scholarly journals High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Mingju Cao ◽  
Xiaojian Shao ◽  
Peter Chan ◽  
Warren Cheung ◽  
Tony Kwan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Sperm ◽  
Distal Region ◽  
Epigenetic Alterations ◽  
Transcription Start Sites ◽  
Neurodevelopmental Disease ◽  
Cpg Sites ◽  
Age Related ◽  
Sperm Dna ◽  
Sperm Dna Methylation

Abstract Background Children of aged fathers are at a higher risk of developing mental disorders. Alterations in sperm DNA methylation have been implicated as a potential cause. However, age-dependent modifications of the germ cells’ epigenome remain poorly understood. Our objective was to assess the DNA methylation profile of human spermatozoa during aging. Results We used a high throughput, customized methylC-capture sequencing (MCC-seq) approach to characterize the dynamic DNA methylation in spermatozoa from 94 fertile and infertile men, who were categorized as young, 48 men between 18–38 years or old 46 men between 46–71 years. We identified more than 150,000 age-related CpG sites that are significantly differentially methylated among 2.65 million CpG sites covered. We conducted machine learning using our dataset to predict the methylation age of subjects; the age prediction accuracy based on our assay provided a more accurate prediction than that using the 450 K chip approach. In addition, we found that there are more hypermethylated (62%) than hypomethylated (38%) CpG sites in sperm of aged men, corresponding to 798 of total differential methylated regions (DMRs), of which 483 are hypermethylated regions (HyperDMR), and 315 hypomethylated regions (HypoDMR). Moreover, the distribution of age-related hyper- and hypomethylated CpGs in sperm is not random; the CpG sites that were hypermethylated with advanced age were frequently located in the distal region to genes, whereas hypomethylated sites were near to gene transcription start sites (TSS). We identified a high density of age-associated CpG changes in chromosomes 4 and 16, particularly HyperDMRs with localized clusters, the chr4 DMR cluster overlaps PGC1α locus, a protein involved in metabolic aging and the chr16 DMR cluster overlaps RBFOX1 locus, a gene implicated in neurodevelopmental disease. Gene ontology analysis revealed that the most affected genes by age were associated with development, neuron projection, differentiation and recognition, and behaviour, suggesting a potential link to the higher risk of neurodevelopmental disorders in children of aged fathers. Conclusion We identified thousands of age-related and sperm-specific epigenetic alterations. These findings provide novel insight in understanding human sperm DNA methylation dynamics during paternal aging, and the subsequently affected genes potentially related to diseases in offspring.

scholarly journals Refraining from use diminishes cannabis-associated epigenetic changes in human sperm

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Rose Schrott ◽  
Susan K Murphy ◽  
Jennifer L Modliszewski ◽  
Dillon E King ◽  
Bendu Hill ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Development ◽  
Bisulfite Sequencing ◽  
Human Sperm ◽  
Whole Genome ◽  
Epigenetic Changes ◽  
Cpg Sites ◽  
Sperm Dna ◽  
Genome Bisulfite Sequencing ◽  
Sperm Dna Methylation

Abstract Cannabis use alters sperm DNA methylation, but the potential reversibility of these changes is unknown. Semen samples from cannabis users and non-user controls were collected at baseline and again following a 77-day period of cannabis abstinence (one spermatogenic cycle). Users and controls did not significantly differ by demographics or semen analyses. Whole-genome bisulfite sequencing identified 163 CpG sites with significantly different DNA methylation in sperm between groups (P < 2.94 × 10−9). Genes associated with altered CpG sites were enriched with those involved in development, including cardiogenesis and neurodevelopment. Many of the differences in sperm DNA methylation between groups were diminished after cannabis abstinence. These results indicate that sustained cannabis abstinence significantly reduces the number of sperm showing cannabis-associated alterations at genes important for early development.

scholarly journals Male obesity impacts DNA methylation reprogramming in sperm

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sanaz Keyhan ◽  
Emily Burke ◽  
Rose Schrott ◽  
Zhiqing Huang ◽  
Carole Grenier ◽  
...  
Keyword(s):  
Dna Methylation ◽  
System Development ◽  
Human Sperm ◽  
Nervous System Development ◽  
Cpg Sites ◽  
Epididymal Maturation ◽  
Sperm Dna ◽  
Stem Cell Pluripotency ◽  
The Impact ◽  
Sperm Dna Methylation

Abstract Background Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47). Results We identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm. Conclusions Male obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.

scholarly journals Sperm DNA methylation mediates the association of male age on reproductive outcomes among couples undergoing infertility treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oladele A. Oluwayiose ◽  
Haotian Wu ◽  
Hachem Saddiki ◽  
Brian W. Whitcomb ◽  
Laura B. Balzer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Developed Countries ◽  
Infertility Treatment ◽  
Reproductive Outcomes ◽  
Neurodevelopmental Outcomes ◽  
Male Age ◽  
Age Related ◽  
Sperm Dna ◽  
Increased Risk ◽  
Sperm Dna Methylation

