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.

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 The combined effect of obesity and aging on human sperm DNA methylation signatures: inclusion of BMI in the paternal germ line age prediction model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Albert Salas-Huetos ◽  
Emma R. James ◽  
Dallin S. Broberg ◽  
Kenneth I. Aston ◽  
Douglas T. Carrell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Germ Line ◽  
Age Groups ◽  
Human Sperm ◽  
Absolute Error ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Sperm Dna ◽  
Epigenetic Age Acceleration ◽  
The Impact

Abstract Male aging and obesity have both been shown to contribute to declines in fertility in men. Recent work in aging has shown consistent epigenetic changes to sperm as a man ages. In fact, our lab has built a tool that utilizes DNA methylation signatures from sperm to effectively predict an individual’s age. Herein, we performed this preliminary cohort study to determine if increased BMI accelerates the epigenetic aging in sperm. A total of 96 participants were divided into four age groups (22–24, 30, 40–41, and > 48 years of age) and additionally parsed into two BMI sub-categories (normal and high/obese). We found no statistically significant epigenetic age acceleration. However, it is important to note that within each age category, high BMI individuals were predicted to be older on average than their actual age (~ 1.4 years), which was not observed in the normal BMI group. To further investigate this, we re-trained a model using only the present data with and without BMI as a feature. We found a modest but non-significant improvement in prediction with BMI [r2 = 0.8814, mean absolute error (MAE) = 3.2913] compared to prediction without BMI (r2 = 0.8739, MAE = 3.3567). Future studies with higher numbers of age-matched individuals are needed to definitively understand the impact of BMI on epigenetic aging in sperm.

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

BMC Genomics ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Timothy G. Jenkins ◽  
Kenneth I. Aston ◽  
Bradley Cairns ◽  
Andrew Smith ◽  
Douglas T. Carrell
Keyword(s):  
Dna Methylation ◽  
Germ Line ◽  
Human Sperm ◽  
Dna Methylation Age ◽  
Age Prediction

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 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.

scholarly journals Intra- and inter-individual differences in human sperm DNA methylation

Andrology ◽  
2016 ◽  
Vol 4 (5) ◽  
pp. 832-842 ◽  
Author(s):  
E. Dere ◽  
S. Huse ◽  
K. Hwang ◽  
M. Sigman ◽  
K. Boekelheide
Keyword(s):  
Dna Methylation ◽  
Individual Differences ◽  
Human Sperm ◽  
Sperm Dna ◽  
Sperm Dna Methylation

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 Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage

Epigenomes ◽  
2021 ◽  
Vol 5 (2) ◽  
pp. 10
Author(s):  
Clotilde Maurice ◽  
Mathieu Dalvai ◽  
Romain Lambrot ◽  
Astrid Deschênes ◽  
Marie-Pier Scott-Boyer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pregnancy Outcomes ◽  
Sperm Quality ◽  
The Arctic ◽  
Congenital Defects ◽  
Developmental Defects ◽  
Early Life Exposure ◽  
Sperm Dna ◽  
Inuit Population ◽  
Sperm Dna Methylation

Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved.

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.

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