H19 Sperm Methylation in Male Infertility: A Systematic Review and Meta-Analysis

Abstract

This systematic review and meta-analysis summarize the difference in the methylation of the H19 gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on H19 methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that H19 methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the H19 methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health.

Sperm epigenetics and male infertility: unraveling the molecular puzzle

“…For instance, Minor et al discovered a notable reduction in DNA methylation of the H19 gene in the testicular sperm of azoospermic men compared to fertile individuals [ 46 ]. Additionally, a significant reduction in the methylation levels of the H19 gene has been observed in the testicular sperm of azoospermic men compared to those in the fertile group [ 46 , 47 ]. Beyond H19, disruptions in the methylation patterns of additional imprinted genes are also implicated in male infertility.…”

Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

“…Finally, there is a growing awareness that exposure to pathogenic environments such as smoking, drugs, and nutrition affects the phenotype of subsequent generations through the reprogramming of the epigenetic signature of spermatozoa. Indeed, there is evidence of high DNA methylation levels in the sperm cells of fathers who have already had one child diagnosed with autism [ 16 , 63 ]. The genes targeted for methylation are mostly DNA variants involved in embryogenesis, in particular brain ontogenesis.…”

A DNA Methylation Perspective on Infertility

“…Imprinted genes play a critical role in spermatogenesis, and errors in their methylation can impede normal spermatogenesis [55]. Sperm samples from infertile males with abnormal sperm parameters have been found to have disruptions in the methylation of imprinted genes like MEST and H19 [56,57], although their prevalence may have been overestimated due to somatic DNA contamination and genetic variation [58]. Hypermethylation of MEST has been associated with male infertility, decreased bi-testicular volume, increased follicle-stimulating hormone (FSH), and abnormal sperm parameters [59][60][61].…”

“…Hypermethylation of MEST has been associated with male infertility, decreased bi-testicular volume, increased follicle-stimulating hormone (FSH), and abnormal sperm parameters [59][60][61]. Hypomethylation of H19 has been associated with oligozoospermic, asthenozoospermic, and teratozoospermic infertile males [56,57]. Notably, H19 hypermethylation has been associated with smoking [62].…”