Metformin improves epigenetic modification involved in oocyte growth and embryo development in polycystic ovary syndrome mice model

Abstract

The possible relationship between dehydroepiandrosterone (DHEA)‐induced polycystic ovary syndrome (PCOS) and epigenetic changes (ECs) leading to the impaired oocyte quality, has not been investigated yet. So, this study aimed to provide an insight into the relationship of the impaired oocyte quality with ECs in a mice DHEA‐induced PCOS model and to further reveal the effect of metformin treatment. For this purpose, 80 female BALB/C mice were randomly divided into four equal groups, named as the control, sham, (DHEA) and DHEA + Metformin groups. The alterations in acetylation of H4K5 and H4K16, and in methylation of DNA (5MeC) and H3K9 were evaluated using immunocytochemical. Moreover, the expression of Hdac1, Hdac2, Dnmt1, and Dnmt3a genes involved in ECs were analyzed using reverse‐transcription polymerase chain reaction. As well, the levels of mitochondrial membrane potential (MMP), oxidative stress (OS), embryo development, ovarian morphology, sexual hormone, ovulatory function, and AMPKα phosphorylation activity were compared in all the studied groups. Metformin attenuated the damages induced by DHEA as indicated by the normalized the estrous cycle, the improved ovarian morphology, the decreased sexual hormone and OS levels, and the increased MMP and AMPKα phosphorylation levels. In the metformin group, the Dnmt1, Dnmt3a, and Hdac2 genes have significantly upregulated compared to the DHEA group. However, metformin was found to have no effect on the expression level of Hdac1. In this regard, significant decrease and increase were observed in both the acetylated H4K16 and methylated H3K9 within MII oocytes in the DHEA + Metformin group compared with the DHEA group. Our results show that metformin could enhance the developmental competence of PCOS oocytes via reducing OS and ECs.

Beneficial Effect of Selenium Doped Carbon Quantum Dots Supplementation on the in vitro Development Competence of Ovine Oocytes

“…The epigenetic alterations induced by advanced maternal aging, mitochondrial dysfunctions, abnormal nutrition supply and abnormal expression levels of hormones trigger seriously meiotic defects of mammalian gametes, subsequently resulting in the incidence of aneuploidy after fertilization and embryonic development defects. 17 In consistent with our present study, these former literature have revealed that the promotion of epigenetic modifications via the amelioration of mitochondrial dysfunctions significantly improved the development potentials of mammalian oocytes, 16,17,[64][65][66] further addressing the future applications of Se/CDs as dietary supplementation in mammalian IVM via the promotion of epigenetic modifications. However, the specific regulation mechanism related to the effect of Se/CDs' supplementation in the epigenetic modifications of ovine MII oocytes and the potential effect of Se/CDs' supplementation on the epigenetic modifications of ovine zygote and/or blastocyst need more detailed investigations.…”

Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice

“…Previously published studies also summarized the effects of metformin on the epigenome, including epigenetic-modifying enzymes, histone and DNA methylation, and gene expression (Bridgeman et al 2018 ; Faure et al 2018 ). Consistent with our findings, a recent study showed that metformin could reduce oxidative stress and H3K9me3 in the oocytes of PCOS (Amani Abkenari et al 2021 ). Unlike the Trim-Away results of RIF1, the metformin intervention improved the DNA methylation status in addition to improving the histone modification.…”

Function of Follicular Cytokines: Roles Played during Maturation, Development and Implantation of Embryo

“…In general, the treatment of the underlying reason of cytokine profile disruption is beneficial and may reverse the diseases' negative effects on fertilisation and pregnancy outcomes. A good example of this is PCOS, in which insulin resistance therapy, body weight reduction, and lifestyle changes, as well as pharmacological treatments, for example, metformin, can have a beneficial effect on the leptin levels and cytokine profile of patients [49][50][51].…”