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

Date Published: July 27, 2018

Publisher: Public Library of Science

Author(s): Riley M. Bove, Ellis Patrick, Cristin McCabe Aubin, Gyan Srivastava, Julie A. Schneider, David A. Bennett, Philip L. De Jager, Lori B. Chibnik, Michel Baudry.


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.

Partial Text

The maintenance of energy metabolism through the oxidative phosphorylation (OXPHOS) apparatus is essential for brain health [1–5]. Underscoring this essential role, mitochondrial injury and oxidation are part of the shared neuropathological mechanisms in neurological disorders including multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease [1–4]. Furthermore, mutations of OXPHOS genes (the majority of which are encoded within the autosomal, not mitochondrial, genome [6]) are implicated in both rare [7] and common neurological disorders (e.g. stroke and neurodegeneration [5]), and in neuronal recovery after oxidative stress [8]. Little is known about the role of epigenetic modifications of the OXPHOS pathways in conferring resilience from or susceptibility to neurologic disease.

Using both a hypothesis-driven and an unsupervised pathway analysis approach, we found that longer reproductive period was significantly associated with subsequent levels of methylation across a set of OXPHOS genes, genes known to be associated with stroke, a major cause of worldwide mortality and neurological morbidity.

Human females are unique among mammals in the duration of post-reproductive longevity. Previous investigations of sex-specific mechanisms leading to neurological resilience have uncovered an association between reproductive period, i.e. a woman’s period of maximal exposure to levels of estradiol and other gonadal hormones, and cognitive decline in old age. Here, we advanced these findings mechanistically with reporting a significant association of reproductive period with methylation levels across genes in the OXPHOS pathway. This provides some mechanistic suggestion that early and mid-life hormonal exposures may influence risk of late-life neurological morbidity and mortality via epigenetic regulation of energy metabolism.




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