scholarly journals Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations

Development ◽  
2021 ◽  
Author(s):  
Gurbet Karahan ◽  
Donovan Chan ◽  
Kenjiro Shirane ◽  
Taylor McClatchie ◽  
Sanne Janssen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylenetetrahydrofolate Reductase ◽  
Embryonic Germ Cells ◽  
Sperm Dna ◽  
Sperm Counts ◽  
F2 Generation ◽  
Successive Generations ◽  
Mthfr Deficiency ◽  
The Impact ◽  
Sperm Dna Methylation

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations. While MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late embryonic germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in embryonic germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR- deficient males, findings compatible with the intergenerational passage of epimutations.

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 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.

scholarly journals Impairment of sperm DNA methylation in male infertility: a meta-analytic study

Andrology ◽  
2017 ◽  
Vol 5 (4) ◽  
pp. 695-703 ◽  
Author(s):  
D. Santi ◽  
S. De Vincentis ◽  
E. Magnani ◽  
G. Spaggiari
Keyword(s):  
Dna Methylation ◽  
Male Infertility ◽  
Analytic Study ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

2019 ◽  
Author(s):  
Patrick J Murphy ◽  
Jingtao Guo ◽  
Timothy G Jenkins ◽  
Emma R James ◽  
John R Hoidal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Dna Methylation ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Epigenetic Changes ◽  
Sperm Dna ◽  
Increased Risk ◽  
Paternal Smoking ◽  
Sperm Dna Methylation

SUMMARYPaternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. This study used mouse models to evaluate: 1) what impact paternal CS exposure has on sperm DNA methylation (DNAme), 2) whether sperm DNAme changes persist after CS exposure ends, 3) the degree to which DNAme and gene expression changes occur in offspring and 4) the mechanism underlying impacts of CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2-/- mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.

Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility

2010 ◽  
Vol 94 (5) ◽  
pp. 1728-1733 ◽  
Author(s):  
Saher Sue Hammoud ◽  
Jahnvi Purwar ◽  
Christian Pflueger ◽  
Bradley R. Cairns ◽  
Douglas T. Carrell
Keyword(s):  
Dna Methylation ◽  
Sperm Dna ◽  
Methylation Patterns ◽  
Sperm Dna Methylation

scholarly journals Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort

2015 ◽  
Vol 44 (4) ◽  
pp. 1199-1210 ◽  
Author(s):  
Jason I Feinberg ◽  
Kelly M Bakulski ◽  
Andrew E Jaffe ◽  
Rakel Tryggvadottir ◽  
Shannon C Brown ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Signs ◽  
Sperm Dna ◽  
Sperm Dna Methylation

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
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