Aberrant sperm DNA methylation predicts male fertility status and embryo quality

Capsule:
Genome wide sperm DNA patterns in fertile and infertile men are highly predictive of fertility status and may predict embryonic developmental capacity during IVF.

Authors:
Kenneth I. Aston, Ph.D., Philip J. Uren, Ph.D., Timothy G. Jenkins, Ph.D., Alan Horsager, Ph.D., Bradley R. Cairns, Ph.D., Andrew D. Smith, Ph.D., Douglas T. Carrell, Ph.D.

Volume 104, Issue 6, Pages 1388-1397

Abstract:

Objective:
To evaluate whether male fertility status and/or embryo quality during in vitro fertilization (IVF) therapy can be predicted based on genomewide sperm deoxyribonucleic acid (DNA) methylation patterns.

Design:
Retrospective cohort study.

Setting:
University-based fertility center.

Patient(s):
Participants were 127 men undergoing IVF treatment (where any major female factor cause of infertility had been ruled out), and 54 normozoospermic, fertile men. The IVF patients were stratified into 2 groups: patients who had generally good embryogenesis and a positive pregnancy (n = 55), and patients with generally poor embryogenesis (n = 72; 42 positive and 30 negative pregnancies) after IVF.

Intervention(s):
Genomewide sperm DNA methylation analysis was performed to measure methylation at >485,000 sites across the genome.

Main Outcome Measure(s):
A comparison was made of DNA methylation patterns of IVF patients vs. normozoospermic, fertile men.

Result(s):
Predictive models proved to be highly accurate in classifying male fertility status (fertile or infertile), with 82% sensitivity, and 99% positive predictive value. Hierarchic clustering identified clusters enriched for IVF patient samples and for poor-quality–embryo samples. Models built to identify samples within these groups, from neat samples, achieved positive predictive value ≥94% while identifying >one fifth of all IVF patient and poor-quality–embryo samples in each case. Using density gradient prepared samples, the same approach recovered 46% of poor-quality–embryo samples with no false positives.

Conclusion(s):
Sperm DNA methylation patterns differ significantly and consistently for infertile vs. fertile, normozoospermic men. In addition, DNA methylation patterns may be predictive of embryo quality during IVF.

  • The authors have used global methylation of sperm DNA to predict embryo quality. Did the authors look at specific genes that influence spermatogenesis / meiosis to identify whether there were methylation differences ?

  • Jason M. Franasiak

    A very interesting study analyzing methylation patterns in fertile and sub-fertile men. Is there any evidence to suggest that this methylation pattern is reproducible over time or would it be limited to assessing the sample utilized for the treatment cycle?

  • The limitation in the male fertility evaluation lies in the semen analysis in that a man with a “normal” semen analysis may be infertility, yet his counterpart with an “abnormal” semen analysis may not have any problems conceiving. This is where specialized sperm testing comes into place. A lot of specialized testing drill down into the DNA of the sperm trying to parse out other abnormalities that may contribute to infertility besides the shape/size/motility. These authors present Sperm DNA methylation patterns as another possible specialized test that may also have the added benefit to predict embryo quality during IVF/ICSI. Larger scale studies will have to be performed to validate these findings, especially in men with severe infertility.

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