ArticleDevelopment (Cambridge, England)2021
Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations.
Article in Development (Cambridge, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Research progress on the role and mechanism of DNA damage repair in germ cell development.Frontiers in endocrinology · 2023Pooled it
- Integrated metabolomic and transcriptomic analyses reveal that glutamine promotes chicken primordial germ cell‑like cell specification potentially through α-ketoglutarate.Animal bioscience · 2026Article
- DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos.Nature communications · 2025Article
- Effects of Gender Differences inInternational journal of genomics · 2025Article
- Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case-control study.Scientific reports · 2024Article
- Genome-wide DNA methylation changes in human spermatogenesis.American journal of human genetics · 2024Article
- Micronutrient Antioxidants for Men (MenevitAntioxidants (Basel, Switzerland) · 2024Article
- 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
- Higher incidence of embryonic defects in mouse offspring conceived with assisted reproduction from fathers with sperm epimutations.Human molecular genetics · 2023Article
- Review
- Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development.Nature communications · 2023Review
- One-carbon metabolism is required for epigenetic stability in the mouse placenta.Frontiers in cell and developmental biology · 2023Article
- Article
- Andrology and humanities.Andrology · 2022Article
- Metabolic pathways regulating the development and non-genomic heritable traits of germ cells.The Journal of reproduction and development · 2022Review
- Association of paternal MTHFR polymorphisms (C677T) with clinical outcomes in ICSI treatment.Frontiers in endocrinology · 2022Article
- Metastable epialleles are stable in their instability.Nature genetics · 2021Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations in mouse. Although MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with >80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late embryonic germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in embryonic germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR-deficient males, compatible with the intergenerational passage of epimutations.
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Registered trials
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