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1.
J Sci Food Agric ; 100(1): 92-101, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31435952

RESUMO

BACKGROUND: Oyster polypeptides have various biofunctions, such as anti-cancer and anti-oxidative stress, but whether it has the protective effects to primary ovarian failure (POF) remains poorly understand. To address this issue, daily gavage of oyster polypeptides was performed to investigate their protective effect, basing on d-galactose-induced POF model in C57BL/6 female mice. RESULTS: Oyster polypeptides restored the irregular estrous cycles and the abnormal serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and progesterone (P) levels as well as the decreased mRNA expression level of Amh that were induced by d-galactose. The follicle development of POF mice was improved by increasing the primordial follicle ratio and decreasing the atretic follicle number after oral administration of oyster polypeptides. Moreover, in the oyster polypeptides treated mice, the total superoxide dismutase (T-SOD) activity was significantly increased, while the malondialdehyde levels were significantly decreased. The mRNA expression levels of stress-related genes (SOD2, SIRT1 and FOXO3a) were remarkably up-regulated after d-galactose induction, but the up-regulation was weakened or disappeared by the gavage of oyster polypeptides. In addition, oyster polypeptides treatment also reduced the apoptosis of the ovarian granulosa cells and down-regulated the mRNA expression levels of apoptosis-related genes (p53 and Bad but not Bcl-2). CONCLUSION: This study reveals that oyster polypeptides may protect ovary against d-galactose-induced POF by their anti-oxidative stress activity to rescue d-galactose-induced ovarian oxidative damage and therefore to prevent ovarian cells apoptosis, thereby tipping the abnormality trigged by POF to get close to the normal levels. © 2019 Society of Chemical Industry.


Assuntos
Ostreidae/química , Peptídeos/administração & dosagem , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Feminino , Galactose/efeitos adversos , Humanos , Hormônio Luteinizante/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Progesterona/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
2.
Life Sci ; 239: 116999, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654746

RESUMO

AIMS: The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. MAIN METHODS: Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. KEY FINDINGS: The serum levels of E2 were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. SIGNIFICANCE: Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Colesterol/biossíntese , Ciclofosfamida/toxicidade , Perfilação da Expressão Gênica , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/biossíntese , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Insuficiência Ovariana Primária/genética , Mapas de Interação de Proteínas
3.
Endocrinology ; 160(10): 2353-2366, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393557

RESUMO

Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.


Assuntos
Infertilidade Feminina/metabolismo , Doenças Mitocondriais/fisiopatologia , Insuficiência Ovariana Primária/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos
4.
Hum Exp Toxicol ; 38(11): 1283-1295, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31370695

RESUMO

BACKGROUND: Cyclophosphamide (CP) causes premature ovarian failure (POF) due to ovarian toxicity. The toxicity mechanism is attributed to oxidative stress, inflammation, and apoptosis. We assessed whether quercetin and rosuvastatin could promote ovarian protection against CP ovotoxicity. METHODS: A total of 80 female BALB/c mice were randomly assigned; 10 mice into each of eight groups. Group 1 (control), group 2 (EH), group 3 (CP), group 4 (QH), group 5 (QL), group 6 (RH), group 7 (RL), and group 8 (COM). RESULTS: Quercetin and rosuvastatin groups (4:8) showed signs of restored ovarian function in the form of a significant, dose-dependent increase in primordial follicles number, serum anti-Mullerian hormone level, and ovarian tissue glutathione level (p < 0.05) versus group 3, and a significant, dose-dependent decrease in atretic follicles number and ovarian tissue level of malondialdehyde (p < 0.05) versus group 3. Immunohistochemistry analysis demonstrated a lower expression of caspase and nuclear factor-kappa B of groups (4:8) versus group 3, although quercetin and rosuvastatin showed a nonsignificant reduction in tumor volume. CONCLUSIONS: We demonstrated the protective effect of quercetin and rosuvastatin against ovarian toxicity and POF induced by CP without compromising its antitumor effect.


