Abstract
BackgroundMale obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the next generation. DNA methylation contributes to gene regulation and is erased and re-established during gametogenesis. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Here we conducted an exploratory analysis that showed that overweight/obesity (n = 20) is associated with differences in mature spermatozoa DNA methylation profiles relative to controls with normal BMI (n = 47).ResultsWe identified 3264 CpG sites in human sperm that are significantly associated with BMI (p < 0.05) using Infinium HumanMethylation450 BeadChips. These CpG sites were significantly overrepresented among genes involved in transcriptional regulation and misregulation in cancer, nervous system development, and stem cell pluripotency. Analysis of individual sperm using bisulfite sequencing of cloned alleles revealed that the methylation differences are present in a subset of sperm rather than being randomly distributed across all sperm.ConclusionsMale obesity is associated with altered sperm DNA methylation profiles that appear to affect reprogramming fidelity in a subset of sperm, suggestive of an influence on the spermatogonia. Further work is required to determine the potential heritability of these DNA methylation alterations. If heritable, these changes have the potential to impede normal development.
Highlights
Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the generation
There was no significant difference between BMI categories in education, biological paternity, sperm concentration, or sperm motility
From our exploratory Illumina Infinium HumanMethylation450 BeadChip (450K) dataset, there was one CpG site that was significant at the false discovery rate (FDR) that is located downstream of the adrenoreceptor alpha 1B gene (ADRA1B)
Summary
Male obesity has profound effects on morbidity and mortality, but relatively little is known about the impact of obesity on gametes and the potential for adverse effects of male obesity to be passed to the generation. Throughout post-pubertal spermatogenesis, there are continual needs to both maintain established methylation and complete DNA methylation programming, even during epididymal maturation. This dynamic epigenetic landscape may confer increased vulnerability to environmental influences, including the obesogenic environment, that could disrupt reprogramming fidelity. Imprinted genes are defined by DNA methylation that is divergent at the same genomic locations in sperm versus oocytes These imprinted regions are differentially established after sex determination in the embryo during gametogenesis and give rise to monoallelic gene expression. We reported significantly altered DNA methylation in sperm of the overweight and obese men as compared to the normal weight men at multiple imprinted gene regulatory regions. We greatly expand our initial studies by conducting an exploratory examination of the influence of overweight/ obesity on DNA methylation throughout the genome
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