Effects of sperm DNA methylation on domesticated animal performance and perspectives on cross-species epigenetics in animal breeding

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.

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

Scientific Reports ◽

10.1038/s41598-020-80857-2 ◽

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

Andrology ◽

10.1111/andr.12379 ◽

2017 ◽

Vol 5 (4) ◽

pp. 695-703 ◽

Cited By ~ 52

Author(s):

D. Santi ◽

S. De Vincentis ◽

E. Magnani ◽

G. Spaggiari

Keyword(s):

Dna Methylation ◽

Male Infertility ◽

Analytic Study ◽

Sperm Dna ◽

Sperm Dna Methylation

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Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

10.1101/750638 ◽

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.

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

Fertility and Sterility ◽

10.1016/j.fertnstert.2009.09.010 ◽

2010 ◽

Vol 94 (5) ◽

pp. 1728-1733 ◽

Cited By ~ 191

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

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

International Journal of Epidemiology ◽

10.1093/ije/dyv028 ◽

2015 ◽

Vol 44 (4) ◽

pp. 1199-1210 ◽

Cited By ~ 67

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

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Exposure to childhood abuse is associated with human sperm DNA methylation

Translational Psychiatry ◽

10.1038/s41398-018-0252-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 16

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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Serum dioxin levels and sperm DNA methylation age: Findings in Vietnam war veterans exposed to Agent Orange

Reproductive Toxicology ◽

10.1016/j.reprotox.2020.06.004 ◽

2020 ◽

Vol 96 ◽

pp. 27-35

Author(s):

Jamaji C. Nwanaji-Enwerem ◽

Timothy G. Jenkins ◽

Elena Colicino ◽

Andres Cardenas ◽

Andrea A. Baccarelli ◽

...

Keyword(s):

Dna Methylation ◽

Vietnam War ◽

Agent Orange ◽

War Veterans ◽

Sperm Dna ◽

Dna Methylation Age ◽

Vietnam War Veterans ◽

Sperm Dna Methylation

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Sperm DNA methylation changes after short‐term nut supplementation in healthy men consuming a Western‐style diet

Andrology ◽

10.1111/andr.12911 ◽

2020 ◽

Author(s):

Albert Salas‐Huetos ◽

Emma R. James ◽

Jordi Salas‐Salvadó ◽

Mònica Bulló ◽

Kenneth I. Aston ◽

...

Keyword(s):

Dna Methylation ◽

Short Term ◽

Healthy Men ◽

Sperm Dna ◽

Sperm Dna Methylation

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Integrating Signals from Sperm Methylome Analysis and Genome-Wide Association Study for a Better Understanding of Male Fertility in Cattle

Epigenomes ◽

10.3390/epigenomes3020010 ◽

2019 ◽

Vol 3 (2) ◽

pp. 10 ◽

Cited By ~ 5

Author(s):

Lingzhao Fang ◽

Yang Zhou ◽

Shuli Liu ◽

Jicai Jiang ◽

Derek M. Bickhart ◽

...

Keyword(s):

Dna Methylation ◽

Complex Traits ◽

Male Fertility ◽

Genome Wide Association ◽

Human Society ◽

Potential Candidate ◽

Genome Wide ◽

Sperm Dna ◽

Genomic Regions ◽

Sperm Dna Methylation

Decreased male fertility is a big concern in both human society and the livestock industry. Sperm DNA methylation is commonly believed to be associated with male fertility. However, due to the lack of accurate male fertility records (i.e., limited mating times), few studies have investigated the comprehensive impacts of sperm DNA methylation on male fertility in mammals. In this study, we generated 10 sperm DNA methylomes and performed a preliminary correlation analysis between signals from sperm DNA methylation and signals from large-scale (n = 27,214) genome-wide association studies (GWAS) of 35 complex traits (including 12 male fertility-related traits). We detected genomic regions, which experienced DNA methylation alterations in sperm and were associated with aging and extreme fertility phenotypes (e.g., sire-conception rate or SCR). In dynamic hypomethylated regions (HMRs) and partially methylated domains (PMDs), we found genes (e.g., HOX gene clusters and microRNAs) that were involved in the embryonic development. We demonstrated that genomic regions, which gained rather than lost methylations during aging, and in animals with low SCR were significantly and selectively enriched for GWAS signals of male fertility traits. Our study discovered 16 genes as the potential candidate markers for male fertility, including SAMD5 and PDE5A. Collectively, this initial effort supported a hypothesis that sperm DNA methylation may contribute to male fertility in cattle and revealed the usefulness of functional annotations in enhancing biological interpretation and genomic prediction for complex traits and diseases.

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