Superovulation by injection of exogenous gonadotropin is the elementary method to produce in vivo-derived embryos for embryo transfer in women. Increased oocyte aneuploidy, embryo mortality, fetal growth retardation, and congenital abnormalities have been studied at higher-dose stimulations. Ovarian and oocyte biological aging possibly may have adverse implications for human oocyte competence with repeated hyperstimulation. In this study, we found that reduced competence for the human oocyte has been associated with degenerative embryo upsurge during embryo culture and failure to develop into the blastocyst stage in the three, four, five, and six stimulation cycles. On the other hand, the numbers of ovulated oocytes were decreased in the groups with more ovarian stimulation. More aggregated mitochondria were found in the cytoplasm of the repetitively stimulated embryos. Higher amounts of oxidative damage including 8-OH-dG, lipoperoxides, and carbonyl proteins were also revealed in the ovaries with more cycle numbers of ovarian stimulation. Higher proportions of mtDNA mutations were also found. The detected molecular size of the mutated band was approximately 675 bp. Increased amounts of carbonyl proteins were also revealed after repeated stimulation. An understanding of the relationship between oocyte competence and ovarian responses to stimulation in the mouse may provide insights into the origin of oocyte defects and the biology of ooplasmic aging that could be of clinical relevance in the diagnosis and treatment of human infertility.
Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-β (ERβ) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ERβ in tumorigenesis remains unclear. Clinical studies of ERβ-related tumorigenesis have shown that ERβ stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ERβ in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ERβ-mediated mitochondrial function and preventing apoptosis.
The endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to disrupt hormone signalling, reduce fertility, interfere with embryo development and cause spontaneous miscarriage in humans. The precise mechanisms of its effects on early implantation in humans are still unclear. In this study, we examined the relationship between mitochondrial function and dioxin-induced toxicity in JAR cells, a human trophoblast-like cell line. Several experiments were performed to address the effects of TCDD on cell viability, reactive oxygen species (ROS) generation, oxidative damage (indicated by the presence of lipoperoxides and oxidized DNA bases), mitochondrial DNA (mtDNA) copy number, ATP content, mtDNA mutations and the protein levels of p53, Bax, Bcl2, cytochrome c and caspase 3. Increased oxidative damage and mitochondrial dysfunction in TCDD-treated trophoblast-like cells was demonstrated. A 2.58-fold increase in lipid peroxides was detected in cells treated with 2 nM TCDD for 4 h. The oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine was significantly increased by TCDD treatment in a time-dependent manner. Meanwhile, reductions in mtDNA copy number and ATP content and an increase in mtDNA deletions were found. Furthermore, we observed increased apoptosis, p53 accumulation, Bax overexpression, cytochrome c release and sequential caspase 3 activation after TCDD exposure. These results indicate that oxidative damage and mitochondrial dysfunction may be responsible for the apoptotic effects of TCDD.
Human peritoneal mesothelial cells (HPMCs) are a critical component of the peritoneal membrane and play a pivotal role in dialysis adequacy. Loss of HPMCs can contribute to complications in peritoneal dialysis. Compelling evidence has shown that high-dialysate glucose is a key factor causing functional changes and cell death in HPMCs. We investigated the mechanism of HPMC apoptosis induced by high-dialysate glucose, particularly the role of mitochondria in the maintenance of HPMCs. HPMCs were incubated at glucose concentrations of 5 mM, 84 mM, 138 mM, and 236 mM. Additionally, N-acetylcysteine (NAC) was used as an antioxidant to clarify the mechanism of high-dialysate-glucose-induced apoptosis. Exposing HPMCs to high-dialysate glucose resulted in substantial apoptosis with cytochrome c release, followed by caspase activation and poly(ADP-ribose) polymerase cleavage. High-dialysate glucose induced excessive reactive oxygen species production and lipid peroxidation as well as oxidative damage to DNA. Mitochondrial fragmentation, multiple mitochondrial DNA deletions, and dissipation of the mitochondrial membrane potential were also observed. The mitochondrial dysfunction and cell death were suppressed using NAC. These results indicated that mitochondrial dysfunction is one of the main causes of high-dialysate-glucose-induced HPMC apoptosis.
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