title: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Soonil
authors.initials: S
authors.lastname: Kwon
authors.forename: David H
authors.initials: DH
authors.lastname: Abbott
authors.forename: David H
authors.initials: DH
authors.lastname: Geller
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Dumesic
authors.forename: Ricardo
authors.initials: R
authors.lastname: Azziz
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001499:Bayes Theorem; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D050152:Intra-Abdominal Fat / Q000473:pathology; D008253:Macaca mulatta; D010865:Pilot Projects; D011085:Polycystic Ovary Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011297:Prenatal Exposure Delayed Effects; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014770:Virilism
chemical_list: D000728:Androgens; D016212:Transforming Growth Factor beta
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