Assuntos
Antineoplásicos , Carcinoma de Ehrlich/tratamento farmacológico , Ciclofosfamida , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Quercetina/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Animais , Hormônio Antimülleriano/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/sangue , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Glutationa/metabolismo , Camundongos Endogâmicos BALB C , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia
5.
J Ovarian Res ; 12(1): 65, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324205

RESUMO

BACKGROUND: Premature ovarian insufficiency (POI) is characterized by early loss of ovarian function that affects women before the age of 40. We aim to explore the protective effects of transcutaneous electrical acupoint stimulation (TEAS) against irradiation-induced ovarian damage in mice. METHODS: C57BL6 mice were randomly divided into control and irradiation (IR) groups. Then, control group was divided into two treatment subgroups: mock TEAS treatment (control-) and TEAS treatment (control+). IR group was divided into four subgroups according to the time of treatment started: mock TEAS treatment initiated at 2 days after irradiation (IR 2D-), TEAS treatment initiated at 2 days after irradiation (IR 2D+), mock TEAS treatment initiated at 1 week after irradiation (IR 1 W-), and TEAS treatment initiated at 1 week after irradiation (IR 1 W+). The radiation model mice were exposed to single whole body X-ray irradiation (4 Gy), and the control mice received 0 Gy. TEAS stimulation (2 Hz, 1 mA, 30 min/day) was given once a day for six consecutive days per week for 2 weeks. Estrous cycle, ovarian weight, serum AMH level and follicle counts were evaluated. Then, proliferation markers, apoptotic markers and oxidative stress markers were examined. RESULTS: Compared with the control group, the estrous cycle was disordered, and the ovarian weight, serum AMH, and primordial, primary and secondary follicles counts decreased (all P < 0.01) in the IR 2D- and IR 1 W- groups. In the irradiation with early TEAS treatment group (IR 2D+), the estrous cycle improved, the AMH level and primordial follicular significantly increased compared to the irradiation with mock group (IR 2D-). However, there were no significant differences in the estrous cycle, AMH level and follicle counts between IR 1 W- and IR 1 W+ groups. Moreover, IR 2D+ mice reduced the expression of Bax protein and increased the levels of Bcl-2 and PCNA compared to the IR 2D- group. Furthermore, the early TEAS treated mice showed significantly lower levels of oxidative stress and number of TUNEL (+) granulosa cells than that in the IR 2D- group. CONCLUSION: This study is first to evaluate TEAS as a potential therapy to attenuate irradiation-induced ovarian failure through inhibiting primordial follicles loss, increasing serum AMH secretion, inducing antioxidant, and anti-apoptotic systems.


Assuntos
Pontos de Acupuntura , Eletroacupuntura , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/prevenção & controle , Radioterapia/efeitos adversos , Estimulação Elétrica Nervosa Transcutânea , Animais , Biomarcadores , Modelos Animais de Doenças , Eletroacupuntura/métodos , Feminino , Expressão Gênica , Camundongos , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Estresse Oxidativo , Insuficiência Ovariana Primária/metabolismo , Lesões Experimentais por Radiação , Estimulação Elétrica Nervosa Transcutânea/métodos , Raios X
6.
Cell Biol Int ; 43(8): 899-909, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31081266

RESUMO

Previous studies have shown that the ovarian failure in autoimmune-induced premature ovarian failure (POF) mice could be improved by the transplantation of human placenta-derived mesenchymal stem cells (hPMSCs); however, the protective mechanism of hPMSCs transplantation on ovarian dysfunction remains unclear. Ovarian dysfunction is closely related to the apoptosis of granulosa cells (GCs). To determine the effects of hPMSCs transplantation on GCs apoptosis, an autoimmune POF mice model was established with zona pellucida glycoprotein 3 (ZP3) peptide. It is reported that the inositol-requiring enzyme 1α (IRE1α) and its downstream molecules play a central role in the endoplasmic reticulum (ER) stress-induced apoptosis pathway. So the aim of this study is to investigate whether hPMSCs transplantation attenuated GCs apoptosis via inhibiting ER stress IRE1α signaling pathway. The ovarian dysfunction, follicular dysplasia, and GCs apoptosis were observed in the POF mice. And the IRE1α pathway was activated in ovaries of POF mice, as demonstrated by, increased X-box binding protein 1 (XBP1), up-regulated 78 kDa glucose-regulated protein (GRP78) and caspase-12. Following transplantation of hPMSCs, the ovarian structure and function were significantly improved in POF mice. In addition, the GCs apoptosis was obviously attenuated and IRE1α pathway was significantly inhibited. Transplantation of hPMSCs suppressed GCs apoptosis-induced by ER stress IRE1α signaling pathway in POF mice, which might contribute to the hPMSCs transplantation-mediating ovarian function recovery.


