Abstract
Epidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10-8; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits.
Highlights
Multiple large-scale epigenome-wide association studies in humans have shown that environmental and acquired phenotypes, including smoking, ageing and obesity, are associated with altered DNA methylation in peripheral blood [1,2,3,4]
We showed that DNA methylation patterns found in the blood of obese individuals are not present in sperm from obese men
We compared DNA methylation patterns in sperm to those in many other tissues, including for example blood and brain samples, and found that sperm has a unique signature of DNA methylation—one that points to genes involved in regulating overall levels of transcription
Summary
Multiple large-scale epigenome-wide association studies in humans have shown that environmental and acquired phenotypes, including smoking, ageing and obesity, are associated with altered DNA methylation in peripheral blood [1,2,3,4]. Whether such phenotypes have the potential to induce epigenetic changes in gametes has generated considerable interest in recent years. There is little evidence for such inter- and transgenerational effects of acquired phenotypes via epigenetic inheritance in humans This is partly due to the fact that human sperm is rarely analysed outside of a reproductive medicine setting and is less accessible than, for example, peripheral blood. Epigenetic signatures are highly tissue- and developmental stage specific [14, 15], making findings from studies using whole blood as a surrogate tissue for spermatozoa difficult to interpret [16]
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