Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations

Gurbet Karahan, Donovan Chan, Kenjiro Shirane, Taylor McClatchie, Sanne Janssen, Jay M Baltz, Matthew Lorincz, Jacquetta Trasler

Research output: Contribution to journalArticlepeer-review

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. While 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, findings compatible with the intergenerational passage of epimutations.

Original languageEnglish
JournalDevelopment (Cambridge, England)
DOIs
Publication statusE-pub ahead of print - Jun 15 2021

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