Roles of Tet2 in meiosis, fertility and reproductive aging.
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ABSTRACT:
SUBMITTER: Wang H
PROVIDER: S-EPMC8225707 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
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Project description:Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age-related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri-phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age-related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte-specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte-specific Pdss2-deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age-associated oocyte deficits causing infertility.
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Project description:We report a comprehensive large-scale expression profiling analysis of mammalian male germ cells undergoing mitotic growth, meiosis, and gametogenesis by using high-density oligonucleotide microarrays and highly enriched cell populations. Among 11,955 rat loci investigated, 1268 were identified as differentially transcribed in germ cells at subsequent developmental stages compared with total testis, somatic Sertoli cells as well as brain and skeletal muscle controls. The loci were organized into four expression clusters that correspond to somatic, mitotic, meiotic, and postmeiotic cell types. This work provides information about expression patterns of approximately 200 genes known to be important during male germ cell development. Approximately 40 of those are included in a group of 121 transcripts for which we report germ cell expression and lack of transcription in three somatic control cell types. Moreover, we demonstrate the testicular expression and transcriptional induction in mitotic, meiotic, and/or postmeiotic germ cells of 293 as yet uncharacterized transcripts, some of which are likely to encode factors involved in spermatogenesis and fertility. This group also contains potential germ cell-specific targets for innovative contraceptives. A graphical display of the data is conveniently accessible through the GermOnline database at http://www.germonline.org.
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Project description:We performed RNAseq analysis to determine the effect of ClpP-deletion on cumulus cells global gene expression profile in mature (3 month-old) and (6 month-old) mice. RNA sequencing revealed about 13,000 genes (FPKM > 0.1) expressed in cumulus cells. A total of 1025 genes were significantly differentially expressed (p<0.05) in 3-month ClpP-/- cumulus cells compared to WT (548 up-regulated and 477 down-regulated). At 6-month, a total of 555 genes were significantly differentially expressed in ClpP-/- cumulus cells compared to WT (464 up-regulated and 91 down-regulated). In addition, 1012 and 1034 genes were significantly differentially expressed in both 6 month ClpP-/- and WT cumulus cells compared to younger ClpP-/- cumulus cells, respectively. In this study, we assessed the effect of ClpP global deletion on cumulus cells gene expression. Our findings provide new insight into the role of CLPP in the cumulus cells, and may help understand the potential mechanism of infertility and reproductive aging associated with ClpP-deficiency.
2017-12-01 | GSE102269 | GEO
Project description:PURPOSE:What are the experience, approach, and knowledge of US Obstetricians and Gynecologists' (ob-gyn) towards counseling patients on reproductive aging (RA) and elective fertility preservation (EFP). METHODS:A cross-sectional survey emailed by the American College of Obstetricians and Gynecologists (ACOG) to 5000 ACOG fellows consisting of 9 demographic and 28 questions relating to counseling patients on RA and EFP. RESULTS:Seven hundred and eighty-four responders completed the survey. Although 82.8% agreed that conversations relating to RA should take place with patients desiring future childbearing and delaying due to social reasons, only 27.6% stated that they frequently counsel these women aged 18-34 years old, compared to 75.8% aged 35-44 years old (P < 0.01). Limited time (75.8%) and limited knowledge (41.4%) were amongst the most frequent reported barriers towards counseling patients on RA. Fifty-eight percent stated that they have been asked about EFP by patients. Although 74.8% agreed that conversations should take place related to EFP in women desiring future childbearing and delaying due to social reasons, only 27.6% stated that they frequently counsel these patients on EFP (P < 0.01). Limited time (75%) and limited knowledge (59.9%) were amongst the most frequent barriers towards counseling on EFP. CONCLUSIONS:In the USA, methods to improve patient counseling and provider knowledge on RA and EFP are warranted and further studies are needed to address optimal methods to improve counseling and knowledge related to these topics.
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Project description: Not available
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Project description:Estrogen receptor alpha (ER alpha) is essential for male fertility. Its activity is responsible for maintaining epithelial cytoarchitecture in efferent ductules and the reabsorption of fluid for concentrating sperm in the head of the epididymis. These discoveries and others have helped to establish estrogen's bisexual role in reproductive importance. Reported here is the molecular mechanism to explain estrogen's role in fluid reabsorption in the male reproductive tract. It is shown that estrogen regulates expression of the Na(+)/H(+) exchanger-3 (NHE3) and the rate of (22)Na(+) transport, sensitive to an NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII), and aquaporin-I (AQP1) was decreased in ER alpha knockout (alpha ERKO) efferent ductules. Targeted gene-deficient mice were compared with alpha ERKO, and the NHE3 knockout and CAII-deficient mice showed alpha ERKO-like fluid accumulation, but only the NHE3 knockout and alpha ERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in alpha ERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in alpha ERKO seemed to be secondary because of the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in alpha ERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na(+) transport. Finally, these data raise the possibility of targeting ER alpha in developing a contraceptive for the male.
| S-EPMC61180 | biostudies-literature
Project description:Cancer may be detected at any age and could affect children, and reproductive age women as well. In recent years, cancer treatment has become less destructive and more specific. As a result, survival rates and quality of life following successful treatment have continuously improved. Cancer treatment typically involves surgery, chemo- or radiation therapy, or the combinations of these. These interventions often adversely affect the function of the reproductive organs. Chemo- and radiation therapy are known to be gonadotoxic. Survivors of oncologic therapy are typically rendered infertile primarily due to the loss of ovarian function. There are, however, several medical, surgical, and assisted reproductive technology options that could be and should be offered to those diagnosed with cancer and wish to maintain their fertility. Embryo cryopreservation has been available for decades and has been successfully applied for fertility preservation in women diagnosed with cancer. Recent advances in cryobiology have increased the efficacy of not just embryo but even oocyte and ovarian tissue freezing-thawing. Oocyte vitrification just like embryo cryopreservation requires the use of stimulation but does not require the patient to be in a stable relationship or accept the use of donor sperm. Ovarian tissue cryopreservation does not require stimulation and, following successful transplantation, provides the patient with the most eggs but is currently still considered experimental. This paper summarizes the various fertility-sparing medical, surgical and assisted reproductive technology options. It reviews the current status of embryo, oocyte, and ovarian tissue cryopreservation and discusses their risks and benefits.
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Project description:Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C), initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.
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Project description:BACKGROUND:Exosomes may have critical roles in the maternal-embryo cross-talk for the recognition and maintenance of pregnancy during maternal aging. Exosomes have the capability to carry developmental signaling molecules with the ability to modulate gene expressions and affect growth and regulation of embryo during pregnancy. Systematic review aims to evaluate age-related alterations in the exosomal content and functions that can influence the reproductive performance in human and animal models as conveyors of senescence signals. METHODS:A literature search of electronic databases including MEDLINE (PubMed), Embase, ProQuest, Scopus, Google Scholar, WHO, SID, MAGIRAN, and Barakat will be conducted. Following the online search, articles will be screened by two independent reviewers according to inclusion and exclusion criteria. Eligible studies will be critically appraised by reviewers at the study level for methodological quality using Joanna Briggs Institute's standardized critical appraisal tools. The extracted data from selected studies will cover the study populations, methods, current evidence about the physiological role of extracellular vesicles and exosomes in reproductive system, relevant outcomes, and possible conclusions about the effectiveness of exposure. DISCUSSION:Regarding the role of exosomes and their cargoes in the function of reproductive tract, the possible beneficial or adverse effects following exosomal administration from younger women to older women will be evaluated in the systematic review. As a result, exosome therapy could be suggested as a novel therapeutic agent if the favorable results are identified.
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