Teratozoospermia and asthenozoospermia are associated with specific epigenetic signatures

Semen analysis is commonly used as a tool to assess the fertility potential of a male, despite its relatively low predictive power. In this study, we have assessed associations between semen analysis findings (low count, low motility, low viability, poor sperm penetration assay results, poor morphology, and increased DNA damage) and DNA methylation patterns in mature spermatozoa. DNA methylation patterns in the mature spermatozoa are thought to be indicative of patterns in the adult germline stem cells and may offer insight into potential perturbations to cellular pathways involved in spermatogenesis. In this study, sperm DNA methylation at >480,000 CpGs was assessed in 94 men using the Illumina 450k HumanMethylation Array and compared to standard measures of sperm quality. We did not identify any global changes to methylation profiles that were associated with reduced semen parameters. Similarly, we found no significant difference in methylation variability that was associated with any abnormal semen analysis parameter, although sperm displaying abnormal parameters tended to have an increased coefficient of variability, suggesting that, in some samples, this may be a contributing factor. Analysis of methylation at single CpGs and genomic regions did identify associations for low viability and low motility, and to a smaller extent, low count. Interestingly, based on GO Term analysis, differentially methylated regions associated with low viability were over-represented in regions important in meiosis, spermatogenesis, and genomic imprinting. These results suggest that while there are not global alterations to the sperm methylome associated with semen abnormalites, some viability associated regional alterations do exist that may be indicative of perturbed cellular pathways during spermatogenesis.