Assuntos
Apoptose/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Placenta/citologia , Insuficiência Ovariana Primária , Animais , Caspase 12/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Feminino , Células da Granulosa/citologia , Proteínas de Choque Térmico/metabolismo , Humanos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos BALB C , Ovário/metabolismo , Gravidez , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/terapia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo , Glicoproteínas da Zona Pelúcida/metabolismo
7.
J Ethnopharmacol ; 239: 111885, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31009706

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kuntai capsule (KTC), a type of herb formulas, was first described in the book of Shang Han Za Bing Lun in the third century. KTC has been widely used for the clinical treatment of menopausal syndrome. Considering that premature ovarian failure is also known as premature menopause, this study was designed to investigate the effects and mechanisms of KTC on a mouse model of premature ovarian failure. MATERIALS AND METHODS: Forty-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the Control group. The remaining thirty were used to establish the premature ovarian failure model by injecting intraperitoneally with 75 mg/kg cyclophosphamide and then by randomly dividing the mice into two groups. One group was considered the Model group, the other group treated with the Kuntai capsule intragastrically every day for one week called the KTC group. After treatment, mice were sacrificed for sampling. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. Western blotting was used to detect the PI3K/AKT/mTOR pathway activation. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-mullerian hormone (AMH)levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. RESULTS: We found that primordial follicle counts were increased in the KTC group compared to the Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in the KTC group significantly reduced compared to Model group. Serum FSH and LH levels in the KTC group were decreased compared to the Model group, while, serum E2 and AMH levels in the KTC group were increased compared with the Model group. The litter size in the KTC group was improved compared to Model group. CONCLUSIONS: The KTC showed protective potentials of ovarian reserve and fertility to attenuate premature ovarian failure, which was relatively associated with activation of the PI3K/AKT/mTOR signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
EBioMedicine ; 42: 524-531, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31000419

RESUMO

BACKGROUND: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1-3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic. METHODS: We performed exome sequencing (WES) of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB). FINDINGS: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs. INTERPRETATION: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob-/- mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB) responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. FUND: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/metabolismo , Adolescente , Adulto , Animais , Biomarcadores , Linhagem Celular , Consanguinidade , Feminino , Expressão Gênica , Humanos , Informática/métodos , Camundongos , Linhagem , Insuficiência Ovariana Primária/diagnóstico , Ligação Proteica , Sequenciamento Completo do Exoma , Adulto Jovem
9.
Ann Clin Lab Sci ; 49(1): 16-22, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814073

