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1.
Ecotoxicol Environ Saf ; 205: 111338, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956867

RESUMO

Lead (Pb) is well-recognized for its great hazards to human and wildlife health. It has negative influences on multiple organs and systems of birds. Especially, lead exposure caused adverse impacts on bird reproduction. In this study, one week old female Japanese quails were randomly allocated into four groups and each group was respectively fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb in drinking water for 36 days to determine the effects of chronic lead exposure on ovarian development and function. The results showed that Pb did accumulate in the ovary and ovarian development was delayed by high dose lead exposure (500 ppm and 1000 ppm). Moreover, high Pb dosage induced ovarian histopathological damages characterized by granulosa cells disorganization, follicle atresia and interstitial cell degeneration. Meanwhile, the concentration of estradiol (E2) was significantly decreased and mRNA levels of genes involved with ovarian steroidogenesis were significantly down-regulated by high concentration Pb. In addition, Pb exposure caused increasing cell apoptosis and significant changes of the expression of genes involved with cell death in the ovary. High dose Pb exposure also inhibited thyroid hormone release and disrupted ovarian thyroid deiodination apart from causing thyroid histopathological injury such as follicular deformation and atrophy. The study indicated that Pb might cause ovarian malfunction by inducing ovary and thyroid microstructural damages, thyroid hormone and estrogen release inhibition and ovarian steroidogenesis disruption.


Assuntos
Coturnix/metabolismo , Poluentes Ambientais/toxicidade , Estradiol/metabolismo , Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Ovário/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Coturnix/genética , Coturnix/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Estradiol/genética , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/patologia , Humanos , Chumbo/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovário/patologia , Distribuição Aleatória , Reprodução/efeitos dos fármacos , Reprodução/genética , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/genética
2.
Ecotoxicol Environ Saf ; 204: 110973, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32781346

RESUMO

Arsenic (As) exerts a wide range of adverse effects on biological systems, including the reproductive organs in males and females. However, the mechanisms of As-induced reproductive toxicity are mostly obscure. Recently, we showed that autophagy is an essential route for As2O3-induced reprotoxicity through the hypothalamic-pituitary-gonadal-sperm (HPG-S) axis in pubertal and matured F1-male mice. However, the role of autophagy in As2O3- induced ovarian toxicity is mostly unknown. Hence, this study aimed to elucidate the role of oxidative stress, mitochondrial impairment, and autophagic processes in the ovary of As-exposed female mice. For this purpose, mature female mice were challenged with 0, low (0.2), medium (2), and high (20 ppm) As2O3 from 35-days before mating till weaning their pups, and the F1- females from weaning until maturity. Then, all the mice were sacrificed, and oxidative stress parameters, mitochondrial indices, electron microscopic evaluation of the ovaries, expression of autophagic-related genes and proteins, and autophagosome formation were assessed. It was shown that medium and high As2O3 doses were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in the ovary of F1-generation. A dose-dependent increment in the gene expression of PDK1, PI3K, TSC2, AMPK, ULK1, ATG13, Beclin1, ATG12, ATG5, LC3, P62, ATG3, ATG7, and p62, as well as protein expression of Beclin1, and LC3- I, II, was evident in the ovaries of the As-treated animals. Moreover, a dose-dependent decrease in the expression of mTOR and Bcl-2 genes, and mTOR protein was detected with increasing doses of As, suggesting that As treatment-induced autophagy. Along with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles, transmission electron microscopy also confirmed more autophagosomes and injured mitochondria in medium and high As2O3 doses groups. As2O3 also negatively affected the mean body weight, litter size, organ coefficient, and stereological indices in female mice. Finally, in physiological conditions, arsenic trioxide (As2O3) leads to an increased level of autophagy in the oocyte when many oocytes were being lost. These findings indicated that an imbalance in the oxidant-antioxidant system, mitochondrial impairment, and the autophagic process, through inhibition of mTOR, dependent and independent pathways, and Bcl-2, as well as activation of AMPK/PI3K/Beclin1/LC3 routes, could play a pivotal role in As-induced reproductive toxicity through ovarian dysfunction in females.


