Kisspeptins are a family of neuropeptides that are critical for initiating puberty and regulating ovulation in sexually mature females
the central control of the hypothalamic-pituitary-gonadal axis. ...Recent studies have shown that kisspeptin and its receptor kisspeptin receptor (KISS1R) are expressed in the mammalian ovary. Convincing evidence indicates that kisspeptins can activate a wide variety of signals
its binding to KISS1R. Experimental data gathered recently suggest a putative role of kisspeptin signaling in the direct control of ovarian function, including follicular development, oocyte maturation, steroidogenesis, and ovulation. Dysregulation or naturally occurring mutations of the kisspeptin/KISS1R system may negatively affect the ovarian function, leading to reproductive pathology or female infertility. A comprehensive understanding of the expression, actions, and underlying molecular mechanisms of this system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in reproductive diseases and infertility.
The present study evaluated the influence of hyperandrogenism on oocyte quality using a murine PCOS model induced by dehydroepiandrosterone (DHEA) and further explored the effect of metformin ...treatment. Female BALB/c mice were treated with a vehicle control or DHEA (6 mg /100 g body weight) or DHEA plus metformin (50 mg /100 g body weight) for 20 consecutive days. DHEA-induced mice resembled some characters of human PCOS, such as irregular sexual cycles and polycystic ovaries. After the model validation was completed, metaphase II (MII) oocytes were retrieved and subsequent analyses of oocyte quality were performed. DHEA-treated mice yielded fewer MII oocytes, which displayed decreased mtDNA copy number, ATP content, inner mitochondrial membrane potential, excessive oxidative stress and impaired embryo development competence compared with those in control mice. Metformin treatment partially attenuated those damages, as evidenced by the increased fertilization and blastocyst rate, ATP content, GSH concentration and GSH/GSSG ratio, and decreased reactive oxygen species levels. No significant difference in normal spindle assembly was observed among the three groups. During in vitro maturation (IVM), the periods of germinal vesicle breakdown (GVBD) and the first polar body (PB1) extrusion were extended and the maturation rate of GVBD oocytes was decreased in DHEA mice compared with controls. Metformin treatment decreased the time elapsed of GVBD while had no effect on PB1 extrusion. These results indicated that excessive androgen is detrimental to oocyte quality while metformin treatment is, directly or indirectly, beneficial for oocyte quality improvement.
To investigate PPARGC1A promoter methylation and mitochondria DNA (mtDNA) content in the leukocytes of women with polycystic ovary syndrome (PCOS) and analyze the relationship between these indices ...and metabolic risk for women with PCOS.
Cross-sectional study.
University hospital.
A total of 175 women with PCOS and 127 healthy controls.
None.
Women with and without PCOS classified using the typical metabolic risk criteria of the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII), methylation of PPARGC1A promoter tested by methylation-specific polymerase chain reaction, and mtDNA content confirmed by quantitative polymerase chain reaction (PCR).
PPARGC1A promoter methylation was specifically increased, but mtDNA content was specifically decreased in women with PCOS compared with the control women after adjustment for body mass index. Moreover, in women with PCOS who have increased metabolic risk, the differences in PPARGC1A promoter methylation and mitochondrial content were aggravated.
In conclusion, PPARGC1A promoter methylation and mitochondrial content were found to be potential biomarkers for the prediction of metabolic risk in women with PCOS.
One of the major obstacles to ovarian tissue preservation is delayed angiogenesis that leads follicles lost after transplantation. The aim of the present study was to investigate the effects of bFGF ...and VEGF on heterotopic transplanted ovarian tissue using a mouse model.
Female mice underwent bilateral ovariectomy. Ovarian tissues encapsulated by fibrin hydrogels were transplanted subcutaneously into recipient mice, in which ovarian hormonal cyclicity was absent. The fibrinogen solution was mixed with bFGF, VEGF, or a mixture of bFGF and VEGF. The grafts were recovered 21 days after transplantation. Follicle morphology and follicle numbers were observed by H&E staining. Blood vessels were observed in transplanted intra-ovarian tissue by CD31 antibody IHC staining. Daily vaginal cytology was performed to determine estrous cycle and functional restoration of transplanted ovarian tissue. Blood was collected weekly and serum FSH levels were measured with a radioimmunoassay kit. Apoptosis analysis was performed by anti-AC-3 staining and survivin mRNA expression.
