Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development.
Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development.
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DOI：
10.1093/humupd/dmac033
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发表时间：
2023-01-05
影响因子：
13.3
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中科院分区：
文献类型：
--
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大多数发达国家的现代生育行为的特点是推迟生育。年龄较大的配子通常不太肥沃，积累和复合各种环境暴露的影响，由生活方式因素改变。临床医生主要关注高龄产妇，而父亲年龄对生育力，早期发育和后代健康的影响仍然没有得到充分重视。对高龄育龄夫妇使用辅助生殖技术的趋势日益明显。因此，由较老的配子所生的孩子的数量正在增加。我们回顾了哺乳动物和人类精子中与年龄相关的表观遗传变化的研究，包括DNA甲基化，组蛋白修饰和非编码RNA。环境，生育力，ART和年龄相关的表观遗传签名之间的相互作用进行了探讨。我们专注于精子表观遗传学对胚胎和后代表观遗传和表型事件的关联。使用PubMed和Web of Science选择过去二十年的同行评审原始和综述文章进行叙述性综述。采用两组主要术语进行统计分析。第一组包括“高龄父龄"、”父龄“、”推迟父龄“、”晚父龄“、”老父龄“;第二组包括”精子表观遗传“、”精子“、”精液"、“表观遗传"、”遗传“、”DNA甲基化“、”染色质“、”非编码RNA“、”辅助生殖“、”表观遗传钟“。在人类和啮齿动物模型中，年龄是一个强有力的因素，与增加的从头突变和修饰的精子表观基因组相关。年龄影响所有已知的表观遗传机制，包括DNA甲基化，组蛋白修饰和小非编码（snc）RNA的概况。虽然DNA甲基化是研究最多的，但对于年龄依赖性变化的方向存在争议，这些变化在不同的低或高甲基化区域中随着年龄的增长而发生。基于横截面数据和四种不同的DNA甲基化分析方法的人类精子表观遗传时钟的成功开发表明，至少一些CpG在甲基化水平和年龄之间表现出线性关系。啮齿类动物的研究表明，通过年龄依赖性差异甲基化区域调控的基因和年龄依赖性sncRNA靶向的基因之间存在显著重叠。这两种年龄依赖性表观遗传机制的目标基因网络丰富的胚胎发育，神经发育，生长和代谢途径。因此，精子表观基因组的年龄依赖性变化不能被描述为随机表观突变的随机积累，并且可能与自闭症谱系障碍有关。化学品和生活方式暴露以及ART技术可能会影响精子的表观遗传老化。虽然大多数表观遗传修饰在早期哺乳动物胚胎中被消除，但越来越多的证据表明，由于父亲的精子随着时间的推移积累表观遗传变化，后代表观基因组和表型的改变与父亲年龄的增长有关。据推测，年龄引起的精子表观基因组的变化是深刻的，生理和动态的多年来，但稳定的几天和几个月，可能是不可逆的。这篇综述引起了人们对精子表观基因组中与年龄相关的父亲身份延迟和变化的关注，这些变化可能会损害父亲的生殖健康，并将改变的表观遗传信息传递给后代。建议使用考虑混杂因素的健康男性进行前瞻性研究。我们建议更广泛的讨论集中在自然和艺术概念的父亲的年龄的调节是必要的。专业界应了解情况，并应提高公众的认识，并在为老年男子提供咨询时提高认识。 年龄是精子表观遗传变化的驱动因素，包括DNA甲基化，组蛋白修饰和可能与后代神经发育障碍有关的小的非编码RNA谱。
Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors. Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced reproductive age. Thus, the number of children born from older gametes is increasing. We review studies reporting age-associated epigenetic changes in mammals and humans in sperm, including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in embryos and offspring. Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included ‘advanced paternal age’, ‘paternal age’, ‘postponed fatherhood’, ‘late fatherhood’, ‘old fatherhood’ and the second group included ‘sperm epigenetics’, ‘sperm’, ‘semen’, ’epigenetic’, ‘inheritance’, ‘DNA methylation’, ‘chromatin’, ‘non-coding RNA’, ‘assisted reproduction’, ‘epigenetic clock’. Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epigenetic modifications are erased in the early mammalian embryo, there is growing evidence that an altered offspring epigenome and phenotype is linked with advanced paternal age due to the father’s sperm accumulating epigenetic changes with time. It has been hypothesized that age-induced changes in the sperm epigenome are profound, physiological and dynamic over years, yet stable over days and months, and likely irreversible. This review raises a concern about delayed fatherhood and age-associated changes in the sperm epigenome that may compromise reproductive health of fathers and transfer altered epigenetic information to subsequent generations. Prospective studies using healthy males that consider confounders are recommended. We suggest a broader discussion focused on regulation of the father’s age in natural and ART conceptions is needed. The professional community should be informed and should raise awareness in the population and when counseling older men. Age is a driver of sperm epigenetic changes, including DNA methylation, histone modifications and small non-coding RNA profiles that may be linked with neurodevelopmental disorders in offspring.
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