Intracytoplasmic oxidative stress reverses epigenetic modifications in polycystic ovary syndrome

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, 6mg per 100g 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.

Thymoquinone reduces intracytoplasmic oxidative stress and improves epigenetic modification in polycystic ovary syndrome mice oocytes, during in‐vitro maturation

“…There were many differences in maturation rate, oxidative stress, and epigenetic alteration between control and PCOS mice oocytes, which we have shown all these datasets in our previous study (Eini et al, ). In that study, we explained that DHEA could cause excessive abnormal morphology, and decrease nuclear and cytoplasmic maturation rates, and make specific epigenetic changes in PCOS mice oocytes.…”

“…Consistently, our previous finding demonstrated a high level of intracytoplasmic ROS affected epigenetic modifications in PCOS mice oocytes. And also we previously showed a relationship between ooplasmic ROS content and the high level of H4K12ac, which was addressing inappropriate epi‐genome modification in PCOS oocytes (Eini et al, ). In the present study, during IVM, treatment with 1.0 and 10 μM TQ increased Hdac1 gene expression, resulting in a reduction of H4K12ac.…”

“…In that study, we explained that DHEA could cause excessive abnormal morphology, and decrease nuclear and cytoplasmic maturation rates, and make specific epigenetic changes in PCOS mice oocytes. Moreover, we showed that defective epigenetic regulation was associated with an increase of oxidative stress in PCOS mice oocyte (Eini et al, ).…”

Improvement of oocyte in vitro maturation from mice with polycystic ovary syndrome by human mesenchymal stromal cell–conditioned media

“…29 Five micrometer-thick sections were mounted on glass slides and stained with haematoxylin and eosin.…”

“…As shown in Figure 2C, serum testosterone levels were markedly (P < 0.01) increased in PCOS as compared with the normal mice. 29 Furthermore, hyperandrogenism increased plasma concentrations of oestradiol, after the increase in the number of dormant follicles, together with the breakdown of later stages of follicle development and subsequently anovulation. These findings are inline with the current observations revealing that the increase in androgen is important to generate PCOS, 5,36 and the progesterone production by PCOS theca cells was higher as compared with control oocytes.…”