The number of primordial follicles and secondary follicles in the bFGF+VEGF group was significantly higher than in the control group. The vascular density in the bFGF+VEGF groups were significantly higher than in the bFGF and the VEGF groups; there was no significant difference between the bFGF and VEGF groups. Estrous cycle was earlier in the bFGF+VEGF group compared with the control group; all mice in this group restored ovarian function. Serum FSH levels in the bFGF+VEGF group were significantly lower than in the control group by day 14 post-transplantation. The AC-3-positive in control group was significantly higher compared with bFGF group and VEGF group, and in bFGF+VEGF group was significantly lower than bFGF group and VEGF group. Survivin mRNA expression in bFGF+VEGF group was significantly higher than control group.
The combination of bFGF and VEGF has beneficial effects on follicle survival, angiogenesis, and resumption of estrous cycles.
Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders accompanied by obvious metabolic abnormalities. Lower-quality oocytes and embryos are often found in PCOS ...women during assisted reproductive technology treatment. However, there is still no clarity about the mechanism of ovarian metabolic disorders and the impact on oocyte maturation in PCOS. The aim of this study was to understand the potential effect of the posttranslational modification on ovarian metabolic homeostasis and oocyte development potential in women with PCOS. A quantitative analysis of acetylated proteomics in ovarian granulosa cells of PCOS and control groups was carried out by mass spectrometry. There was widespread lysine acetylation of proteins, of which 265 proteins had increased levels of acetylation and 68 proteins had decreased levels of acetylation in the PCOS group. Most notably, differentially acetylated proteins were significantly enriched in the metabolic pathways of glycolysis, fatty acid degradation, TCA cycle, tryptophan metabolism, and branched-chain amino acid degradation. Acetyl-CoA acetyltransferase 1 (ACAT1) was an enzyme central to these metabolic pathways with increased acetylation level in the PCOS group, and there was a negative correlation of ACAT1 acetylation levels in PCOS granulosa cells with oocyte quality and embryo development efficiency in the clinic. Lysine acetylation changes of key enzymes in PCOS granulosa cells might attenuate their activities and alter metabolic homeostasis of follicular microenvironment for oocyte maturation and embryo development.
Proper reprogramming of parental DNA methylomes is essential for mammalian embryonic development. However, it is unknown whether abnormal methylome reprogramming occurs and is associated with the ...failure of embryonic development. Here we analyzed the DNA methylomes of 57 blastocysts and 29 trophectoderm samples with different morphological grades during assisted reproductive technology （ART） practices. Our data reveal that the global methylation levels of high-quality blastocysts are similar （0.30 ± 0.02, mean ± SD）, while the methylation levels of low-quality blastocysts are divergent and away from those of high-quality blastocysts. The proportion of blastocysts with a methylation level falling within the range of 0.30± 0.02 in different grades correlates with the live birth rate for that grade. Moreover, abnormal methylated regions are associated with the failure of embryonic development. Furthermore, we can use the methylation data of cells biopsied from trophectoderm to predict the blastocyst methylation level as well as to detect the aneuploidy of the blastocysts. Our data indicate that global abnormal methylome reprogramming often occurs in human embryos, and suggest that DNA methylome is a potential biomarker in blastocyst selection in ART.
DNA methylation plays important roles during development. However, the DNA methylation reprogramming of functional elements has not been fully investigated during mammalian embryonic development. ...Herein, using our modified MethylC-Seq library generation method and published post-bisulphite adapter-tagging (PBAT) method, we generated genome-wide DNA methylomes of human gametes and early embryos at single-base resolution and compared them with mouse methylomes. We showed that the dynamics of DNA methylation in functional elements are conserved between humans and mice during early embryogenesis, except for satellite repeats. We further found that oocyte-specific hypomethylated promoters usually exhibit low CpG densities. Genes with oocyte-specific hypomethylated promoters generally show oocyte-specific hypomethylated genic and intergenic regions, and these hypomethylated regions contribute to the hypomethylation pattern of mammalian oocytes. Furthermore, hypomethylated genic regions with low CG densities correlate with gene silencing in oocytes, whereas hypomethylated genic regions with high CG densities correspond to high gene expression. We further show that methylation reprogramming of enhancers during early embryogenesis is highly associated with the development of almost all human organs. Our data support the hypothesis that DNA methylation plays important roles during mammalian development.