Assuntos
Arsênico/toxicidade , Autofagia/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Folículo Ovariano/crescimento & desenvolvimento , Ovário/ultraestrutura , Distribuição Aleatória
3.
Toxicol Lett ; 332: 42-55, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629074

RESUMO

Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats.


Assuntos
Carboidratos da Dieta/toxicidade , Reserva Ovariana/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal , Dieta , Ciclo Estral/efeitos dos fármacos , Feminino , Fibrose , Intolerância à Glucose/sangue , Intolerância à Glucose/induzido quimicamente , Resistência à Insulina , Leptina/sangue , Metabolismo dos Lipídeos , Folículo Ovariano/efeitos dos fármacos , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar
4.
PLoS One ; 15(5): e0232120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407351

RESUMO

Decades of work indicate that female birds can control their offspring sex ratios in response to environmental and social cues. In laying hens, hormones administered immediately prior to sex chromosome segregation can exert sex ratio skews, indicating that these hormones may act directly on the germinal disc to influence which sex chromosome is retained in the oocyte and which is discarded into an unfertilizable polar body. We aimed to uncover the gene pathways involved in this process by testing whether treatments with testosterone or corticosterone that were previously shown to influence sex ratios elicit changes in the expression of genes and/or gene pathways involved in the process of meiotic segregation. We injected laying hens with testosterone, corticosterone, or control oil 5h prior to ovulation and collected germinal discs from the F1 preovulatory follicle in each hen 1.5h after injection. We used RNA-sequencing (RNA-seq) followed by DESeq2 and gene set enrichment analyses to identify genes and gene pathways that were differentially expressed between germinal discs of control and hormone-treated hens. Corticosterone treatment triggered downregulation of 13 individual genes, as well as enrichment of gene sets related to meiotic spindle organization and chromosome segregation, and additional gene sets that function in ion transport. Testosterone treatment triggered upregulation of one gene, and enrichment of one gene set that functions in nuclear chromosome segregation. This work indicates that corticosterone can be a potent regulator of meiotic processes and provides potential gene targets on which corticosterone and/or testosterone may act to influence offspring sex ratios in birds.


Assuntos
Corticosterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Meiose/efeitos dos fármacos , Meiose/genética , Folículo Ovariano/citologia , Ovulação , Testosterona/farmacologia , Animais , Galinhas , Feminino , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia
5.
Poult Sci ; 99(5): 2757-2765, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359613

RESUMO

In the present study, for the purpose of investigating the effects of the total flavonoids of Epimedium (TFE) in regard to preventing the development of atrophied oviducts and follicles induced by forced molting, 300-day-old Hy-Line Brown layer hens were divided into 3 study groups as follows: the control (CON) group was the normal group, without forced molting and TFE treatments; the TFE1 group was treated by adding a 1‰ TFE treatment after forced molting; and the TFE0 group was not treated by TFE after forced molting. During this study's experimental process, the egg production rates were recorded each day. In addition, the hens were randomly chosen to be weighed every 4 D and also randomly selected to be sacrificed every 7 D. Then, sample tissues of albumen-secreting part and uterus from the fallopian tube of the layer hens were collected for PCR and hematoxylin-eosin staining tests. The results showed that the body weights, number of follicles, and weights and sizes of the fallopian tube for the TFE1 and TFE0 groups were significantly reduced when compared with those of the control group on the 15th D of the experiment. Furthermore, at the end of study, it was found that the egg production rates, weights of the fallopian tube, and ovarian follicles of TFE1 had recovered to normal levels. At the same time, the serum estrogen and the expressions of the progesterone receptor and estrogen receptor mRNA in fallopian tube were higher than those observed for the TFE0 group. The results of this study provided valuable evidence that TFE could improve the development of atrophied oviducts and increase the egg laying rates, thereby making it a potential multicomponent natural drug for egg production in the future.


