Paternal germ line aging: DNA methylation age prediction from human sperm

Jenkins, Timothy G.; Aston, Kenneth I.; Cairns, Bradley R.; Smith, Andrew D.; Carrell, Douglas T.

doi:10.1186/s12864-018-5153-4

Cited by 75 publications

(106 citation statements)

References 28 publications

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“…At each time point, the internal and external environments appear to have a major influence on how the epigenome is modified (Soubry et al , ). For example, sperm DNA methylation patterns have recently been shown to predict paternal age with a high degree of accuracy (Jenkins et al , ). Preliminary data suggest that environmental factors, such as smoking, may alter DNA methylation patterns to an age beyond actual chronologic age.…”

Section: Beyond the Male Genomementioning

confidence: 99%

“…Preliminary data suggest that environmental factors, such as smoking, may alter DNA methylation patterns to an age beyond actual chronologic age. As the database grows using this unique sperm DNA methylation model (Jenkins et al , ), it will be important to learn how lifestyle, that is, environmental factors, may artificially age a man’s spermatozoa and, in consequence, how it may impact the gestating fetus, neonate, and child.…”

Section: Beyond the Male Genomementioning

confidence: 99%

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The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap

2019

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Background: There is a global crisis in male reproductive health. Evidence comes from globally declining sperm counts and increasing male reproductive system abnormalities, such as cryptorchidism, germ cell tumors, and onset of puberty. Male factor infertility occurs in~40% of couples experiencing infertility. Data demonstrate an association between male infertility and overall health. Associated significant health conditions include diabetes mellitus, metabolic disorders, and cardiovascular disease. Adding to the complexity is that men typically do not seek health care unless there is acute medical need or, as in the case of the infertile couple, the male goes for a reproductive examination and semen analysis. However, 25% of the time a reproductive health examination does not occur. Couples are increasingly utilizing IVF at more advanced ages, and advanced paternal age is associated with increased risk for (i) adverse perinatal outcomes for both offspring and mother; (ii) early child mortality, cancer, and mental health issues. In addition to age, paternal lifestyle factors, such as obesity and smoking, impact not only the male fertility but also the offspring wellness.Objectives: The purpose of this paper was (i) to spotlight emerging and concerning data on male reproductive health, the relationship(s) between male reproductive and somatic health, and the heritable conditions father can pass to offspring, and (ii) to present a strategic roadmap with the goals of increasing (a) the awareness of men and society on the aforementioned, (b) the participation of men in healthcare seeking, and (c) advocacy to invigorate policy and funding agencies to support increased research into male reproductive biology. Conclusions: The Male Reproductive Health Initiative (MRHI) is a newly established and rapidly growing global consortium of key opinion leaders in research, medicine, funding and policy agencies, and patient support groups that are moving forward the significant task of accomplishing the goals of the strategic roadmap.

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Section: Beyond the Male Genomementioning

confidence: 99%

Section: Beyond the Male Genomementioning

confidence: 99%

The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap

2019

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“…This is likely because the Horvath DNA methylation was developed using only 45 samples of semen in a total of 7,844 samples (0.6%) of different tissue samples, including 4,180 blood-derived samples (53%) [4]. However, age could more accurately be predicted using the model recently developed by Jenkins and colleagues [22], which was specifically trained on sperm samples (r = 0.68, P = 1.78 ´ 10 -7 , Figure S1B).…”

Section: General Characterisation Of the Sperm Dna Methylomementioning

confidence: 99%

“…DNA methylation age was estimated on the discovery sample from both blood and sperm DNA methylation using Horvath's DNA methylation age estimator [4]. We additionally estimated DNA methylation age from sperm using the method described by Jenkins and colleagues [22].…”

Section: Dna Methylation Age Estimatesmentioning

confidence: 99%

DNA methylation covariation in human whole blood and sperm: implications for studies of intergenerational epigenetic effects

Åsenius

Gorrie-Stone

Brew

et al. 2020

Preprint

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BackgroundEpidemiological studies suggest that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals suggest that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero.Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genomewide DNA methylation using the Illumina MethylationEPIC array in matched human blood and sperm from lean (discovery n=47; replication n=21) and obese (n=22) males to analyse tissue covariation of DNA methylation, and identify whether this covariation is influenced by obesity. ResultsDNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). While at the majority of these sites, DNA methylation appears to be influenced by genetic variation, obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity did not influence covariation patterns. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P=8.95 ´ 10 -8 ; beta=0.02) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n=5,917), spermatozoa displayed differential DNA methylation in pathways enriched in transcriptional regulation. ConclusionsHuman sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. Obesity only nominally influences sperm DNA methylation, making it an unlikely mediator of intergenerational effects of metabolic traits. BackgroundMultiple large-scale epigenome-wide association studies in humans have shown that environmental and acquired phenotypes, including smoking, ageing and obesity, are associated with altered DNA methylation in peripheral blood [1][2][3][4]. Whether such phenotypes also have the potential to induce epigenetic changes in gametes has generated considerable interest in recent years. Studies in nonhuman mammals suggest that the spermatozoal DNA methylome can be influenced by factors such as dietary alterations, toxicants and even psychological stress [5-10], although the majority of these results have yet to be replicated independently. A small number of studies also suggest that acquired traits in male mice induce epigenetic changes in sperm, which in turn influence the physiology of offspring [7,11,12].There is little evidence for such inter-and transgenerational effects of acquired phenotypes via epigenetic inheritance in humans. This is partly due to the fact that human sperm is rarely analysed outside of a reproductive medicine setting and is less accessible than, for example, peripheral blood.Further, it is ethically and practically impossible to perform a study of transgenerational effects in hum...

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“…Among the hypotheses put forward to explain the detrimental effects of age on male fertility and offspring health, epigenetic changes to the DNA stand out. Changes in DNA methylation accumulate in the male germline with age (15)(16)(17), however only a small portion of all CpG sites in the genome have so far been interrogated.…”

Section: Introductionmentioning

confidence: 99%

Healthy ageing men have normal reproductive function but display germline-specific molecular changes

Laurentino

Cremers

Horsthemke

et al. 2019

Preprint

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Children of older fathers have higher risk for certain diseases. Nevertheless, how ageing specifically affects male germ cells is so far not completely understood. In a cohort of 197 healthy men (18-84 years), we found that semen and reproductive parameters remained normal over six decades. Along with an age-dependent increase in telomere length in sperm (r=0.41, p>0.001), we found accelerated DNA fragmentation, more prominent after the sixth decate of life, and with around 60% of men older than 66 showing abnormal levels of DNA breaks. At the epigenetic level, by whole genome bisulfite sequencing we identified 236 sperm-specific differentially methylated regions between the youngest and oldest group, affecting mostly regions associated with homeobox genes and nervous system development. Therefore, we propose that during ageing, male germ cells are affected by an intrinsic and specific ageing process, distinguishable from the soma. These age-dependent changes might have consequences for fertility and offspring of older men.

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Paternal germ line aging: DNA methylation age prediction from human sperm

Cited by 75 publications

References 28 publications

The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap

The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap

DNA methylation covariation in human whole blood and sperm: implications for studies of intergenerational epigenetic effects

Healthy ageing men have normal reproductive function but display germline-specific molecular changes

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