Classic polycystic ovary syndrome (PCOS) is a high-risk phenotype accompanied by increased risks of reproductive and metabolic abnormalities; however, the local metabolism characteristics of the ...ovaries and their effects on germ cell development are unclear. The present study used targeted metabolomics to detect alterations in the intermediate metabolites of follicular fluid from classic PCOS patients, and the results indicated that hyperandrogenism but not obesity induced the changed intermediate metabolites in classic PCOS patients. Regarding the direct contact, we identified mitochondrial function, redox potential, and oxidative stress in cumulus cells which were necessary to support oocyte growth before fertilization, and suggested dysfunction of mitochondria, imbalanced redox potential, and increased oxidative stress in cumulus cells of classic PCOS patients. Follicular fluid intermediary metabolic profiles provide signatures of classic PCOS ovary local metabolism and establish a close link with mitochondria dysfunction of cumulus cells, highlighting the role of metabolic signal and mitochondrial cross talk involved in the pathogenesis of classic PCOS.
•Classic PCOS patients suffered from poor ongoing pregnancy outcome.•Intermediate metabolites of follicle fluid were abnormal in classic PCOS patients.•Dysfunctional mitochondria in cumulus cells were shown around with follicle fluid.•Hyperandrogenism but not obesity impaired ovarian local metabolism level.
The mechanisms coordinating maturation with an environment-driven metabolic shift, a critical step in determining the developmental potential of human in vitro maturation (IVM) oocytes, remain to be ...elucidated. Here we explored the key genes regulating human oocyte maturation using single-cell RNA sequencing and illuminated the compensatory mechanism from a metabolic perspective by analyzing gene expression.
Three key genes that encode CoA-related enzymes were screened from the RNA sequencing data. Two of them, ACAT1 and HADHA, were closely related to the regulation of substrate production in the Krebs cycle. Dysfunction of the Krebs cycle was induced by decreases in the activity of specific enzymes. Furthermore, the activator of these enzymes, the calcium concentration, was also decreased because of the failure of influx of exogenous calcium. Although release of endogenous calcium from the endoplasmic reticulum and mitochondria met the requirement for maturation, excessive release resulted in aneuploidy and developmental incompetence. High nicotinamide nucleotide transhydrogenase expression induced NADPH dehydrogenation to compensate for the NADH shortage resulting from the dysfunction of the Krebs cycle. Importantly, high NADP
levels activated DPYD to enhance the repair of DNA double-strand breaks to maintain euploidy.
The present study shows for the first time that exposure to the in vitro environment can lead to the decline of energy metabolism in human oocytes during maturation but that a compensatory action maintains their developmental competence.
In vitro maturation of human oocytes is mediated through a cascade of competing and compensatory actions driven by genes encoding enzymes.
Kisspeptin as a potential biomarker throughout pregnancy Hu, Kai-Lun; Zhao, Hongcui; Yu, Yang ...
European journal of obstetrics & gynecology and reproductive biology,
September 2019, 2019-Sep, 2019-09-00, 20190901, Letnik:
240
Journal Article
Recenzirano
Kisspeptins are a family of neuropeptides that are critical for the puberty initiation and female fertility. Plasma or serum kisspeptin is mainly derived from the placenta during pregnancy and plasma ...kisspeptin levels significantly increase across pregnancy. Plasma kisspeptin levels could be used as a potential biomarker for the detection of miscarriage, pre-eclampsia, gestational trophoblastic neoplasia (GTN), and fetal development. Kisspeptin may also be involved in the process of parturition by stimulating oxytocin secretion during term pregnancy. This review discussed the potential use of kisspeptin as a marker across pregnancy and highlighted the unresolved problems in this area.
Tweetable abstract: Plasma kisspeptin levels could be used as a potential biomarker across pregnancy.
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