Methylation Status of Imprinted Genes and Repetitive Elements in Sperm DNA from Infertile Males

Abstract

Stochastic, environmentally and/or genetically induced disturbances in the genome-wide epigenetic reprogramming processes during male germ-cell development may contribute to male infertility. To test this hypothesis, we have studied the methylation levels of 2 paternally (H19 and GTL2) and 5 maternally methylated (LIT1, MEST, NESPAS, PEG3, and SNRPN) imprinted genes, as well as of ALU and LINE1 repetitive elements in 141 sperm samples, which were used for assisted reproductive technologies (ART), including 106 couples with strictly male-factor or combined male and female infertility and 28 couples with strictly female-factor infertility. Aberrant methylation imprints showed a significant association with abnormal semen parameters, but did not seem to influence ART outcome. Repeat methylation also differed significantly between sperm samples from infertile and presumably fertile males. However, in contrast to imprinted genes, ALU methylation had a significant impact on pregnancy and live-birth rate in couples with male-factor or combined infertility. ALU methylation was significantly higher in sperm samples leading to pregnancy and live-birth than in those that did not. Sperm samples leading to abortions showed significantly lower ALU methylation levels than those leading to the birth of a baby.

Semen samples showing an increased rate of spermatozoa with imprinting errors have a negligible effect in the outcome of assisted reproduction techniques

“…In any case, according to the clinical data at our disposal, our results coincide with the four studies published to date, 19,22,25,47 in which no evidence was found that these anomalies affect the results of assisted reproduction treatments.…”

“…Even though the reported epidemiological data lead one to consider maternal methylation defects exclusively, a relationship between male infertility and imprinting abnormalities in the sperm has also been described. [18][19][20][21][22][23][24][25][26] Since paternal imprinted genes mainly contribute to extra-embryonic tissue development, it is not discarded that loss of imprinting (LOI) at paternal methylated loci could cause phenotypes that prevent placenta development or could cause intrauterine growth retardation (IUGR). IUGR has been described as being associated with imprinting defects 8 and also related to assisted reproduction.…”

Application of FISH method for preimplantation genetic diagnostics of reciprocal and Robertsonian translocations

“…About 35% of the issues involved with infertility are due to the man, another 30% due to the woman, and 10% result from complications associated with both partners [1]. There are many causes of infertility, however, approximately 30% of cases are associated with genetic factors such as translocations [2].…”

Paternal contribution to development: Sperm genetic damage and repair in fish

“…Maintenance of a proper methylation at specific gene promoters is required for an appropriate sperm function and aberrant methylation patterns have been associated with infertility and poor sperm quality in men (Jenkins and Carrell 2012b;Jenkins and Carrell 2012a;Houshdaran et al 2007). Moreover inappropriate methylation status has been suggested to be related with recurrent pregnancy loss (El Hajj et al 2011). …”