ArticleHuman molecular genetics2015
High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
52 citing papers in PubMed, 4 syntheses or guidelines pooled it, 110 citations in OpenAlex.
- Pooled it
- Association of the MTHFR 677C>T and 1298A>C polymorphisms and male infertility risk: a meta-analysis.Reproductive biology and endocrinology : RB&E · 2020Pooled it
- Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta-Analysis.Molecular nutrition & food research · 2020Pooled it
- Association between MTHFR A1298C polymorphism and male infertility: A meta-analysis.Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · 2017Pooled it
- The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).Fertility and sterility · 2022Trial
- Association of the Serum Folate and Total Calcium and Magnesium Levels Before Ovarian Stimulation With Outcomes of FreshFrontiers in endocrinology · 2022Trial
- Stability of the human sperm DNA methylome to folic acid fortification and short-term supplementation.Human reproduction (Oxford, England) · 2017Trial
- The dual role of inflammatory microenvironment in modulating the effect of red blood cell folic acid on sperm DNA integrity: A retrospective study.Scientific reports · 2026Article
- Epigenetic effects of Qixiong Formula on sperm DNA methylation in a rat model of asthenozoospermia.Translational andrology and urology · 2025Article
- Fortification with folic acid and early human embryo development: lessons from assisted reproduction.Journal of assisted reproduction and genetics · 2025Article
- Health professionals require more defined protocols, better funding and patient resources to support couples with recurrent pregnancy loss.Scientific reports · 2025Article
- Can some metabolic one-carbon cycle linked diseases be prevented? The impact of treating hypo-fertile couples carrying MTHFR SNPs with folic acid and 5-MTHF on outcomes in the offspring: a case retrospective series.Journal of assisted reproduction and genetics · 2025Article
- Treatment with 5-MTHF to support the one-carbon cycle can overcome the deleterious impact of a triple SNP mutation in the male partner's MTHFR gene for a couple with a history of repeated miscarriage.Journal of assisted reproduction and genetics · 2025Article
- Folic acid and sperm quality improvement: insights from snRNA sequencing and RNA splicing mechanisms.Frontiers in nutrition · 2025Review
- Effects of Gender Differences inInternational journal of genomics · 2025Article
- Review
- Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case-control study.Scientific reports · 2024Article
- Separation of reproductive decline from lifespan extension during methionine restriction.Nature aging · 2024Article
- Testing Reported Associations of Gene Variants with Non-Syndromic Orofacial Clefts in the Polish Population.Biomedicines · 2024Article
- Combined Analysis of the Transcriptome, Proteome and Metabolome in Human Cryopreserved Sperm.The world journal of men's health · 2024Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.