Assuntos
Proteínas Aviárias/metabolismo , Galinhas/metabolismo , Epimedium/química , Tubas Uterinas/efeitos dos fármacos , Flavonoides/metabolismo , Folículo Ovariano/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Animais , Estrogênios/metabolismo , Tubas Uterinas/crescimento & desenvolvimento , Feminino , Flavonoides/administração & dosagem , Muda , Folículo Ovariano/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
6.
Arch Gynecol Obstet ; 302(2): 529-534, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32451660

RESUMO

OBJECTIVE: This study aimed at improving fertility rates among infertile women with poor ovarian reserve. METHODS: This was a randomized clinical trial conducted in the outpatient clinic of a tertiary hospital. We recruited infertile women with poor ovarian reserve. The study population was divided into 2 groups, each of 25 participants. Both had induction of ovulation for three consecutive cycles. Study group took DHEA supplementation 25 mg/8 h for two consecutive cycles before induction of ovulation. Both groups were compared for outcomes of induction. Baseline ovarian reserve tests and antral follicle count (AFC) were done for both groups before induction of ovulation. The study group repeated these baseline tests after DHEA treatment to compare ovarian reserve before and after DHEA supplementation. Outcome measures were the number of mature follicles at the time of ovulation, the number of gonadotrophin ampoules needed for induction of ovulation, the duration of ovarian stimulation, E2 level at the day of HCG injection. RESULTS: The study group baseline investigations after DHEA treatment showed a statistically significant improvement compared to the control group. The outcomes of induction of ovulation in the study group showed a statistically better response than the control group. CONCLUSION: DHEA may help many poor responders so better considered for poor responder patients. TRIAL REGISTRATION NUMBER: PACTR201911829230395.


Assuntos
Desidroepiandrosterona/uso terapêutico , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Adulto , Desidroepiandrosterona/farmacologia , Feminino , Humanos , Estudos Prospectivos
7.
Poult Sci ; 99(4): 2185-2195, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241504

RESUMO

The signal pathway of target of rapamycin (TOR) plays an important role in regulating cell growth and proliferation, follicular development, and ovulation. Melatonin (N-acetyl-5-methoxytryptamine) (MT) is involved in the regulation of many physiological functions in animals. Recent studies have shown that MT affects the number and the degree of maturation of follicles in the ovary, but there are few studies concerning its mechanism. Therefore, the aim of this study was to investigate the mechanism of TOR signal pathway in the regulation of ovarian function by MT in aging laying hens. In the present study, a total of 60 hens (70-week-old) were randomly divided into 2 groups: control group and melatonin group (M). Melatonin was administered intraperitoneally at a dose of 20 mg/kg/D for 28 D in the M group. The results showed that MT significantly increased the levels of the antioxidant enzymes superoxide dismutase and total antioxidant capacity (P < 0.01) as well as levels of immunoglobulin (IgA, IgG, and IgM) (P < 0.05) and the reproductive hormones estradiol and luteinizing hormone (P < 0.01) in the plasma and also increased the numbers of middle white follicles and small white follicles (P < 0.05) and decreased the level of reactive oxygen species in plasma (P < 0.01) in laying hens. There were higher expression levels in MT receptor A (P < 0.05), melatonin receptor B (P < 0.01), and tuberous sclerosis complex 2 (P < 0.01). Activation of TOR, 4E binding protein-l (4E-BP1), and ribosomal protein 6 kinase (P < 0.01) was found in the M. The levels of mTOR and p-mTOR protein were increased in the M (P < 0.05). The mTORC1-dependent 4E-BP1 and p-4E-BP1 were increased in the M (P < 0.05). This study indicated that MT may enhance follicle growth by increasing levels of antioxidant enzymes and reproductive hormones and by activating the mTOR and downstream components in aging laying hens.


