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Factors affecting DNA methylation in the sperm of men with male factor infertility Ng, Richard


Infertility currently affects an estimated 8-12% of couples globally and the male factor is suspected as the primary cause in about half of these cases. There are several identified genetic causes for male infertility such as Y chromosome microdeletions and chromosomal rearrangements; however, these known genetic causes only account for 15-30% of male infertility cases, with the majority being idiopathic. Recently, there has been a shift toward studying epigenetic mechanisms as a potential avenue to explain idiopathic cases of male infertility. Most commonly, DNA methylation of imprinted genes is studied as these genes are not erased from gamete to embryo and the function of these genes is critical for embryonic development. Furthermore, methylation of DNA is tightly linked to the folate cycle as the metabolism of folate generates the methyl donors used in methylation reactions. There is also evidence to suggest DNA damage may affect methylation by producing an inadequate substrate for methylation enzymes. We investigated DNA methylation, the folate cycle, and DNA damage in men with oligospermia and azoospermia and compared these to fertile control men. Similar to previously published studies, we found that the sperm of infertile men carries methylation defects in imprinted genes. To further the analysis, we investigated if any relationship with folate enzyme genotypes or folate concentration exists. The genotypes of folate enzymes were not different between groups and there were no effects on DNA methylation. We observed that the concentration of folate was positively correlated with GTL2 methylation, but no correlations were found for any other regions. Finally, GST genotypes and DNA fragmentation were examined for possible associations with DNA methylation. The frequency GST genotypes were not different between groups and had no effect on DNA methylation. DNA fragmentation was also determined to have no associations with DNA methylation. We provide evidence that DNA methylation at imprinted genes in the sperm of infertile men may be affected by folate concentration. The modest association found here can be supplemented in future studies by expanding the coverage of DNA methylation to other regions, investigating homocysteine and methionine, or adding a measure of ROS.

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