Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis

Abstract

Scope: The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results: Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full-text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta-analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3-6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions: This systematic review and meta-analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

Epigenetics of Male Infertility: The Role of DNA Methylation

“…In addition, sperm from mice under a folate-deficient diet showed differential DNA methylation marks at genes implicated in development, diabetes, autism, and schizophrenia (Lambrot et al, 2013). In humans, several studies have reported on the relationship between paternal and/or maternal diet and sperm DNA methylation in male infertility (Shukla et al, 2014;Hoek et al, 2020;Toschi et al, 2020). 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).…”

Sperm DNA Methylation at Metabolism-Related Genes in Vegan Subjects

“…Despite the exact relationship between diet and the epigenome remains unclear, several studies reported an association between epigenetic modifications and dietary depletion or supplementation (1,(42)(43)(44)(45)(46)(47)(48).…”

Review of evidence for environmental causes of uveal coloboma

“…It is becoming clear that paternal factors may also have significant epigenetic implications 84,61 , and therefore become important when considering environmental causes of congenital malformations. This is particularly relevant given the increasing prevalence of intracytoplasmic sperm injection, which similarly subjects oocytes to foreign environments.…”