AbstractParental 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.

scholarly journals Exposure to childhood abuse is associated with human sperm DNA methylation

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Andrea L. Roberts ◽  
Nicole Gladish ◽  
Evan Gatev ◽  
Meaghan J. Jones ◽  
Ying Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Childhood Abuse ◽  
Human Sperm ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Sperm DNA methylation epimutation biomarker for paternal offspring autism susceptibility

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicolás Garrido ◽  
Fabio Cruz ◽  
Rocio Rivera Egea ◽  
Carlos Simon ◽  
Ingrid Sadler-Riggleman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Autism Spectrum ◽  
Epigenetic Alterations ◽  
Genome Wide ◽  
Sperm Dna ◽  
A Genome ◽  
Potential Biomarker ◽  
Test Sets ◽  
Autism Susceptibility ◽  
Sperm Dna Methylation

Abstract Background Autism spectrum disorder (ASD) has increased over tenfold over the past several decades and appears predominantly associated with paternal transmission. Although genetics is anticipated to be a component of ASD etiology, environmental epigenetics is now also thought to be an important factor. Epigenetic alterations, such as DNA methylation, have been correlated with ASD. The current study was designed to identify a DNA methylation signature in sperm as a potential biomarker to identify paternal offspring autism susceptibility. Methods and results Sperm samples were obtained from fathers that have children with or without autism, and the sperm then assessed for alterations in DNA methylation. A genome-wide analysis (> 90%) for differential DNA methylation regions (DMRs) was used to identify DMRs in the sperm of fathers (n = 13) with autistic children in comparison with those (n = 13) without ASD children. The 805 DMR genomic features such as chromosomal location, CpG density and length of the DMRs were characterized. Genes associated with the DMRs were identified and found to be linked to previously known ASD genes, as well as other neurobiology-related genes. The potential sperm DMR biomarkers/diagnostic was validated with blinded test sets (n = 8–10) of individuals with an approximately 90% accuracy. Conclusions Observations demonstrate a highly significant set of 805 DMRs in sperm that can potentially act as a biomarker for paternal offspring autism susceptibility. Ancestral or early-life paternal exposures that alter germline epigenetics are anticipated to be a molecular component of ASD etiology.

scholarly journals Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression

2014 ◽  
Vol 20 (8) ◽  
pp. 995-1001 ◽  
Author(s):  
M H Milekic ◽  
Y Xin ◽  
A O’Donnell ◽  
K K Kumar ◽  
M Bradley-Moore ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Abnormal Behavior ◽  
Age Related ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants

2020 ◽  
Author(s):  
J.Richard Pilsner ◽  
Alex Shershebnev ◽  
Haotian Wu ◽  
Chelsea Marcho ◽  
Olga Dribnokhodova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Flame Retardants ◽  
Natural Aging ◽  
Paternal Age ◽  
Epigenetic Changes ◽  
Age Related ◽  
Sperm Dna ◽  
Age Dependent ◽  
Environmental Xenobiotic ◽  
Sperm Dna Methylation

Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2&rsquo;,4,4&rsquo;-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; &ge; 10x coverage depth, &ge; 3 CpGs per cluster, &ge; 5% methylation change, q &lt; 0.05) were identified via MethPipe package. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, Hippo and Wnt pathways. Age-related changes in sncRNA, reported in different study, target similar list of genes and biological categories.In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of epigenetic mechanisms as a likely link betwen paternal age and offspring health and development.

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

2017 ◽  
Author(s):  
Timothy G Jenkins ◽  
Kenneth I Aston ◽  
Andrew Smith ◽  
Douglas T Carrell
Keyword(s):  
Dna Methylation ◽  
Germ Line ◽  
Human Sperm ◽  
Chronological Age ◽  
Methylation Array ◽  
Data Set ◽  
Sperm Dna ◽  
High Degree ◽  
Age Prediction ◽  
Sperm Dna Methylation

AbstractBackgroundThe relationship between aging and epigenetic profiles has been highlighted in many recent studies. Models using somatic cell methylomes to predict age have been successfully constructed. However, gamete aging is quite distinct and as such age prediction using sperm methylomes is ineffective with current techniques.ResultsWe have produced a model that utilizes human sperm DNA methylation signatures to predict chronological age by utilizing methylation array data from a total of 329 samples. The dataset used for model construction includes infertile patients, sperm donors, and individuals from the general population. Our model is capable of accurately predicting age with an R2 of 0.928 in our test data set. We additionally investigated the repeatability of prediction by processing the same sample on 6 different arrays and found very robust age prediction with an average standard deviation of only 0.877 years. Additionally, we found that smokers have approximately 5% increased age profiles compared to ‘never smokers.’ConclusionsThe predictive model described herein was built to offer researchers the ability to assess “germ line age” by accessing sperm DNA methylation signatures at genomic regions affected by age. Our data suggest that this model can predict an individual’s chronological age with a high degree of accuracy regardless of fertility status and with a high degree of repeatability. Additionally, our data appear to show age acceleration patterns as a result of smoking suggesting that the aging process in sperm may be impacted by environmental factors, though this effect appears to be quite subtle.

