BMP15
Bone morphogenetic protein 15 precursor (BMP-15) (Growth/differentiation factor 9B) (GDF-9B) [GDF9B]
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Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-KIT according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.
Keywords
- BMP15
- C-KIT
- GDF9
- Ovarian aging
- biomarkers
Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.
MeSH Terms
- Adipose Tissue, Brown
- Animals
- Cellular Senescence
- Female
- Longevity
- Male
- Mice
- Ovarian Follicle
- Ovary
- Rats
- Rats, Sprague-Dawley
- Transplantation, Heterologous
Keywords
- aging
- brown adipose tissue (BAT)
- lifespan
- mice
- ovary
- rat
- xenotransplant
The citrus flavonoid hesperetin has a variety of pharmacological actions, including antioxidant, antiinflammatory, and anticancer activities. This study investigated whether hesperetin prevents aging of oocytes in vitro in which it determined the maturation of nuclear and cytoplasm and the developmental capacity of embryo by modulating the reactive oxygen species (ROS) level. Porcine oocytes were matured in vitro for 44 hr (control) and for an additional 24 hr in the presence of 0, 1, 10, 100, and 250 μM hesperetin (aging, H-1, H-10, H-100, and H-250, respectively). Although there was no difference in the rate of maturation among all the groups, both the control and H-100 groups significantly increased in the rate of cleavage and blastocyst formation compared to the aging group. The H-100 group significantly decreased ROS activity and increases the level of glutathione (GSH) and expression of the antioxidant genes (PRDX5, NFE2L, SOD1, and SOD2) compared with the aging group. The H-100 groups prevented aberrant spindle organization and chromosomal misalignment, blocked the decrease in the level of phosphorylated-p44/42 mitogen-activated protein kinase and increased the messenger RNA expression of cytoplasmic maturation factor genes (GDF9, CCNB1, BMP15, and MOS). Subsequently, both the control and H-100 groups significantly increased the total cell number and decreased the apoptosis cells at the blastocyst stage compared with aging group. The results indicate that hesperetin improves the quality of porcine oocytes by protecting them against oxidative stress during aging in vitro.
MeSH Terms
- Animals
- Blastocyst
- Cellular Senescence
- Embryonic Development
- Hesperidin
- Oocytes
- Oxidative Stress
- Reactive Oxygen Species
- Swine
Keywords
- aging in vitro
- antioxidant
- hesperetin
- oocyte
- porcine
The aim of this study was to investigate the impact of diosgenin, an important monomer of sapogenins in yams, on ovarian reserve in a natural aging mice model. This randomized controlled trial included 60 9-month-old C57 naturally aging female mice. Twenty-one mice were assigned to the dio group and were fed a single dose of diosgenin (200 mg/kg/day) suspended in 0.3% CMC. Twenty mice were assigned to the DHEA group and were fed a single dose of DHEA (1.25 mg/kg/day) suspended in 0.3% CMC. The remaining 20 mice were assigned to the old control group and were fed a single dose of 0.3% CMC. Three months later, the reproductive performance of these female mice was determined by evaluating ovarian follicles and oocyte number and quality in IVF and comparing age-matched and young controls. The impact of NOBOX, GDF9 and BMP15 mRNA expression was also evaluated. Diosgenin improves ovarian reserve in naturally aging mice in terms of increasing the number of primary follicles (P < 0.05) and serum levels of AMH (P < 0.05). Diosgenin could counteract age-associated ovarian dysfunction by improving the ovarian reserve in a natural aging mice model.
MeSH Terms
- Animals
- Anti-Mullerian Hormone
- Bone Morphogenetic Protein 15
- Diosgenin
- Female
- Growth Differentiation Factor 9
- Homeodomain Proteins
- Mice
- Mice, Inbred C57BL
- Oocytes
- Ovarian Reserve
- Ovary
- Transcription Factors
Keywords
- Aging
- Diosgenin
- Mouse model
- Ovarian reserve
We hypothesised that advanced mare age is associated with follicle and oocyte gene alterations. The aims of the study were to examine quantitative and temporal differences in mRNA for LH receptor (LHR), amphiregulin (AREG) and epiregulin (EREG) in granulosa cells, phosphodiesterase (PDE) 4D in cumulus cells and PDE3A, G-protein-coupled receptor 3 (GPR3), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and mitochondrial (mt) DNA in oocytes. Samples were collected from dominant follicles of Young (3-12 years) and Old (≥20 years) mares at 0, 6, 9 and 12h after administration of equine recombinant LH. LHR mRNA declined after 0h in Young mares, with no time effect in Old mares. For both ages, gene expression of AREG was elevated at 6 and 9h and EREG was expression was elevated at 9h, with higher expression in Old than Young mares. Cumulus cell PDE4D expression increased by 6h (Old) and 12h (Young). Oocyte GPR3 expression peaked at 9 and 12h in Young and Old mares, respectively. Expression of PDE3A increased at 6h, with the increase greater in oocytes from Old than Young mares at 6 and 9h. Mean GDF9 and BMP15 transcripts were higher in Young than Old, with a peak at 6h. Copy numbers of mtDNA did not vary over time in oocytes from Young mares, but a temporal decrease was observed in oocytes from Old mares. The results support an age-associated asynchrony in the expression of genes that are essential for follicular and oocyte maturation before ovulation.
