Differential DNA methylation pattern and sperm quality in men with varicocele.

OBJECTIVE:To study the global DNA methylation pattern in spermatozoa of patients with varicocele as well as investigate their semen quality. DESIGN:Prospective observational case-control study. SETTING:University-affiliated hospital. PATIENT(S):A total of 26 men with varicocele and 26 fertile men without the disorder. INTERVENTIONS:Analysis of semen quality and sperm DNA methylation patterns. MAIN OUTCOME MEASURE(S):Semen quality evaluated by semen analysis, and sperm DNA methylation patterns investigated using the Infinium MethylationEPIC BeadChip platform. RESULT(S):Men with varicocele displayed decreased semen quality. The sperm DNA methylation analysis showed that men with varicocele exhibit global hypomethylation in comparison with the control group. A total of 59 differentially methylated CpG sites were identified, most of them hypomethylated in the varicocele group. In regional analyses, 1,695 DNA regions were differentially methylated in men with varicocele. These regions show associations with gamete generation, meiotic and meiosis cell cycle, and semen quality based on gene ontology analysis. CONCLUSION(S):Gene ontology results suggest that changes in methylation may be associated with the low semen quality phenotype observed in some varicocele patients because the observed differentially methylated regions in varicocele patients are related to male reproductive pathways. Additionally, the varicocele grade may influence the magnitude of global sperm DNA methylation change. To our knowledge, this is the first report analyzing changes at a regional or CpG-specific level in men with varicocele.