DNA methylation defects in spermatozoa of male partners from couples experiencing recurrent pregnancy loss

2020 ◽  
Author(s):  
Kushaan Khambata ◽  
Sanketa Raut ◽  
Sharvari Deshpande ◽  
Sweta Mohan ◽  
Shobha Sonawane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Methylation Status ◽  
Differentially Methylated Region ◽  
Imprinted Genes ◽  
Epigenetic Factors ◽  
Cpg Sites ◽  
Sperm Dna ◽  
Sperm Dna Methylation

Abstract STUDY QUESTION What is the sperm DNA methylation status of imprinted genes in male partners from couples experiencing recurrent pregnancy loss (RPL)? SUMMARY ANSWER Aberrations in sperm DNA methylation status of several imprinted genes, such as insulin like growth factor-2-H19 differentially methylated region (IGF2-H19 DMR), intergenic differentially methylated region (IG-DMR), mesoderm specific transcript (MEST), zinc finger protein which regulates apoptosis and cell cycle arrest (ZAC), DMR in intron 10 of KCNQ1 gene (KvDMR), paternally expressed gene 3 (PEG3) and paternally expressed gene 10 (PEG10), as well as decreased sperm global 5-methylcytosine (5mC) levels, are associated with RPL. WHAT IS KNOWN ALREADY RPL is defined as loss of two or more pregnancies, affecting 1–2% of couples of reproductive age. Although there are several maternal and paternal aetiological factors contributing to RPL, nearly 50% of the cases remain idiopathic. Thus, there is a need to identify putative paternal factors that could be contributing towards pregnancy loss in cases of idiopathic RPL. STUDY DESIGN, SIZE, DURATION In this case–control study, 112 couples undergoing RPL with no identifiable cause were recruited from September 2015 to May 2018. The control group comprised of 106 healthy proven fertile couples with no history of infertility or miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, we investigated the paternal genetic and epigenetic factors that could be associated with RPL. We studied DNA methylation, by pyrosequencing, of selected imprinted genes implicated in embryo development, such as IGF2-H19 DMR, IG-DMR, MEST, ZAC, KvDMR, PEG3, PEG10 and small nuclear ribonucleoprotein polypeptide N (SNRPN) in sperm of men whose partners present RPL. Global DNA methylation in sperm was evaluated by studying 5mC content and long interspersed nuclear element 1 (LINE1) promoter methylation. We also studied polymorphisms by pyrosequencing in the IGF2-H19 DMR as well in the IGF2 promoter in both groups. MAIN RESULTS AND THE ROLE OF CHANCE In the RPL group, we found a significant decrease in the global sperm 5mC levels and significant decrease in DNA methylation at three CpG sites in LINE1 promoter. For IGF2-H19 DMR and IG-DMR, a significant decrease in sperm DNA methylation at specific CpG sites was observed in RPL group. For maternally imprinted genes like MEST, ZAC, KvDMR, PEG3 and PEG10 hypermethylation was noted. Polymorphism studies for IGF2-H19 DMR and IGF2 revealed significant differences in the genotypic frequencies in males. LIMITATIONS, REASONS FOR CAUTION In this study, we analysed the methylation levels of selected candidate imprinted genes implicated in embryo development. Detection of methylation changes occurring at the genome-wide level may reveal further candidate genes having a better distinction between the control and study groups. WIDER IMPLICATIONS OF THE FINDINGS Our study demonstrates that certain polymorphisms and aberrant sperm methylation status in imprinted genes are associated with RPL and could contribute to the aetiology of RPL. This study suggests that investigation of paternal genetic and epigenetic factors could be useful in identification of possible causes of idiopathic RPL. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Department of Science and Technology-Science and Engineering Research Board (EMR/2014/000145) and National Institute for Research in Reproductive Health intramural funds (RA/872/01-2020). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

scholarly journals Age-associated sperm DNA methylation patterns do not directly persist trans-generationally

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Timothy G. Jenkins ◽  
Emma R. James ◽  
Kenneth I. Aston ◽  
Albert Salas-Huetos ◽  
Alexander W. Pastuszak ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Human Sperm ◽  
Paternal Age ◽  
Sperm Dna ◽  
Two Generations ◽  
Methylation Patterns ◽  
The Impact ◽  
Sperm Dna Methylation

Abstract 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.

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