Intracytoplasmic oxidative stress reverses epigenetic modifications in polycystic ovary syndrome
Fatemeh Eini A , Marefat Ghaffari Novin B E , Khojasteh Joharchi C , Ahmad Hosseini B , Hamid Nazarian A , Abbas Piryaei A and Arash Bidadkosh D
+ Author Affiliations
- Author Affiliations
A Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran.
B Cellular and Molecular Biology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran.
C Department of Pharmacology and Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, PO Box 19615-1179, Tehran, Iran.
D Department of Nephrology, Royal Alexandra, Hospital for Children, PO Box 11428-2709, Sydney, NSW, Australia.
E Corresponding author. Email: mghaffarin@sbmu.ac.ir
Reproduction, Fertility and Development 29(12) 2313-2323 https://doi.org/10.1071/RD16428
Submitted: 28 October 2016 Accepted: 9 March 2017 Published: 26 April 2017
Abstract
In polycystic ovary syndrome (PCOS), substantial genetic and environmental alterations, along with hyperandrogenism, affect the quality of oocytes and decrease ovulation rates. To determine the mechanisms underlying these alterations caused specifically by an increase in plasma androgens, the present study was performed in experimentally-induced PCOS mice. As the study model, female B6D2F1 mice were treated with dehydroepiandrosterone (DHEA, 6 mg per 100 g bodyweight). After 20 days, oocytes at the germinal vesicle and metaphase II stages were retrieved from isolated ovaries and subsequent analyses of oocyte quality were performed for each mouse. DHEA treatment resulted in excessive abnormal morphology and decreased polar body extrusion rates in oocytes, and was associated with an increase in oxidative stress. Analysis of fluorescence intensity revealed a significant reduction of DNA methylation and dimethylation of histone H3 at lysine 9 (H3K9) in DHEA-treated oocytes, which was associated with increased acetylation of H4K12. Similarly, mRNA expression of DNA methyltransferase-1 and histone deacetylase-1 was significantly decreased in DHEA-treated mice. There was a significant correlation between excessive reactive oxygen species (ROS) production and increased histone acetylation, which is a novel finding and may provide new insights into the mechanism causing PCOS. The results of the present study indicate that epigenetic modifications of oocytes possibly affect the quality of maturation and ovulation rates in PCOS, and that the likely mechanism may be augmentation of intracytoplasmic ROS.
Additional keywords: acetylation, dehydroepiandrosterone, methylation.
References
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