Stability of the human sperm DNA methylome to folic acid fortification and short-term supplementation

Abstract

STUDY QUESTION: Do short-term and long-term exposures to low-dose folic acid supplementation alter DNA methylation in sperm?SUMMARY ANSWER: No alterations in sperm DNA methylation patterns were found following the administration of low-dose folic acid supplements of 400 μg/day for 90 days (short-term exposure) or when pre-fortification of food with folic acid and post-fortification sperm samples (long-term exposure) were compared.WHAT IS KNOWN ALREADY: Excess dietary folate may be detrimental to health and DNA methylation profiles due to folate's role in one-carbon metabolism and the formation of S-adenosyl methionine, the universal methyl donor. DNA methylation patterns are established in developing male germ cells and have been suggested to be affected by high-dose (5 mg/day) folic acid supplementation.STUDY DESIGN, SIZE, DURATION: This is a control versus treatment study where genome-wide sperm DNA methylation patterns were examined prior to fortification of food (1996)(1997) in men with no history of infertility at baseline and following 90-day exposure to placebo (n = 9) or supplement containing 400 μg folic acid/day (n = 10). Additionally, pre-fortification sperm DNA methylation profiles (n = 19) were compared with those of a group of post-fortification (post-2004) men (n = 8) who had been exposed for several years to dietary folic acid fortification. PARTICIPANTS/MATERIALS, SETTING, METHODS:Blood and seminal plasma folate levels were measured in participants before and following the 90-day treatment with placebo or supplement. Sperm DNA methylation was assessed using the whole-genome and genome-wide techniques, MassArray epityper, restriction landmark genomic scanning, methyl-CpG immunoprecipitation and Illumina HumanMethylation450 Bead Array.MAIN RESULTS AND THE ROLE OF CHANCE: Following treatment, supplemented individuals had significantly higher levels of blood and seminal plasma folates compared to placebo. Initial first-generation genome-wide analyses of sperm DNA methylation showed little evidence of changes when comparing pre-and post-treatment samples. With Illumina HumanMethylation450 BeadChip arrays, no significant changes were observed in individual probes following low-level supplementation; when compared with those of the post-fortification cohort, there were also few differences in methylation despite exposure to years of fortified foods. † These authors contributed equally to the work.

The relationship between major dietary patterns and fertility status in Iranian men: a case- control study

“…Researchers have showed anomalies in sperm DNA methylation and homocysteine accumulation in men with infertility. As regards to high level folate and B12 in traditional and healthy dietary pattern and above mechanisms, this diet can prevent DNA damage and also improved sperm concentration and motility (32,37).studies showed increase oxidative stress level can effect on sperm motility and increase DNA fragmentation, also based on this finding, intake of antioxidants increases sperm concentration and improves its progressive motility (21,35).…”

“…Folate and B12 are critical nutrients for methylation, stability and DNA replication. DNA methylation is a biochemical process that is involved in normal development and cellular differentiation (35). Much research has demonstrated that abnormal DNA methylation and acetylation associated with chronic and congenital diseases (36).…”

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

“…[ 5–7,12,14–22 ] A total of five studies investigated the association between folate status and sperm epigenetics, of which two were animal studies [ 10,13 ] and three were human studies. [ 5,12,23 ] Six studies investigated the associations between folate status and sperm DNA damage and apoptosis, including two animal studies [ 11,13 ] and four human studies ( Table 2 ). [ 7,19,21,24 ]…”

“…A total of three studies investigated the effect of folate status on sperm DNA methylation. [ 5,12,23 ] The recent study of Chan et al. showed that multiple years of FA food fortification in Canada had no significant influence on sperm overall DNA methylation.…”

“…showed that multiple years of FA food fortification in Canada had no significant influence on sperm overall DNA methylation. [ 23 ] However, 6 months of 5 mg per day FA supplement use caused genome wide hypomethylation and hypermethylation covering intergenic regions, introns, and exons of the sperm DNA. [ 5 ] This effect is aggravated in individuals who are homozygous for the MTHFR 677C>T polymorphism.…”