Assuntos
Antioxidantes/farmacologia , Galinhas/fisiologia , Melatonina/farmacologia , Folículo Ovariano/crescimento & desenvolvimento , Ovário/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Antioxidantes/administração & dosagem , Proteínas Aviárias/metabolismo , Feminino , Injeções Intraperitoneais/veterinária , Melatonina/administração & dosagem , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Distribuição Aleatória
8.
J Dairy Sci ; 103(6): 5641-5646, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307164

RESUMO

The aim of this study was to determine the association between estrous expression, measured using a breeding indicator and an automated activity monitor (AAM), and the success of embryo collection after superovulation. Holstein heifers (n = 51; 10.5 to 14.5 mo, and 325.0 ± 21.1 kg of body weight) were superovulated (n = 69 events) for the collection of embryos using a protocol based on sequential administration of FSH for follicle superstimulation and GnRH to induce ovulation. Artificial insemination (AI) was performed twice, once at the moment of GnRH administration and again 12 h later, using thawed, sexed semen. Ovaries were scanned via ultrasonography on the day of the first AI to count the total number of preovulatory follicles and 7 d later for the total number of corpora lutea present. Embryos were collected 7 d post-AI, counted, and assessed for viability. A breeding indicator (Estrotect, Rockway Inc., Spring Valley, WI) and a collar-mounted AAM (CowScout Activity Monitoring System, GEA, Dusseldorf, Germany) were used to measure standing mounts and an algorithmic estimate of estrous expression, respectively. A score for the breeding indicator was given as follows: score 1 = 100% of the indicator was intact; score 2 = 50% of the indicator was rubbed off; score 3 = greater than 50% of the indicator was rubbed off. Estrous expression detected by the AAM was quantified through the relative increase in physical activity and duration of time spent above a set threshold. Data were analyzed by ANOVA using the MIXED procedures of SAS (SAS Institute Inc., Cary, NC). The number of follicles present at AI was not affected by estrous expression. The mean (± SD) ovulatory response was 67.5 ± 26.3%. We found an effect of estrous expression as detected by the breeding indicator on the ovulatory response (42.1 ± 8.0, vs. 78.2 ± 9.0, vs. 74.0 ± 4.9%, for scores 1, 2, and 3, respectively) but not from the AAM. Heifers that had a score of 3 (versus those with scores of 1 and 2) on the breeding indicator had a greater number of embryos (4.1 ± 0.5, vs. 1.2 ± 1.0, vs. 1.8 ± 1.0 embryos), and a greater percentage of these embryos were viable (43.1 ± 0.05, vs. 35.5 ± 0.1, vs. 34.3 ± 0.1%). Similarly, heifers that showed a greater intensity of activity (as measured by the AAM) had a greater number of embryos collected (10.2 ± 1.2 vs. 6.0 ± 1.3 embryos), and a greater percentage of those embryos were viable (53.1 ± 5.0 vs. 23.4 ± 5.1%). Longer-duration estrus episodes were associated with a higher percentage of viable embryos (51.2 ± 5.2 vs. 25.3 ± 5.3%). In conclusion, stronger estrous intensity was associated with a greater number of total embryos collected and a greater percentage of viable embryos. These results suggest that monitoring the intensity of estrus could be used to predict superovulatory response as well as embryo quality in Holstein heifers.


Assuntos
Bovinos/embriologia , Embrião de Mamíferos/fisiologia , Estro/fisiologia , Superovulação , Animais , Corpo Lúteo/efeitos dos fármacos , Sincronização do Estro/métodos , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Inseminação Artificial/veterinária , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Progesterona/farmacologia , Coleta de Tecidos e Órgãos
9.
Int J Gynaecol Obstet ; 150(1): 72-76, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32286686

RESUMO

OBJECTIVES: To investigate the role of sildenafil citrate in improving ovulation induction success rate in women with unexplained infertility. METHODS: A randomized clinical trial from January to December 2018 of 80 women with unexplained infertility randomized into two groups. Both groups received 100 mg clomiphene citrate once daily from days 3-7 of the menstrual cycle. The study group also received 25 mg oral sildenafil citrate twice daily from days 8-12 of the same cycle. Transvaginal ultrasound assessed ovulation, endometrial thickness, and number of follicles. Pregnancy was assessed 2 weeks after ovulation. Primary outcome measures were endometrial thickness, number of mature follicles, and pregnancy rates. RESULTS: Pregnancy rates (26 (65%) and 16 (40%), P=0.043) and endometrial thickness (10.4 ± 1.4 and 9.2 ± 1.9, P=0.007) were significantly higher in the study group. More women in the study group reported adverse effects compared with the control group (17 [42.5%] vs 9 [22.5%]; P=0.034), with headache the most common adverse effect in the study group, reported by 8 (20.0%) patients. CONCLUSION: Adding sildenafil citrate improved ovulation success rate and increased pregnancy rate. PAN AFRICAN CLINICAL TRIAL REGISTRY: PACTR201907658492123.


