Document Type

Article

Publication Date

8-2019

Identifier

DOI: 10.1289/EHP4812; PMCID: PMC6792365

Abstract

Background: The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprograming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias toward CpG-dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements.

Objectives: Our goal was to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome.

Methods: To characterize variation in sperm DNA methylation, we performed whole genome bisulfite sequencing (WGBS) on an equimolar pool of sperm DNA from a wide cross section of 30 men varying in age, fertility status, methylenetetrahydrofolate reductase (MTHFR) genotype, and exposures. With our targeted capture panel, in individual samples, we examined the effect of MTHFR genotype ([Formula: see text] 677CC, [Formula: see text] 677TT), as well as high-dose folic acid supplementation ([Formula: see text], per genotype, before and after supplementation).

Results: Through WGBS we discovered nearly 1 million CpGs possessing intermediate methylation levels (20-80%), termed dynamic sperm CpGs. These dynamic CpGs, along with 2 million commonly assessed CpGs, were used to customize a capture panel for targeted interrogation of the human sperm methylome and test its ability to detect effects of altered folate metabolism. As compared with MTHFR 677CC men, those with the 677TT genotype (50% decreased MTHFR activity) had both hyper- and hypomethylation in their sperm. High-dose folic acid supplement treatment exacerbated hypomethylation in MTHFR 677TT men compared with 677CC. In both cases, [Formula: see text] of altered methylation was found in dynamic sperm CpGs, uniquely measured by our assay.

Discussion: Our sperm panel allowed the discovery of differential methylation following conditions affecting folate metabolism in novel dynamic sperm CpGs. Improved ability to examine variation in sperm DNA methylation can facilitate comprehensive studies of environment-epigenome interactions. https://doi.org/10.1289/EHP4812.

Journal Title

Environmental health perspectives

Volume

127

Issue

8

First Page

87002

Last Page

87002

MeSH Keywords

Adult; DNA Methylation; Epigenome; Folic Acid; Genetic Techniques; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Spermatozoa

Keywords

Adult; DNA Methylation; Epigenome; Folic Acid; Genetic Techniques; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Spermatozoa

Comments

EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted.

Publisher's online access: https://doi.org/10.1289/EHP4812

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