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Cited by 155Ovarian function and disordersEpigenetics and DNA MethylationBirth, Development, and Health

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

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Xu, Ning, Kwon, Soonil, Abbott, David H., Geller, David H., Dumesic, Daniel A., Azziz, Ricardo, Guo, Xiuqing, Goodarzi, Mark O.·2011·PLoS ONE
DOI 10.1371/journal.pone.0027286PMC PMC3208630
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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.

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  • In experimental animals, excess androgen exposure in utero or in early neonatal life programmes the female offspring to have changes in adipose tissue biology.

    “As shown in Table 7, work in experimental animals has shown that excess androgen exposure in utero or in early neonatal life programmes the female offspring to have changes in adipose tissue biology [132–135].”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [133]

    The Abstract and Discussion report altered DNA methylation in the visceral adipose tissue of female rhesus monkeys exposed to excess androgen in utero. The paper does not study early neonatal androgen exposure, and it describes developmental programming as a suggestion from a pilot study rather than an established causal finding. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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  • Methylation of multiple genes is aberrant in the visceral WAT of infant and adult offspring exposed to excess androgens, which likely contributed to the development of obesity and PCOS in the experimental model.

    “Finally, the methylation of multiple genes was aberrant in the visceral WAT of infant and adult offspring exposed to excess androgens, which likely contributed to the development of obesity and PCOS in the experimental model [133].”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [133]

    The Abstract reports differentially methylated loci in infant and adult visceral adipose tissue of prenatally androgenized rhesus monkeys, and the Discussion suggests epigenomic changes may contribute to PCOS-like traits. It does not establish that methylation contributed to obesity; the Discussion also says it cannot determine whether adult methylation changes are a cause or consequence of PCOS-like features. The indexed passages provide section labels but no page numbers. (LLM, conf=0.87)

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Authors
Xu, N., Kwon, S., Abbott, D. H., Geller, D. H., Dumesic, D. A., Azziz, R., Guo, X., & Goodarzi, M. O.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • University of Wisconsin–Madison (US)
Corresponding author
Goodarzi, Mark O.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-11-04
Volume
6
Issue
11
Pages
e27286
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0027286
PMC
PMC3208630
OpenAlex
W2072345165
Cited by
155
References
6
Citations by year
2026: 6 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 10 · 2020: 16 · 2019: 14 · 2018: 6 · 2017: 12 · 2016: 11 · 2015: 11 · 2014: 13 · 2013: 12 · 2012: 13
FWCI
13.98
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Cedars-Sinai Medical Center
  • National Institutes of Health (5u01hd044650-05, UL1TR000124, RR00167, RR000425, HD044405, RR000169)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK079888)
  • National Center for Research Resources (P51RR000169, RR015459-01, R01RR013635, RR 000169, RR 00167, C06RR020141, RR000425, C06RR015459, P51RR00167, M01RR000425, RR 020141-01, P51RR000167)
  • National Center for Advancing Translational Sciences
  • California National Primate Research Center (RR000169)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K24HD001346, P50HD044405, U01-HD044650, R01HD029364)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
polycystic ovary syndrome, prenatal androgen exposure, DNA methylation, epigenetics, visceral adipose tissue, rhesus monkeys, differentially methylated loci, T cell signaling, TGF-beta signaling, PCOS pathogenesis
MeSH terms
Androgens, Animals, Animals, Newborn, Bayes Theorem, Female, Macaca mulatta, Pilot Projects, Polycystic Ovary Syndrome, Pregnancy, Pregnancy Complications, Neoplastic, Prenatal Exposure Delayed Effects, Virilism, Signal Transduction, Transforming Growth Factor beta, DNA Methylation, Epigenesis, Genetic, Intra-Abdominal Fat

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