In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism

Science. 2014 Aug 15;345(6198):1255903. doi: 10.1126/science.1255903. Epub 2014 Jul 10.


Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caloric Restriction
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Fetal Nutrition Disorders / genetics
  • Fetal Nutrition Disorders / metabolism*
  • Insulin / metabolism
  • Insulin Secretion
  • Male
  • Metabolic Diseases / metabolism
  • Mice
  • Mice, Inbred ICR
  • Nucleosomes / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Spermatozoa / metabolism*
  • Spermatozoa / physiology


  • Insulin
  • Nucleosomes

Associated data

  • GEO/GSE58747