，世代传递的绝好机会。结果我们利用Illumina MethylationEPIC阵列分析了16例年龄较大（> 40岁）祖父（'老年祖父年龄'患者; OGPA）和16例年龄较小（<25岁）祖父的精子（通过生育力健康辅助生殖与环境（SHARE）队列鉴定出的“年轻祖父母年龄”患者（YGPA），以研究DNA甲基化的差异。在OGPA和YGPA组之间未发现差异甲基化区域。此外，当仅评估先前显示随年龄改变的位点时，在OGPA和YGPA之间没有发现统计学上的显着差异。即使在有针对性的方法中删除了多个比较校正后，即使重要性的下限较低，也是如此。不过，有趣的是，在对140个已知随着年龄增长而甲基化程度降低的基因座的分析中，与YGPA相比，OGPA中的大多数（〜72％）甲基化程度较低，尽管差异非常小（〜1.5％）。结论这项研究表明，人类精子中发生的与年龄相关的强而一致的甲基化改变是“复位”的。在大规模表观遗传重编程过程中，不是跨代直接继承的（超过两代）。YGPA和OGPA组之间存在极小的趋势，类似于老年精子的衰老模式。但是，这种趋势并不明显，而且很小，以至于几乎可以肯定在生物学上是惰性的。