Repeated superovulation may affect mitochondrial functions of cumulus cells in mice

Abstract

Controlled ovarian stimulation by exogenous gonadotrophins is a key procedure during the in vitro fertilization cycle to obtain a sufficient number of oocytes in humans. Previous studies demonstrated that repeated superovulation had deleterious effects on the ovaries. However, whether repeated superovulation adversely affects the mitochondrial functions of cumulus cells remains unclear. In this study, mice were divided into three groups: superovulation once (R1); superovulation three times (R3), and superovulation five times (R5). We evaluated the effects of repeated superovulation on mitochondrial DNA copies (mtDNA) and observed decreased mtDNA copies per cell with increasing number of superovulation cycles. Further, we investigated the DNA methylation status in exon 2 and the mRNA expression level of nuclear-encoded DNA polymerase gamma A (PolgA). The results showed that the DNA methylation levels of PolgA in R1 and R5 were slightly lower than in R3. Additionally, the altered DNA methylation in PolgA coincided with the changes in PolgA expression in cumulus cells. We also found that the mRNA expression of COX1, CYTB, ND2, and ND4 was altered by repeated superovulation in cumulus cells. Thus, repeated superovulation had adverse effects on mitochondrial function.

Embryo responses to stress induced by assisted reproductive technologies

“…Besides, blastocyst and hatching rates decreased and elevated apoptosis was found in these blastocysts (Kalthur et al, ). In addition, messenger RNA expression of some genes such as Cox1 , Cytb , Nd2 , and Nd4 was altered in cumulus cells in response to repeated superovulation in mice (Xie et al, ).…”

Melatonin alleviates the deterioration of oocytes from mice subjected to repeated superovulation

“…**p < 0.01, ***p < 0.001. 5mc: 5-methylcytosine [Color figure can be viewed at wileyonlinelibrary.com] Albertini, 2003; Kalthur et al, 2016;Xie et al, 2016). By using a murine model, we found that repeated superovulation reduces oocyte quality by disrupting meiotic cytoskeletal assemblies, mitochondrial function, and genomic DNA methylation; elevating oocyte apoptosis; and inducing oxidative stress.…”

Repeated hyperstimulation affects the ultrastructure of mouse fallopian tube epithelium

“…The oxidative damage, including an increased content of 8-OH-dG, lipid peroxides and protein carbonyls, positively correlated with the number of COH cycles [ 51 ]; it induced mitochondrial abnormalities and a decrease in antioxidants compatible with ovarian aging [ 52 ]. The effects of COH were determined also in mouse cumulus cells, where the mtDNA copy number decreased as the number of stimulation increased, together with altered DNA methylation in nuclear-encoded DNA polymerase gamma A (PolgA] and consequent changes in PolgA expression [ 53 ]. Moreover, mRNA expression levels of cytochrome b (CYTB), cytochrome c oxidase subunit 1 (COX1), NADH dehydrogenase subunit (ND4), and NADH dehydrogenase subunit 2 (ND2), all encoded by mtDNA, were altered following repeated superovulation in cumulus cells [ 53 ].…”

“…The effects of COH were determined also in mouse cumulus cells, where the mtDNA copy number decreased as the number of stimulation increased, together with altered DNA methylation in nuclear-encoded DNA polymerase gamma A (PolgA] and consequent changes in PolgA expression [ 53 ]. Moreover, mRNA expression levels of cytochrome b (CYTB), cytochrome c oxidase subunit 1 (COX1), NADH dehydrogenase subunit (ND4), and NADH dehydrogenase subunit 2 (ND2), all encoded by mtDNA, were altered following repeated superovulation in cumulus cells [ 53 ]. Detrimental effects of repeated cycles of COH on mitochondria were seen by the reduction of ATP production on GV-stage mouse oocytes matured in vitro after four rounds [ 54 ].…”