Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations.
Development
; 148(13)2021 07 01.
Article
em En
| MEDLINE
| ID: mdl-34128976
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Reprodução
/
Retroelementos
/
Metilação de DNA
/
Metilenotetra-Hidrofolato Redutase (NADPH2)
Limite:
Animals
Idioma:
En
Revista:
Development
Assunto da revista:
BIOLOGIA
/
EMBRIOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Canadá