Decreased fecundity and sperm DNA methylation patterns

Capsule:
Sperm DNA methylation profiles at five distinct genomic regions are associated with decreased fecundity in a well-characterized patient population.

Authors:
Timothy G. Jenkins, Ph.D., Kenneth I. Aston, Ph.D., Tyson D. Meyer, B.S., James M. Hotaling, M.D., M.S., Monis B. Shamsi, Ph.D., Erica B. Johnstone, M.D., Kyley J. Cox, M.P.H., Joseph B. Stanford, M.D., M.S.P.H., Christina A. Porucznik, Ph.D., M.S.P.H., Douglas T. Carrell, Ph.D.

Volume 105, Issue 1, Pages 51-57

Abstract:

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):
27 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.

  • This study lifts the proverbial hood of the sperm and looks deeper into the engine. Genomics is the future of male infertility evaluation. We have relied on semen analysis for a long time. Although it is a good start to the evaluation, it is incomplete as this study demonstrates, normal sperm does not equate to normal ability to fertility and conceive. Now that a potential marker at HSP gene has been found, lets find out what etiology result in increased methylation at this region, and then ultimately, how do we treat it?

  • Ranjith Ramasamy

    A great study that demonstrates that we need to look beyond “bulk” semen parameters to identify causes of male infertility. It would be interesting to find out whether men who had increased methylation in the HSP genes had varicoceles since previous studies have identified an association between varicocele and HSP gene function.

  • Jason M. Franasiak

    A fascinating study which identifies 2 areas which are aberrantly methylated in a well-defined cohort. In this particular group SA parameters didn’t differ, just clinical outcomes. Is there any known data connecting these methylation patterns to abnormalities in SA parameters or would this be proposed as a stand-alone separate work-up pathway for male infertility given SA poor prognostic performance? Any data to suggest the stability of these methylation patterns over time? Thank you for your time and interesting work.

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