Objective To evaluate the relationship between epigenetic patterns in sperm and fecundity. Design Prospective study of couples trying to conceive, utilizing semen samples collected through the HOPE study, at the University of Utah. Setting Academic Andrology and IVF Laboratory Patients DNA methylation alterations associated with fecundity were analyzed in 124 semen samples. 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 were analyzed to identify regions of interest. Interventions None. Main Outcome Measures Genome-wide assessment of differential sperm DNA methylation and standard semen analysis. Results 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 2 genomic regions with significantly decreased (FDR <0.01) methylation and 3 genomic regions with significantly increased methylation in the “failure-to-conceive” group. Interestingly, 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. Conclusions 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.

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.