Reproductive period and epigenetic modifications of the oxidative phosphorylation pathway in the human prefrontal cortex

PLoS One. 2018 Jul 27;13(7):e0199073. doi: 10.1371/journal.pone.0199073. eCollection 2018.


Purpose: Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway.

Methods: Using DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database.

Results: We observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair.

Conclusion: This study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.

Publication types

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

MeSH terms

  • Aged, 80 and over
  • Autopsy
  • Cognition / physiology*
  • CpG Islands
  • DNA Methylation
  • DNA Repair
  • Disease Susceptibility
  • E2F Transcription Factors / genetics*
  • E2F Transcription Factors / metabolism
  • Epigenesis, Genetic*
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Fatty Acids / genetics
  • Fatty Acids / metabolism
  • Female
  • Humans
  • Lipid Metabolism / genetics
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Oxidative Phosphorylation / drug effects
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • Prospective Studies
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reproduction
  • Stroke / diagnosis
  • Stroke / genetics*
  • Stroke / pathology


  • E2F Transcription Factors
  • Fatty Acids
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Estradiol
  • Mechanistic Target of Rapamycin Complex 1