Epigenetic Mechanism Underlying the Development of Polycystic Ovary Syndrome (PCOS)-Like Phenotypes in Prenatally Androgenized Rhesus Monkeys

Abstract

The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05). Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β) signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

Epigenética del síndrome de ovario poliquístico

“…Tejido adiposo visceral analizado en monas Rhesus androgenizadas prenatalmente mostró que en éstas existe un patrón de metilación del DNA alterado tanto en infantes como adultas, en comparación a controles 26 . Se identificaron genes involucrados en la vía de señalización de TNF-β significativamente metilados en adultos e infantes.…”

Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause

“…DNA methylation, in which the chemical structure of cytosine is modified through the addition of a methyl group (CH3), is one such epigenetic alteration (Li & Huang 2008). Xu et al (2011) have shown that exposure of foetal female monkeys to testosterone excess changes the epigenome of their visceral fat cells. Therefore, epigenetic alterations might represent the molecular basis of developmental programming related to the reproductive and metabolic phenotypes exhibited by women with PCOS over the course of their lives .…”

Genetikai és epigenetikai faktorok polycystás ovarium szindróma esetén

“…Az egyik legjelentősebb ilyen kutatást Xu és mtsai publikálták 2011-ben [50]. Az epigenetikai változáso-kat olyan nőstény Rhesus majmokon vizsgálták, amelyeket a gesztációs idő alatt androgén hatásnak tettek ki.…”

“…A felnőttmintákból pedig következtethettek a postnatalis változásokra, mint az öregedés, környezeti és/vagy metabolikus hatásokra. Vizsgálataikban hét gén abberáns metilációját figyelték meg felnőtt majmokban [50]. Ezek a sejtszerkezet, illetve a sejtmembránfunkció kialakításában és fenntartásában játszanak szerepet.…”