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

Abstract

Parental 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.

Changes in Phenotypes and DNA Methylation of In Vitro Aging Sperm in Common Carp Cyprinus carpio

“…The observation is consistent with numerous studies that put into context aberrant sperm quality parameters and changes in mCpG levels in aged and/or infertile males [ 17 , 49 , 50 ]. Surprisingly, the majority of these studies, which also include other vertebrate species, observed an increase [ 51 , 52 , 53 , 54 , 55 ] rather than a decrease [ 23 ] in global DNA methylation. The DNA methylation change after 24 HPS can be explained in relation to the environmental changes that have occurred by the spermatozoa.…”

A higher preconceptional paternal body mass index influences fertilization rate and preimplantation embryo development

“…Significantly, lower DNA methylation levels were observed on Maternally Expressed Gene 3 (MEG3) and Necdin (NDN), but higher levels on the H19 gene 33 . A recent study shows that paternal aging can impact on the fertilization rate and day 5 embryo quality and that is preceded by deregulated methylation at imprinted genes in sperm 34 . Interestingly, the methylation status of sperm is dynamic and under environmental pressure.…”

“… 33 A recent study shows that paternal aging can impact on the fertilization rate and day 5 embryo quality and that is preceded by deregulated methylation at imprinted genes in sperm. 34 Interestingly, the methylation status of sperm is dynamic and under environmental pressure. More than 1500 unique genes had altered sperm DNA methylation profiles in six men undergoing Roux‐en‐Y gastric bypass surgery already 1 week after the surgery, which remained until at least 1 year after surgery.…”

Epigenetics in Male Infertility

“…DNA methylation is a reversible epigenetic mark and its effects may be reversed by using either demethylating agents, like DNA methyltransferase (DNMT) inhibitors, 5-azacitidine, and 5-aza-20 -deoxycytidine, or methyl donors, like choline, methionine, and folate [85,86]. However, a new study suggest that sperm methylation is a possible mechanism of age-induced poor reproductive outcomes among couples undergoing infertility treatment and that it can be used to identify the possible candidate genes for mediating the effects [87]. On the other hand, sperm cells from Norwegian red bulls of inferior fertility have less compact chromatin structure, higher levels of DNA damage, and are hypermethylated compared with bulls of superior fertility [88].…”