Spermatozoa from infertile patients exhibit differences of DNA methylation associated with spermatogenesis-related processes: an array-based analysis

Abstract

The influence of aberrant sperm DNA methylation on the reproductive capacity of couples has been postulated as a cause of infertility. This study compared the DNA methylation of spermatozoa of 19 fertile donors and 42 infertile patients using the Illumina 450K array. Clustering analysis of methylation data arranged fertile and infertile patients into two groups. Bivariate clustering analysis identified a differential distribution of samples according to the characteristics of seminogram and age, suggesting a possible link between these parameters and specific methylation profiles. The study identified 696 differentially methylated cytosine-guanine dinucleotides (CpG) associated with 501 genes between fertile donors and infertile patients. Ontological enrichment analysis revealed 13 processes related to spermatogenesis. Data filtering identified a set of 17 differentially methylated genes, some of which had functions relating to spermatogenesis. A significant association was identified between RPS6KA2 hypermethylation and advanced age (P = 0.016); APCS hypermethylation and oligozoospermia (P = 0.041); JAM3/NCAPD3 hypermethylation and numerical chromosome sperm anomalies (P = 0.048); and ANK2 hypermethylation and lower pregnancy rate (P = 0.040). This description of a set of differentially methylated genes provides a framework for further investigation into the influence of such variation in male fertility in larger patient cohorts.

The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations

“…It constitutes the largest unbiased analysis of DNA methylation in matched human sperm and blood samples performed to date, and is one of the largest studies of spermatozoal DNA methylation in healthy males of proven fertility. In contrast to several previous analyses of DNA methylation in human spermatozoa [45][46][47], our study includes a replication group, increasing the robustness of our findings. Crucially, our analyses include the use of large existing datasets; blood-sperm correlated CpG sites were interrogated for overlap with previously identified mQTLs in whole blood [28], as well as with a list of recently reported CorSIVs [26].…”

Impairment of sperm DNA methylation in male infertility: a meta‐analytic study

“…This difference in inclusion criteria justifies the high heterogeneity found in these studies. Aside from these selected studies, several works evaluated the overall DNA methylation in male infertility using a genome‐wide approach on sperm DNA (Aston et al ., ; Camprubi et al ., ; Du et al ., ; Jenkins et al ., ). These studies confirmed that male infertility could be associated to alterations in the mature epigenome, although each study recognized a specific cluster of genes probably implicated in its pathogenesis.…”

DNA methylation in bull spermatozoa: evolutionary impacts, interindividual variability, and contribution to the embryo

“…In humans, numerous studies have reported altered DNA methylation patterns in the context of decreased sperm count and motility and morphological defects (Boissonnas et al 2010;Laqqan et al 2017), in vitro fertilisation (IVF) outcomes (Aston et al 2015;Camprubi et al 2016) or unexplained infertility (Urdinguio et al 2015). Given the negative impact that subfertile AI bulls can have on the sustainability of the dairy sector, it is not surprising that work on interindividual variations affecting the sperm DNA methylome in cattle has been undertaken to pinpoint the methylation changes associated with altered semen parameters, decreased field fertility, or IVF outcomes.…”