MeSH Terms
- Aging
- Amphiregulin
- Animals
- Bone Morphogenetic Protein 15
- Cumulus Cells
- Cyclic Nucleotide Phosphodiesterases, Type 4
- DNA, Mitochondrial
- Epiregulin
- Female
- Gene Expression
- Growth Differentiation Factor 9
- Horses
- Oocytes
- Ovarian Follicle
- Receptors, LH
- Transcriptome
The onset of menopause has important implications on women's fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, [[AMHR2]], BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in [[AMHR2]] (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.
MeSH Terms
- Age Factors
- Aging
- Anti-Mullerian Hormone
- Epistasis, Genetic
- Female
- Humans
- Menopause
- Middle Aged
- Ovarian Follicle
- Polymorphism, Single Nucleotide
- Receptors, Peptide
- Receptors, Transforming Growth Factor beta
Timing of menopause is largely influenced by genetic factors. Because menopause occurs when the follicle pool in the ovaries has become exhausted, genes involved in primordial follicle recruitment can be considered as candidate genes for timing of menopause. The aim was to study the association of 23 tagging single nucleotide polymorphisms in five genes [Anti-Müllerian hormone (AMH), AMH type II receptor ([[AMHR2]]), bone morphogenetic protein 15 (BMP15), forkhead transcription factor L2 (FOXL2), and growth differentiation factor-9 (GDF9)] involved in recruitment of the primary follicle pool, including the [[AMHR2]] gene, which has recently been associated with age at menopause. We conducted a cross-sectional association study. We studied a population-based sample of 3616 Dutch women with natural menopause. We measured age at natural menopause. Both studied [[AMHR2]] tagging single nucleotide polymorphisms (rs2002555 and rs11170547) in the [[AMHR2]] gene were associated with age at natural menopause in interaction with parity. Parous rs2002555 G/G carriers had menopause 1 yr later compared with A/A carriers (P = 0.01). For rs11170547, each minor allele (T) was associated with a 0.41-yr later onset of menopause in parous women (P = 0.01). Additionally, rs6521896 in BMP15 was associated with later menopause (β = 0.41; P = 0.007). Variants in the AMH, FOXL2, and GDF9 genes were not associated with timing of menopause. The present study confirms an earlier finding that variation in the [[AMHR2]] gene modifies the relation between parity and age at natural menopause. In combination with the association of BMP15 with menopausal age, we find that there is evidence that genes involved in primary follicle recruitment influence timing of menopause.
MeSH Terms
- Aged
- Aging
- Alleles
- Anti-Mullerian Hormone
- Bone Morphogenetic Protein 15
- Cohort Studies
- Cross-Sectional Studies
- Female
- Forkhead Box Protein L2
- Forkhead Transcription Factors
- Genotype
- Growth Differentiation Factor 9
- Humans
- Menopause
- Middle Aged
- Netherlands
- Ovarian Follicle
- Parity
- Polymorphism, Single Nucleotide
- Postmenopause
- Receptors, Peptide
- Receptors, Transforming Growth Factor beta
Improving human nuclear transfer (NT) efficiencies is paramount for the development of patient-specific stem cell lines, although the opportunities remain limited owing to difficulties in obtaining fresh mature oocytes. Therefore, the developmental competence of aged, failed-to-fertilize human oocytes as an alternate cytoplasmic source for NT was assessed and compared with use of fresh, ovulation-induced oocytes. To further characterize the developmental potential of aged oocytes, parthenogenetic activation, immunocytochemical analysis of essential microtubule proteins involved in meiotic and mitotic division, and RT-PCR in single oocytes (n = 6) was performed to determine expression of oocyte-specific genes [oocyte-specific histone 1 (H1FOO), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), zygote arrest 1 (ZAR1)] and microtubule markers [nuclear mitotic arrest (NuMA), minus-end directed motor protein HSET and the microtubule kinesin motor protein EG5]. For NT, enucleation and fusion rates of aged oocytes were significantly lower compared with fresh oocytes (P < 0.05). Cleavage rates and subsequent development were poor. In addition, parthenote cleavage was low. Immunocytochemical analysis revealed that many oocytes displayed aberrant expression of NuMA and EG5, had disrupted meiotic spindles and tetrapolar spindles. One of the six oocytes misexpressed GDF9, BMP15 and ZAR1. Two oocytes expressed EG5 messenger RNA (mRNA), and HSET and NuMA were not detectable. RT-PCR of mRNA for oocyte specific genes and microtubule markers in single aged oocytes. Thus, aneuploidy and spindle defects may contribute to poor parthenogenetic development and developmental outcomes following NT.
MeSH Terms
- Aging
- Antigens, Nuclear
- Cell Cycle Proteins
- Female
- Fertilization in Vitro
- Humans
- Kinesin
- Nuclear Matrix-Associated Proteins
- Nuclear Transfer Techniques
- Oocytes
- Parthenogenesis
- Reverse Transcriptase Polymerase Chain Reaction
- Sperm Injections, Intracytoplasmic
- Tubulin