The Involvement of VDR Promoter Methylation, CDX-2 VDR Polymorphism and Vitamin D Levels in Male Infertility

Abstract

Introduction. Vitamin D (VD) levels were correlated with different health conditions, including reproductive disorders in males. Vitamin D action is mediated through vitamin D receptor (VDR), which acts as a transcription factor. VDR gene promoter is embedded in a GC-rich island. The VDR gene has been shown to have several polymorphisms that affect the receptor function.Aim. To examine the relationship between Cdx-2 polymorphism (rs17883968), the methylation status of VDR's promoter and serum levels of 25-hydroxyvitamin D in male infertility.Patients and Methods. A total of 69 infertile men and 37 age-matched controls were enrolled in this study. Vitamin D level assessments were detected using the electrochemiluminescent method. Cdx-2 VDR polymorphism identification was performed by PCR on DNA samples from blood, followed by restriction. Methylation of VDR gene promoter was assessed by qMS-PCR using bisulfite-treated DNA from fresh sperm.Results. Vitamin D levels was found to be significantly decreased in infertile groups compared the controls (p=0.0279). The GG genotype was found in a higher percentage in controls and the AA genotype was higher in infertile group (p=0.0056). Infertile homozygote (GG) and heterozygote (GA) individuals had significantly higher vitamin D levels than AA homozygote. Methylation is higher in individuals with lower vitamin D levels and AA genotype is characterized by higher methylation values. Conclusion.The results provide new insights of Cdx-2 polymorphism is involved in vitamin D deficiency, highlighting the important role of epigenetic modification of vitamin D receptor and male infertility along with the genetic context.

Assessment of serum vitamin D level and seminal vitamin D receptor gene methylation in a sample of Egyptian men with idiopathic infertility

“…Consistent with the current results, Vladoiu et al. (2017) and Hussain et al. (2018) found that serum levels of VD were significantly lower in infertile compared to fertile group.…”

“…Results of the present study were in accordance with Vladoiu et al. (2017), who were the first to assess seminal methylation of VDR gene in male infertility. The methylation of the VDR gene was found to be significantly higher in infertile patients compared to fertile group ( p = .0335).…”

“…Several authors studied serum levels of 25OHD in fertile and infertile men, with different causes of infertility, not specifically idiopathic infertility, using reference values similar to the current study (Ciccone et al., 2021; Hussain et al., 2018; Vladoiu et al., 2017; Yang et al., 2012). Consistent with the current results, Vladoiu et al.…”

Epigenetics of Male Infertility: The Role of DNA Methylation

“…A recent study conducted on infertile males who underwent oral supplementation with micronutrients in support of folate, B vitamins, zinc, and cysteines reported an increase in DNA methylation levels, resulting in improved sperm nuclear maturation and antioxidant defenses, with a possible positive effect on reproductive function (Bassiri et al, 2020). Furthermore, evidences on sperm DNA from infertile males indicate a high methylation of vitamin D receptor promoter in vitamin D-deficient conditions, thus suggesting the role of diet in epigenetic modifications and male reproductive dysfunction (Vladoiu et al, 2017). Similarly, one investigation indicated that parental diet can modulate the methylation levels of several genes, including liver-specific genes involved in cholesterol/lipid metabolism, whereas no effect of paternal diet on sperm DNA methylation was found in other studies (Carone et al, 2010;Rando and Simmons, 2015;Shea et al, 2015;Whitelaw, 2015).…”

Association Between Serum Vitamin D Concentration with Spermiogram Parameters and Reproductive Hormones Among Infertile Iranian Males: a Cross-sectional Study

“…The most prevalent polymorphisms include VDR-FokI, VDR-BsmI, VDR-TaqI, VDR-ApaI, and CDX-2 VDR [21]. The effect of Cdx2 polymorphism on infertility was examined by Vladoiu et al, and as a result, a significant association was detected [22].…”