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

Abstract

Considering the widespread use of assisted reproductive techniques (ART), DNA methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub-fertility and sperm DNA methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm DNA methylation of imprinted genes is associated with impaired sperm parameters. Meta-analysis of controlled clinical trials evaluating imprinted genes sperm DNA methylation comparing men with idiopathic infertility to fertile controls. Twenty-four studies were included, allowing a meta-analytic evaluation for H19, MEST, SNRPN, and LINE-1. When a high heterogeneity of the results was demonstrated, the random effect model was used. H19 methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% CI: 5.14-9.93%, p < 0.001), suggesting a 9.91-fold higher risk ratio to show aberrant sperm DNA methylation (95% CI: 5.55-17.70, p < 0.001, I = 19%) in infertile men. The mean MEST methylation level was significantly higher in 846 infertile compared with 353 fertile men (3.35%, 95% CI: 1.41-5.29%, p < 0.001), as well as for SNRPN comparing 301 infertile men with 124 controls (3.23%, 95% CI: 0.75-5.72%, p < 0.001). LINE-1 methylation levels did not differ between 291 infertile men and 198 controls (0.44%, 95% CI: -2.04-1.16%, p = 0.63). The meta-analytic approach demonstrated that male infertility is associated with altered sperm methylation at H19, MEST, and SNRPN. Although its role in infertility remains unclear, sperm DNA methylation could be associated with the epigenetic risk in ART. In this setting, before proposing this analysis in clinical practice, an accurate identification of the most representative genes and a cost-effectiveness evaluation should be assessed in ad hoc prospective studies.

Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility

“…Furthermore, global sperm DNA methylation has been shown to inversely correlate with sperm DNA fragmentation [34]. In line with these findings, meta-analytic data report a decrease in the sperm H19-IGF2 methylation rate in infertile patients compared to fertile controls [35]. Importantly, methylation of imprinted genes is inherited by the embryo [26] and, therefore, this abnormality can be transmitted to the offspring.…”

Alterations in DNA methylation patterns and gene expression in spermatozoa of subfertile males

“…(UBE2G2/UBC7) is involved in protein degradation, including a process known as endoplasmic reticulum-associated degradation (ERAD) (Arai et al, 2006). According to several studies, the epigenetic modifications (DNA methylation, histone modifications) and gene expression have a close association with infertility in males (Boissonnas et al, 2013;Rajender, Avery, & Agarwal, 2011;Santi, De Vincentis, Magnani, & Spaggiari, 2017). However, we still need to more deep study to clarify the relationship between various epigenetic modifications and male infertility problems.…”

Male Infertility is a Women’s Health Issue—Research and Clinical Evaluation of Male Infertility Is Needed

“…Despite best efforts, none of the current male infertility assessments are enough to precisely predict sperm quality, and the search for a single assay that could predict fertility has been mostly fruitless [98][99][100]. The assessment deficiency is echoed by the presence of a large population of unexplained infertility, as well as the low ability of each individual assay to predict a successful pregnancy [101][102][103]. While many of these assays currently available or under development have shown correlations with fertility, in most cases they have been highly variable depending on the study [104,105].…”