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Stable Isotope In-Vivo Labeling for Mass-Spectrometry Identification of Paternal Metabolites Transferred from Sperm to Oocyte During Fertilization
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Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF.

Kaichi Yoshizaki1,2, Ryuichi Kimura1,3, Hisato Kobayashi4,5,6

  • 1Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan.

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|January 5, 2021
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Summary

Advanced paternal age impacts offspring neurodevelopment. Sperm DNA hypomethylation in aged fathers alters REST/NRSF target gene expression, affecting offspring traits.

Keywords:
DNA hypo-methylationREST/NRSFpaternal agingtransgenerational epigenetic inheritanceultrasonic vocalization

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Area of Science:

  • Reproductive Biology
  • Neuroscience
  • Epigenetics

Background:

  • Advanced paternal age is linked to adverse effects on offspring.
  • Understanding the molecular basis of these effects is crucial for reproductive health.

Purpose of the Study:

  • To investigate the molecular mechanisms of transgenerational epigenetic inheritance due to paternal aging.
  • To identify specific genomic alterations in sperm from aged mice and their impact on offspring.

Main Methods:

  • Established a paternal-aging mouse model.
  • Performed whole-genome target DNA methylome analysis on sperm from aged mice.
  • Conducted gene set enrichment analyses on embryonic forebrain tissue.
  • Utilized a DNA demethylation drug in young mice to assess phenocopying.

Main Results:

  • Aged mice sperm showed increased hypomethylated genomic regions, particularly those with REST/NRSF binding motifs.
  • REST/NRSF target genes were upregulated in the forebrain of embryos from aged fathers.
  • Offspring from young mice treated with a demethylation drug exhibited abnormal vocal communication, similar to offspring of aged fathers.

Conclusions:

  • Sperm DNA hypomethylation is a key molecular feature in paternal aging.
  • This hypomethylation influences neurodevelopmental programs in offspring via altered REST/NRSF target gene expression.
  • Paternal age-associated epigenetic changes can be transmitted across generations, affecting offspring phenotype.