ArticleHuman molecular genetics2018
Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.
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Who cites it
33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 49 citations in OpenAlex.
- Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis.Journal of assisted reproduction and genetics · 2021Pooled it
- Pooled it
- Association between serum vitamins and sex hormone levels in adolescent males: based on the National Health and Nutrition Examination Survey (NHANES).Hormones (Athens, Greece) · 2026Article
- Environmental and Genetic Perturbations of the Sperm Epigenome.Advances in experimental medicine and biology · 2026Review
- 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
- How do lifestyle and environmental factors influence the sperm epigenome? Effects on sperm fertilising ability, embryo development, and offspring health.Clinical epigenetics · 2025Review
- DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos.Nature communications · 2025Article
- Folic acid and sperm quality improvement: insights from snRNA sequencing and RNA splicing mechanisms.Frontiers in nutrition · 2025Review
- Folic Acid and Methyltetrahydrofolate Supplementation in theNutrients · 2024Article
- The Role of One-Carbon Metabolism and Methyl Donors in Medically Assisted Reproduction: A Narrative Review of the Literature.International journal of molecular sciences · 2024Review
- Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase 677C>T variant and correction with moderate dose folic acid supplementation.Molecular human reproduction · 2024Article
- Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review.Nutrients · 2023Review
- Variations in folate prescriptions for patients with the MTHFR genetic polymorphisms: A case series study.Exploratory research in clinical and social pharmacy · 2023Article
- Hyperhomocysteinemia in hypofertile male patients can be alleviated by supplementation with 5MTHF associated with one carbon cycle support.Frontiers in reproductive health · 2023Article
- Effects of folic acid deficiency on genetic damage in colorectal cancer cells.American journal of translational research · 2023Article
- T677T Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms Increased Prevalence in a Subgroup of Infertile Patients with Endometriosis.Journal of women's health (2002) · 2022Article
- Article
- The association between dietary fat and mineral intake with semen parameters: A cross-sectional study in infertile men.International journal of reproductive biomedicine · 2022Article
- Evaluation of methylenetetrahydrofolate reductase and S-adenosyl-methionine level in male infertility: A case-control study.International journal of reproductive biomedicine · 2022Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation with 5 mg folic acid (>10× the daily recommended intake-DRI), exacerbated in men homozygous for a common variant in the gene encoding an important enzyme in folate metabolism, methylenetetrahydrofolate reductase (MTHFR 677C>T). To investigate the epigenomic impact and mechanism underlying effects of folic acid on male germ cells, wild-type and heterozygote mice for a targeted inactivation of the Mthfr gene were fed high-dose folic acid (10× the DRI) or control diets (CDs) for 6 months. No changes were detected in general health, sperm counts or methylation of imprinted genes. Reduced representation bisulfite sequencing revealed sperm DNA hypomethylation in Mthfr+/- mice on the 10× diets. Wild-type mice demonstrated sperm hypomethylation only with a very high dose (20×) of folic acid for 12 months. Testicular MTHFR protein levels decreased significantly in wild-type mice on the 20× diet but not in those on the 10× diet, suggesting a possible role for MTHFR deficiency in sperm DNA hypomethylation. In-depth analysis of the folic acid-exposed sperm DNA methylome suggested mouse/human susceptibility of sequences with potential importance to germ cell and embryo development. Our data provide evidence for a similar cross-species response to high dose folic acid supplementation, of sperm DNA hypomethylation, and implicate MTHFR downregulation as a possible mechanism.
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Registered trials
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