RESUMO

OBJECTIVE: This study aims to investigate the role of X-linked inhibitor of apoptosis protein (XIAP) in the pathogenesis of premature ovarian failure (POF) and the effects of the Modified Bazhen Decoction (MBD) in the treatment of POF. MATERIALS AND METHODS: Twenty-four eight-week-old Sprague Dawley (SD) rats were randomly divided into four groups: control group, POF group, MBD treatment group, and Fufang Ejiao Syrup (FES) treatment group. After adaptive feeding for one week, 18 SD rats in the POF, MBD and FES groups were subcutaneously injected with D-galactose (dissolved in saline) at the back of neck for eight weeks (150 mg/kg/day) to establish the POF model. Six SD rats in the control group received equal volumes of subcutaneous injection of saline. Tail blood was collected, and the concentration of follicle stimulating hormones (FSHs) and estradiol (E2) was measured, in order to evaluate the success of the POF model. SD rats in the MBD and FES treatment groups were intragastrically administered with MBD (10 ml/kg/day) and FES (10 ml/kg/day), respectively. Rats in the control and POF groups were intragastrically administered with saline (10 ml/kg/day). After four weeks of intragastrical administration with different medicines and saline, ovarian tissues were collected; and the expression level of XIAP, miR-23a and miR-27a were measured and compared among different groups. RESULTS: Compared with the control group, XIAP expression was significantly lower, and miR-23a and miR-27a expression significantly higher in the POF group. Furthermore, XIAP expression was significantly higher, and miR-23a and miR-27a expression was significantly lower in the MBD group. CONCLUSION: XIAP is involved in the regulation of oocyte and granulosa cells via the cysteinyl aspartate specific proteinase (caspase) pathway, and plays an important role in POF. MBD can dramatically activate XIAP, but inhibit the expression of miR-23a and miR-27a; preventing the apoptosis of oocyte and granulosa cells. Our study suggests that MBD may be a useful traditional Chinese medicine for the treatment of POF.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Células da Granulosa/efeitos dos fármacos , Fitoterapia , Insuficiência Ovariana Primária/tratamento farmacológico , Animais , Feminino , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Proteínas Inibidoras de Apoptose/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Sprague-Dawley
10.
J Endocrinol ; 240(2): 243-256, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530902

RESUMO

Cancer therapy can cause off-target effects including ovarian damage, which may result in primary ovarian insufficiency in girls and premenopausal women. Loss of ovarian follicles within the ovarian reserve leads to ovarian endocrine dysfunction and impaired fertility. Cyclophosphamide (CPA), a commonly used chemotherapeutic and immunosuppressant agent, is a gonadotoxic agent that destroys ovarian cells by crosslinking DNA. To protect the ovary against CPA damage, we sought to precisely map the mechanism by which the ovarian reserve is depleted by CPA. We found that CPA specifically depletes primordial follicles without affecting primary and secondary follicles in three independent murine strains (CD-1, C57BL/6J and BALB/cJ) in vivo. We directly tested the effect of the active metabolite of CPA, 1 µM 4-hydroxyperoxycyclophophamide (4-HC), in vitro and confirmed the loss of primordial oocytes but no change in the number of primary and secondary follicles. We demonstrated that phospho-AKT (p-AKT) and cleaved PARP (cPARP) are present in primordial oocytes 3 days after CPA injection, consistent with the role of these markers as part of the apoptotic cascade. Interestingly, p-AKT positive primordial oocytes co-expressed cPARP. Treatment of animals with specific inhibitors of apoptotic pathway components, ETP46464 and CHK2, blocked 4-HC‒induced DNA damage in vitro. These data suggest that CPA targets primordial germ cells in the ovarian reserve by stimulating apoptosis pathways. Adjuvant therapies to protect primordial germ cells from the off-target effects of CPA may reduce the risk of POI.


Assuntos
Apoptose/efeitos dos fármacos , Ciclofosfamida/toxicidade , Reserva Ovariana/efeitos dos fármacos , Oxazinas/farmacologia , Quinolinas/farmacologia , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/toxicidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/metabolismo , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Reserva Ovariana/fisiologia , Poli(ADP-Ribose) Polimerases/metabolismo , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/prevenção & controle , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Biomed Pharmacother ; 109: 293-303, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30396087

RESUMO

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-ß protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-ß/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.


