Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm.

Sahar Houshdaran,Allen Yang,Rebecca Z Sokol,Peter W Laird,Kimberly Siegmund,Victoria K Cortessis,Rodolfo Aramayo

doi:10.1371/journal.pone.0001289

Sahar Houshdaran, Allen Yang + Show 5 more

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https://doi.org/10.1371/journal.pone.0001289

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Journal: PloS one	Publication Date: Dec 12, 2007
Citations: 322	License type: CC BY 4.0

Affiliation: University of Southern California

Abstract

BackgroundMale-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis.Methodology/Principal FindingWe determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm.ConclusionsThis is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.

Highlights

Five million women in the United States reported difficulty in achieving a pregnancy in comprehensive surveys conducted by the CDC and National Survey of Family Growth from 1982 until 1995 [1,2,3], indicating that ten to twenty percent of couples attempting pregnancy are infertile
Dramatic chromatin remodeling occurs during spermatogenesis [12,13], and widespread erasure of DNA methylation followed by de novo DNA methylation occurs developmentally in two broad waves [12,14,15,16,17]
The buffy coat-specific set comprises 7.2% of the 1,421 sequences including the majority of differentially methylated regions (DMRs) associated with imprinted genes that are on the Illumina panel

Summary

Introduction

Five million women in the United States reported difficulty in achieving a pregnancy in comprehensive surveys conducted by the CDC and National Survey of Family Growth from 1982 until 1995 [1,2,3], indicating that ten to twenty percent of couples attempting pregnancy are infertile. Well defined causes of male-factor infertility include congenital and acquired dysfunction of the hypothalamic-pituitary-testicular endocrine axis, anatomic defects, chromosomal abnormalities, and point mutations [8,9,10]. These diagnoses account for only a small proportion of cases, and etiology remains unknown for most male-factor infertility patients [7,11]. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line

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Conclusion