Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA.
Hum Reprod Update. 2023 Jan 5;29(1):24-44. doi: 10.1093/humupd/dmac033.
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.
大多数发达国家的现代生殖行为的特点是延迟生育。年龄较大的配子通常生育能力较低，同时积累和加剧了各种环境暴露的影响，这些影响又受到生活方式因素的改变。临床医生主要关注高龄产妇，而父亲年龄对生育能力、早期发育和后代健康的影响仍未得到充分认识。越来越多的高龄夫妇倾向于使用辅助生殖技术。因此，越来越多的孩子是由年龄较大的配子生育的。
我们综述了报道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。探讨了环境、生育能力、ART 和与年龄相关的表观遗传特征之间的相互作用。我们专注于精子表观遗传学与胚胎和后代的表观遗传和表型事件之间的关联。
使用 PubMed 和 Web of Science 检索过去二十年的同行评议原始研究和综述文章，以进行此叙述性综述。通过采用两组主要术语进行搜索。第一组包括“高龄父亲”、“父亲年龄”、“推迟父亲身份”、“晚育父亲”、“年老父亲”，第二组包括“精子表观遗传学”、“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”、“表观遗传时钟”。
年龄是人类和啮齿动物模型中的一个强大因素，与新发生突变和精子表观基因组的改变有关。年龄会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 谱。虽然 DNA 甲基化是研究最多的，但关于随着年龄增长而出现差异低甲基化或高甲基化区域的方向存在争议。基于横断面数据和四种不同的 DNA 甲基化分析方法成功开发了人类精子表观遗传时钟，表明至少一些 CpG 表现出甲基化水平与年龄之间的线性关系。啮齿动物研究表明，通过年龄依赖性差异甲基化区域调控的基因与通过年龄依赖性 sncRNA 靶向的基因之间存在显著重叠。这两种年龄依赖性的表观遗传机制都靶向了富含胚胎发育、神经发育、生长和代谢途径的基因网络。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的表观突变的随机积累，并且可能与自闭症谱系障碍有关。化学和生活方式暴露以及 ART 技术可能会影响精子的表观遗传衰老。尽管大多数表观遗传修饰在早期哺乳动物胚胎中被抹去，但越来越多的证据表明，由于父亲的精子随时间积累表观遗传变化，后代的表观基因组和表型发生改变与高龄父亲有关。有人假设，精子表观基因组的年龄诱导变化是深刻的、生理的、多年来是动态的，但在数天和数月内是稳定的，而且可能是不可逆转的。
本综述引起了人们对延迟生育和与年龄相关的精子表观遗传变化的关注，这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。我们建议更广泛地讨论自然和 ART 受孕中父亲年龄的调节问题。专业界应了解并在人群中以及在为老年男性提供咨询时提高认识。
