DNA methylation covariation in human whole blood and sperm: implications for studies of intergenerational epigenetic effects

Abstract

BackgroundEpidemiological studies suggest that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals suggest 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 genomewide DNA methylation using the Illumina MethylationEPIC array in 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 whether this covariation is influenced by obesity. ResultsDNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). While 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 did not influence covariation patterns. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P=8.95 ´ 10 -8 ; beta=0.02) 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 in pathways enriched in transcriptional regulation. ConclusionsHuman sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. Obesity only nominally influences sperm DNA methylation, making it an unlikely mediator of intergenerational effects of metabolic traits. BackgroundMultiple 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 also have the potential to induce epigenetic changes in gametes has generated considerable interest in recent years. Studies in nonhuman mammals suggest that the spermatozoal DNA methylome can be influenced by factors such as dietary alterations, toxicants and even psychological stress [5-10], although the majority of these results have yet to be replicated independently. A small number of studies also suggest that acquired traits in male mice induce epigenetic changes in sperm, which in turn influence the physiology of offspring [7,11,12].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.Further, it is ethically and practically impossible to perform a study of transgenerational effects in hum...

Male-specific age estimation based on Y-chromosomal DNA methylation

“…Unfortunately, while there is a high number of datasets in whole blood, suitable data for non-blood tissues, such as sperm that could be relevant in sexual assault cases, are not of sufficient quantity or quality to conduct analysis of high power. For example, existing data in small numbers use a different type of platform used [ 43 ], do not include age information or include only elderly males (>70 years old, [ 44 ]). Nevertheless, we expect that the collection of large genome-wide DNA methylation data in sperm (such as by Jenkins et al, [ 6 , 45 ]) will raise soon in the coming, ‘open-access’ era.…”