Assuntos
Apoptose/efeitos dos fármacos , Flavonoides/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Lesões Experimentais por Radiação/tratamento farmacológico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Apoptose/fisiologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Feminino , Flavonoides/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
12.
Life Sci ; 217: 169-175, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521869

RESUMO

AIMS: Electro-acupuncture (EA) is frequently recommended as a complementary therapy for premature ovarian failure (POF) in the clinical. However, little information exists about its potential treatment mechanisms. The study was designed to observe the effect of EA to ovarian function and fertility in POF mice model, and investigated its potential mechanisms on PI3K/AKT/mTOR signaling pathway. MATERIALS AND METHODS: Forty-five female C57/BL6 mice were divided into the Control, the Model and the EA group. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. The protein expression of PI3K, phospho-PI3K, AKT, phospho-AKT, mTOR, phospho-mTOR, S6, phospho-S6, 4E-BP1 and phospho-4E-BP1 were detected by western blotting. The data was presented as the ratio of phosphorylation protein to total protein. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-Mullerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. KEY FINDINGS: We found that primordial follicle counts were increased in EA group compared to Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in EA group significantly reduced compared to Model group. Serum FSH and LH levels in EA group were decreased compared to Model group, while, serum E2 and AMH levels in EA group were increased compared with Model group. The litter size in EA group was improved compared to Model group. SIGNIFICANCE: The effects of EA on the PI3K/AKT/mTOR signaling pathway may represent one of the mechanisms involved in attenuating the mice POF.


Assuntos
Eletroacupuntura/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Ovariana Primária/terapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Fosforilação , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Transdução de Sinais
13.
PLoS One ; 13(12): e0209309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576349

RESUMO

Low FMR1 variants (CGGn<26) have been associated with premature ovarian aging, female infertility and poor IVF treatment success. Until now, there is little published information concerning possible molecular mechanisms for this effect. We wished to examine whether relative expression of RNA and the FMR1 gene's fragile X mental retardation protein (FMRP) RNA isoforms differ in women with various FMR1 sub-genotypes (normal, low CGGn<26 and/or high CGGn≥34). This prospective cohort study was conducted between 2014 and 2017 in a clinical research unit of the Center for Human Reproduction in New York City. The study involved a total of 98 study subjects, including 18 young oocyte donors and 80 older infertility patients undergoing routine in vitro fertilization (IVF) cycles. The main outcome measure was RNA expression in human luteinized granulosa cells of 5 groups of FMRP isoforms. The relative expression of FMR1 RNA in human luteinized granulosa cells was measured by real-time PCR and a possible association with CGGn was explored. All 5 groups of FMRP RNA isoforms examined were found to be differentially expressed in human luteinized granulosa cells. The relative expression of four FMR1 RNA isoforms showed significant differences among 6 FMR1 sub-genotypes. Women with at least one low allele expressed significantly lower levels of all 5 sets of FRMP isoforms in comparison to the non-low group. While it would be of interest to see whether FMRP is also decreased in the low-group we recognize that in recent years it has been increasingly documented that information flow of genetics may be regulated by non-coding RNA, that is, without translation to a protein product. We, thus, conclude that various CGG expansions of FMR1 allele may lead to changes of RNA levels and ratios of distinct FMRP RNA isoforms, which could regulate the translation and/or cellular localization of FMRP, affect the expression of steroidogenic enzymes and hormonal receptors, or act in some other epigenetic process and therefore result in the ovarian dysfunction in infertility.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Infertilidade Feminina/genética , Insuficiência Ovariana Primária/genética , Regiões 5' não Traduzidas , Adulto , Alelos , Sequência de Aminoácidos , Sequência de Bases , Estudos de Coortes , Feminino , Fertilização In Vitro , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/genética , Expressão Gênica , Células da Granulosa/metabolismo , Humanos , Infertilidade Feminina/etiologia , Infertilidade Feminina/metabolismo , Reserva Ovariana/genética , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/metabolismo , Estudos Prospectivos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA/genética , RNA/metabolismo , Homologia de Sequência de Aminoácidos , Expansão das Repetições de Trinucleotídeos
14.
Cell Physiol Biochem ; 51(5): 2341-2358, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30537739

