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Additional systematic studies will be critical in defining the normal sperm epigenome. In addition, studies to assess the degree of epigenetic heterogeneity in sperm from a single collection are critical, as essentially all studies to date report average methylation for the entire sperm population. Lastly, characterization of the persistence of altered sperm epigenetic marks following fertilization is critical in order to predict the potential impact of altered sperm DNA methylation on offspring health. Analysis of the epigenetic status of sperm may well prove to be be a valuable diagnostic tool for male infertility, and it will certainly lend new insights into the mechanisms for transgenerational epigenetic inheritance; but in order for the field to reach its full potential, careful and thoughtful studies are needed to fully characterize the normal sperm epigenome, then assays to predict epigenetic abnormalities in sperm must be preceded by large-scale, repeatable validation studies. Until such studies are completed, the clinical utility of sperm epigenetic assays remains a hypothesis.

Prospects for clinically relevant epigenetic tests in the andrology laboratory