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

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 brai...

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Bibliographic Details
Published in:PloS one 2018-07, Vol.13 (7), p.e0199073-e0199073
Main Authors: Bove, Riley M, Patrick, Ellis, Aubin, Cristin McCabe, Srivastava, Gyan, Schneider, Julie A, Bennett, David A, De Jager, Philip L, Chibnik, Lori B
Format: Article
Language:English
Subjects:
Aged, 80 and over
Aging
Autopsy
Biology and life sciences
Bipolar disorder
Brain
Cognition - physiology
Cognitive ability
CpG Islands
Deoxyribonucleic acid
Disease Susceptibility
DNA
DNA Methylation
DNA Repair
E2F protein
E2F Transcription Factors - genetics
E2F Transcription Factors - metabolism
Energy metabolism
Epigenesis, Genetic
Epigenetics
Estradiol - metabolism
Estradiol - pharmacology
Estrogens
Exposure
Fatty acids
Fatty Acids - genetics
Fatty Acids - metabolism
Female
Females
Genes
Humans
Lipid Metabolism - genetics
Mechanistic Target of Rapamycin Complex 1 - genetics
Mechanistic Target of Rapamycin Complex 1 - metabolism
Medicine and Health Sciences
Memory
Menarche
Menopause
Metabolism
Myc protein
Oxidative metabolism
Oxidative phosphorylation
Oxidative Phosphorylation - drug effects
Phosphorylation
Prefrontal cortex
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
Womens health
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0199073