RESUMO

BACKGROUND/AIMS: This study investigated the effect of consecutive superovulation on the ovaries and established a premature ovarian failure (POF) model in mice. METHODS: The mouse POF model was induced by 5-15 consecutive superovulation treatments with pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG) and prostaglandin F2α (PGF2α). Normal adult mice were compared with mice displaying natural ovarian aging. The following serum biochemical parameters were measured: including follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), inhibin B (INH B), malondialdehyde (MDA), total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Follicles were counted using H&E staining. Levels of 8-hydroxyguanosine (8-OhdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), anti-Mullerian hormone (AMH) and CDKN2A/ p16 (p16) were detected using immunohistochemical staining. Reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE) staining. Cell apoptosis was detected using an in situ TUNEL fluorescence staining assay. Levels of proteins involved in ROS-related pathways and the p16 protein were detected using Western blotting. Sod1, Sod2 and Sod3 mRNA levels were detected using quantitative polymerase chain reaction (Q-PCR). Oocyte quality was evaluated using in vitro fertilization (IVF) and zygote culture. RESULTS: Consecutive superovulation groups presented lower P, E2, SOD, GSH-Px and INH B levels, significantly higher FSH, LH, MDA and ROS levels, and significantly fewer primordial follicles compared with the control group. Consecutive superovulation groups presented significantly increased levels of Sod2, 8-OhdG, 4-HNE, NTY, significantly increased levels of the SIRT1 and FOXO1 proteins, significantly increased levels of the senescence-associated protein p16, as well as decreased AMH, Sod1 and Sod3 levels and increased granulosa cell apoptosis compared with the control group. CONCLUSION: Consecutive superovulation significantly decreased ovarian function and oocyte quality and increased oxidative stress and apoptosis in the ovary via a mechanism involving the p16 and SIRT1/FOXO1 signaling pathways. These findings suggest that consecutive superovulation may be used to establish a mouse model of ovarian aging.


Assuntos
Ovário/fisiopatologia , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/fisiopatologia , Superovulação , Animais , Apoptose , Modelos Animais de Doenças , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Inibinas/sangue , Hormônio Luteinizante/sangue , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/metabolismo , Oócitos/patologia , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Folículo Ovariano/fisiopatologia , Ovário/metabolismo , Ovário/patologia , Estresse Oxidativo , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Progesterona/sangue
15.
Stem Cell Res Ther ; 9(1): 263, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30286808

RESUMO

With the development of regenerative medicine, a variety of mesenchymal stem cells (MSCs) are increasingly considered for the treatment of premature ovarian failure (POF). Reportedly, bone marrow-derived MSCs (BMSCs) improve the ovarian reserve, which mainly depends on homing and paracrine activities. Furthermore, paracrine factors secreted by these stem cells play an important role in ovarian recovery. Relevant studies indicate that BMSC transplantation has some positive effects on the treatment of POF in animals, but BMSCs are not widely applied in clinical therapy. Clinical trials are ongoing despite the fact that several patients experiencing BMSC transplantation recover their normal menstrual cycles and even give birth to babies. In this review, we discuss the possible therapeutic mechanisms of BMSCs for POF, migration, antiapoptosis, antifibrosis, angiogenesis, anti-inflammation, immunoregulation, and oxidative stress, which provide the theoretical basis for further study and clinical therapy.


Assuntos
Células da Medula Óssea/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica , Insuficiência Ovariana Primária/terapia , Animais , Células da Medula Óssea/fisiologia , Movimento Celular , Citocinas/biossíntese , Citocinas/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ciclo Menstrual/fisiologia , Células-Tronco Mesenquimais/fisiologia , Ovário/metabolismo , Ovário/patologia , Comunicação Parácrina , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Medicina Regenerativa/métodos
16.
Cell Death Dis ; 9(10): 943, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237472

RESUMO

There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.


Assuntos
Dano ao DNA/genética , Genes abl/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Feminino , Genes abl/genética , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Humanos , Mesilato de Imatinib/uso terapêutico , Immunoblotting , Injeções Intraperitoneais , Camundongos , Camundongos Nus , Oócitos/citologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Orphanet J Rare Dis ; 13(1): 164, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231941

RESUMO

BACKGROUND: Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17-51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. RESULTS: Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = - 0.68) and (rs = - 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). CONCLUSIONS: These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.


