Decreased fecundity and sperm DNA methylation patterns

Timothy G Jenkins; Kenneth I Aston; Tyson D Meyer; James M Hotaling; Monis B Shamsi; Erica B Johnstone; Kyley J Cox; Joseph B Stanford; Christina A Porucznik; Douglas T Carrell

doi:10.1016/j.fertnstert.2015.09.013

Male Fertility Male Endocrine and Genetic Factors

Decreased fecundity and sperm DNA methylation patterns

Jenkins TG, Aston KI, Meyer TD, Hotaling JM, Shamsi MB, Johnstone EB, Cox KJ, Stanford JB, Porucznik CA, Carrell DT

Published January 2016 Fertility and sterility, 105(1), 51-57.e3

DOI 10.1016/j.fertnstert.2015.09.013 PMID 26453269 PMC PMC4890464

RRM Academy Synopsis

Sperm DNA Methylation Marks Linked To Lower Fecundity In Men

Lower methylation at two sperm genes, HSPA1L and HSPA1B, was linked to partners not conceiving within 12 months, versus partners who conceived within 2 months, in a University of Utah study of sperm from the HOPE preconception study. The groups had 27 and 29 men. A standard sperm count, shape, and volume test found no difference.

Key Findings

Standard semen analysis measures, including sperm count, concentration, morphology, and volume, showed no significant difference between the 27 early-pregnancy couples and 29 not-pregnant couples (Table 1).
A genome-wide methylation array found 2 regions with significantly decreased methylation and 3 regions with significantly increased methylation in the not-pregnant group, at a corrected false discovery rate of 0.01 or lower.
The two regions with decreased methylation sit in closely related, sperm-expressed genes HSPA1L and HSPA1B; the HSPA1L finding reached a corrected false discovery rate below 0.00000001.
Methylation levels at HSPA1L and HSPA1B tracked each other closely within individual men (R2 = 0.6113, p < 0.0001).
About 54% of men with strong hypomethylation at both HSP genes were in couples that did not conceive, meaning the marks alone did not reliably separate the two groups.

Interpretation

This prospective study compared sperm from men whose partners conceived within 2 months to sperm from men whose partners had not conceived within 12 months. Splitting samples into four time-to-pregnancy groups, the share with strong hypomethylation rose as time to pregnancy grew longer. The no-pregnancy group's female partners had a higher body mass index on average. The authors note this as a possible confounder but say it does not explain the methylation result. The findings support larger studies of this methylation marker in couples trying to conceive.

RRM Context

The study authors say male factors cause reduced fertility on their own in about 30% of couples having trouble conceiving, and play a part in another 20%. Yet a standard sperm test often misses these cases, so many couples are told their infertility has no cause. This study looked past the standard sperm test for a hidden marker. Restorative reproductive medicine looks for an underlying cause when standard semen measures come back normal. The samples came from the HOPE study, which tracked couples over time while trying to get pregnant.

Our editorial summary of this paper, not the article's abstract.

Abstract

Objective

To evaluate the relationship between epigenetic patterns in sperm and fecundity.

Design

Prospective study.

Setting

Academic andrology and in vitro fertilization laboratory.

Patients

Twenty-seven 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.

Interventions

None.

Main Outcome Measures

Genomewide assessment of differential sperm DNA methylation and standard semen analysis.

Results

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.

Conclusions

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.

Topics

Male Fertility › Male Endocrine and Genetic Factors › Genetic Causes of Male Infertility · Genetics and Immunology › Reproductive Genetics › Epigenetics

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

Tim Jenkins, T Jenkins, Ken Aston, K Aston, T Meyer, Jim Hotaling, Jimmy Hotaling, J Hotaling, M Shamsi, E Johnstone, K Cox, Joe Stanford, Joey Stanford, J Stanford, C Porucznik, Doug Carrell, D Carrell

PMID 26453269 26453269 DOI 10.1016/j.fertnstert.2015.09.013 10.1016/j.fertnstert.2015.09.013 Jenkins et al. 2016, Jenkins 2016

Decreased fecundity and sperm DNA methylation patterns

Sperm DNA Methylation Marks Linked To Lower Fecundity In Men

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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