• Impact of epigenetic modifications on male fertility
  • Reyhaneh Khodadadi,1 Amir Jalali,2,* Mohadese Farahani,3
    1. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    2. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    3. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran


  • Introduction: Infertility is the inability to achieve pregnancy after 12 or more months of regular and unprotected intercourse as defined by the World Health Organization (WHO). Male infertility is a complex disease caused by anatomical defects, injuries, endocrine disorders, immune system problems, genetic factors, and viruses. There are over 48.5 million couples worldwide who suffer from infertility. Additionally, it is estimated that there are more than 30 million infertile men globally. Despite the alarming prevalence, the causes of male infertility remain enigmatic in a large percentage of cases, this is why researchers have recently tried to study the epigenetic origin of male infertility. Epigenetic research focuses on changes in gene expression inherited through meiosis or mitosis without altering the DNA sequence. These modifications include histone modifications (a post-translational modification in histones that is very important in the proper functioning of cells. The N-terminal contains amino acids that can be used for methylation, acetylation, phosphorylation, and ubiquitylation of the receptor), DNA methylation (an essential epigenetic modification specifically related to gene silencing), chromatin remodeling, and RNA-based mechanisms (we can refer to changes in miRNA, mRNA, and piRNA).
  • Methods: In this review study, we analyzed articles related to male infertility from 2015 to 2023 using keywords such as epigenomics, DNA methylation, and chromatin rearrangement, obtained from the PubMed and Google Scholar databases.
  • Results: Recent studies suggest a link between male infertility and methylation modifications. Specifically, MTHFR is the most crucial gene in the methylation process. Numerous studies show that hypermethylation in the promoter of this gene is associated with idiopathic male infertility. It has been reported that hypermethylation of the promoter region of SFN and PAX8 genes can result in weak parameters in human semen. However, if the same genes are hypermethylated, it can lead to low sperm concentration in semen. This process negatively affects the morphology and motility of sperm. LIT1 promoter hypermethylation is associated with poor sperm parameters in humans. Additionally, infertile individuals have a distinct methylation pattern of CpG islands in this gene. NTF3 hypermethylation is linked to low sperm concentration, morphology, and motility. Increased methylation is associated with decreased semen quality in CREM, DAZL, and RHOX genes. Meanwhile, the H19 gene is linked to male infertility when its methylation is reduced also H19/IGF2 gene expression may influence human fertility. The studies on the relationship between chromatin changes and male infertility indicate that protamines are phosphorylated before binding to DNA and dephosphorylated during nucleoprotamine maturation. Camk4 is a protein that is responsible for phosphorylating protamine type II. Mutations in this protein can lead to infertility and defective spermatogenesis in men. Since type 1 and type 2, protamines are vital for sperm function, the semi-insufficient state of these two genes makes the chromatin structure abnormal, and DNA is damaged resulting in infertility. Research has also shown that the proportion of protamine type 1 to type 2 is a significant factor in this process. These deviations also can affect semen quality, reducing sperm concentration and changing movement and morphology. They also impact DNA stability. Research has shown that individuals with low sperm motility have lower levels of mRNA BDNF compared to those with normal sperm production. A protein called GP130 is also involved in sperm motility and has been found to have high levels of mRNA in men with very low sperm motility. In people with oligospermia, low levels of DDX4 and VAS transcripts, which are essential for sex line development, have been reported.
  • Conclusion: Diagnosing the cause of male infertility and available treatments currently do not provide a solution for all cases. Epigenetic factors play a role in this type of infertility and should be considered when examining infertile individuals. Correcting these factors is easier than correcting genetics due to the dynamics of the epigenetic pattern. Researching these factors shortly will allow for the development of epidurals to correct epigenetic processes and improve fertility in individuals.
  • Keywords: male infertility, epigenetic, methylation modifications, chromatin rearrangement