Assuntos
Galactose/metabolismo , Galactosemias/sangue , Galactosemias/fisiopatologia , Infertilidade/sangue , Infertilidade/fisiopatologia , Adolescente , Adulto , Feminino , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Galactosemias/metabolismo , Humanos , Infertilidade/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Leptina/sangue , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/fisiopatologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Septinas/genética , Septinas/metabolismo , Adulto Jovem
18.
PLoS One ; 13(8): e0201136, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30071053

RESUMO

Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.


Assuntos
Ciclofosfamida/toxicidade , Proteína Forkhead Box O3/metabolismo , Ovário/efeitos dos fármacos , Extratos Placentários/farmacologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos Alquilantes/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hormônios/sangue , Humanos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Ovário/metabolismo , Ovário/patologia , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/prevenção & controle , Proteína Companheira de mTOR Insensível à Rapamicina/antagonistas & inibidores , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/antagonistas & inibidores , Proteína de Morte Celular Associada a bcl/metabolismo
19.
Ginekol Pol ; 89(7): 364-369, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30091445

RESUMO

OBJECTIVES: Premature ovarian insufficiency (POI) is associated with hypoestrogenism and an increased risk of metabolic disorders. In many clinics, a variety of insulin resistance (IR) tests are used during routine clinical assessments. To date, there is no clear opinion about which of these tests should be applied in women with premature ovarian insufficiency (POI). Therefore, our preliminarily aim was to compare the most frequently used insulin resistance indexes in the clinical assessment of a group of POI women and a control group. MATERIAL AND METHODS: Our retrospective study included 98 women with karyotypically normal spontaneous POI aged 18-39 years and a control group of 78 healthy women. Each patient was given an oral glucose tolerance test (OGTT) to evaluate their insulin release and insulin resistance. In addition, each woman's insulin resistance (IR) was evaluated us-ing the homeostasis model assessment for insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), the fasting glucose-to-insulin ratio (FGIR), and Matsuda and McAuley indexes. The two groups' glucose levels were compared at 0, 60 and 120 min of the OGTT. RESULTS: At 0 and 60 min of the OGTT, the insulin levels of the POI women were significantly higher than those of the control group. The number of women in whom IR was detected using the various kits was comparable between the two groups. CONLUSIONS: In conclusion, only the OGTT evaluation revealed a significant difference in insulin concentrations between the two study groups. The indexes most commonly used to detect IR did not detect differences in IR between the POI women and the members of the healthy control group. QUICKI detected significantly more women with IR within both study groups than other tests did.


Assuntos
Glicemia/metabolismo , Resistência à Insulina , Insulina/sangue , Insuficiência Ovariana Primária/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Teste de Tolerância a Glucose , Humanos , Projetos Piloto , Estudos Retrospectivos , Adulto Jovem
20.
Reprod Toxicol ; 80: 60-67, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29969652

RESUMO

Humans are at daily risk by simultaneous exposures to a broad spectrum of man-made chemicals in the commercial products. Several classes of chemicals have been shown to alter follicle development and reduce fertility, leading to premature ovarian failure (POF) in mammals. We investigate the synergistic effects of 4-vinylcyclohexene diepoxide (VCD) and phthalate, including di(2-ethylhexyl) phthalate (DEHP), butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP) on POF. Combination exposure with VCD and phthalate significantly reduced the numbers of primary follicles. The expressions of Amh and Sohlh2 were significantly decreased in the combination groups. Serum Amh levels were significantly lower in the combination groups. Additionally, serum levels of follicle-stimulating hormone were significantly increased in combination groups. Taken together, exposure to phthalates promotes the depletion of follicular follicles and consequently increases the risk of premature menopause, and combined exposure of phthalates and VCD to early menopausal women is likely to aggravate the POF syndrome.


Assuntos
Cicloexenos/toxicidade , Disruptores Endócrinos/toxicidade , Ciclo Estral/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Insuficiência Ovariana Primária/induzido quimicamente , Compostos de Vinila/toxicidade , Animais , Hormônio Antimülleriano/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Sinergismo Farmacológico , Feminino , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Insuficiência Ovariana Primária/metabolismo , Ratos Sprague-Dawley
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