Methylation patterns of methylenetetrahydrofolate reductase gene promoter in infertile males

Abstract

Epigenetic changes, especially DNA methylation, are essential for the differentiation and development of the male germ cell line (Gunes & Esteves, 2020). Disturbances in the DNA methylation process may cause imprinting errors, global and/or gene-specific methylation changes, leading to infertility in men (Gunes et al., 2016). Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that provides a methyl group for purine synthesis and DNA methylation and therefore participates in the one-carbon cycle which is an essential pathway for replication and cell division (Del Gobbo, Price, Hanna, & Robinson, 2018). MTHFR converts 5,10 methylenetetrahydrofolate into 5-methyl tetrahydrofolate, the active form of folate, which is subsequently necessary for the conversion of homocysteine to methionine (Liu et al., 2015). Methionine is necessary for the synthesis of S-Adenosyl methionine (SAM), a universal cofactor for methylation reactions (Del Gobbo et al., 2018). Studies have shown that various polymorphisms in MTHFR gene may cause inactivation of the enzyme and these variants may play a role in the pathology of many diseases including infertility

Epigenetics of Male Infertility: The Role of DNA Methylation

“…Several genes carrying defective methylation have been associated with abnormalities in semen parameters (Table 1). One of the most highly studied genes is methylenetetrahydrofolate reductase (MTHFR) (Haggarty, 2015;Saraswathy et al, 2018;Coppedè et al, 2019;Mishra et al, 2019;Kulac et al, 2021), which is a key regulatory enzyme involved in folate metabolism and in DNA synthesis and methylation (Födinger et al, 2000). In male mice testes, the activity of MTHFR is five times higher than in other organs (Chen, 2001), whereas its inactivation results in hyperhomocysteinemia, decreased methylation capacity, and the arrest of spermatogenesis due to sperm DNA hypomethylation (Chen, 2001).…”

A DNA Methylation Perspective on Infertility

“…Methylation abnormalities of methylenetetrahydrofolate reductase (MTHFR) have been studied in greater detail than other genes [37][38][39]. MTHFR is fundamental in regulating DNA and folate synthesis, and DNA methylation [40].…”