The Sperm Epigenome, Male Aging, and Potential Effects on the Embryo.

The effect of paternal aging on fertility, embryo quality, and offspring health is an important area of study that has received far less attention than the age effect in women. This is, in part, due to the fact that in females there are dramatic alterations to fertility and pregnancy outcomes that abruptly occur as a female ages. Such abrupt alterations to pregnancy success and/or embryonic and offspring health are not seen in males. Instead, there are subtle alterations to pregnancy success and offspring phenotypes that occur as a man ages. It is believed that, at least in part, these alterations can be explained by perturbations to the sperm epigenome that occur over time. This chapter will explore the effect of aging on the sperm epigenome and the potential impacts these perturbations may have on embryonic development and ultimately offspring health.

Decreased fecundity and sperm DNA methylation patterns.

OBJECTIVE: To evaluate the relationship between epigenetic patterns in sperm and fecundity. DESIGN: Prospective study. SETTING: Academic andrology and in vitro fertilization laboratory. PATIENT(S): Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genomewide assessment of differential sperm DNA methylation and standard semen analysis. RESULT(S): We analyzed DNA methylation alterations associated with fecundity in 124 semen samples, and identified regions of interest in 27 semen samples from couples who conceived within 2 months of attempting a pregnancy and a total of 29 semen samples from couples who were unable to achieve a pregnancy within 12 months. No differences in sperm count, sperm morphology, or semen volume were observed between the patients achieving a pregnancy within 2 months of study time and those not obtaining a pregnancy within 12 months. However, using data from the human methylation 450k array analysis we did identify two genomic regions with statistically significantly decreased (false discovery rate <0.01) methylation and three genomic regions with statistically significantly increased methylation in the failure-to-conceive group. The only two sites where decreased methylation was associated with reduced fecundity are at closely related genes known to be expressed in sperm, HSPA1L and HSPA1B. CONCLUSION(S): Our data suggest that there are genomic loci where DNA methylation alterations are associated with decreased fecundity. We have thus identified candidate loci for future study to verify these results and investigate the causative or contributory relationship between altered sperm methylation and decreased fecundity.