Assuntos
Fármacos para a Fertilidade Feminina/administração & dosagem , Infertilidade Feminina/tratamento farmacológico , Indução da Ovulação/métodos , Citrato de Sildenafila/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Folículo Ovariano/efeitos dos fármacos , Gravidez , Taxa de Gravidez , Citrato de Sildenafila/efeitos adversos , Citrato de Sildenafila/uso terapêutico , Adulto Jovem
10.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32141511

RESUMO

Over the entire reproductive lifespan in mammals, a fixed number of primordial follicles serve as the source of mature oocytes. Uncontrolled and excessive activation of primordial follicles can lead to depletion of the ovarian reserve. We observed that disruption of estrogen receptor ß (ESR2) signaling results in increased activation of primordial follicles in Esr2-null (Esr2-/-) rats. However, follicle assembly was unaffected, and the total number of follicles remained comparable between neonatal wild-type and Esr2-/- ovaries. While the activated follicle counts were increased in Esr2-/- ovary, the number of primordial follicles were markedly decreased. Excessive recruitment of primordial follicles led to premature ovarian senescence in Esr2-/- rats and was associated with reduced levels of serum AMH and estradiol. Disruption of ESR2 signaling through administration of a selective antagonist (PHTPP) increased the number of activated follicles in wildtype rats, whereas a selective agonist (DPN) decreased follicle activation. In contrast, primordial follicle activation was not increased in the absence of ESR1, indicating that the regulation of primordial follicle activation is ESR2 specific. Follicle activation was also increased in Esr2 mutants lacking the DNA binding domain, suggesting a role for the canonical transcriptional activation function. Both primordial and activated follicles express ESR2, suggesting a direct regulatory role for ESR2 within these follicles. We also detected that loss of ESR2 augmented the activation of AKT, ERK, and mTOR pathways. Our results indicate that the lack of ESR2 upregulated both granulosa and oocyte factors, which can facilitate AKT and mTOR activation in Esr2-/- ovaries leading to increased activation of primordial follicles.


Assuntos
Hormônio Antimülleriano/sangue , Estradiol/sangue , Receptor beta de Estrogênio/genética , Folículo Ovariano/metabolismo , Reserva Ovariana/fisiologia , Animais , Moduladores de Receptor Estrogênico/farmacologia , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Alvo Mecanístico do Complexo 1 de Rapamicina , Nitrilos/farmacologia , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Transdução de Sinais/efeitos dos fármacos
11.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32141513

RESUMO

Follicle-stimulating hormone (FSH)-induced growth of ovarian follicles is independent of follicular vascularization. Recent evidence has indicated that follicular vascularization is critical to ovarian follicle development and survival. FSH, a gonadotropin that induces follicular growth and development, also acts as the major survival factor for antral follicles. FSH has been reported to stimulate angiogenesis in the theca layers mediated in part by the vascular endothelial growth factor A (VEGFA) and the transcription factor hypoxia inducible factor 1α (HIF-1α). However, it remains largely undetermined whether FSH-dependent growth and survival of antral follicles relies on FSH-induced vascularization. Here, we first demonstrated that induction of angiogenesis through the FSH-HIF-1α-VEGFA axis is not required for FSH-stimulated follicular growth in mouse ovary. FSH increased the total number of blood vessels in mouse ovarian follicles, which was correlated with elevated expression of VEGFA and HIF-1α in granulosa cells. In contrast, blocking of follicular angiogenesis using inhibitors against the HIF-1α-VEGFA pathway repressed vasculature formation in follicles despite FSH administration. Interestingly, by measuring follicular size and ovarian weight, we found that the suppression of angiogenesis via HIF-1α-VEGFA pathway did not influence FSH-mediated follicular growth. However, inhibition of FSH-induced follicular vascularization by PX-478, a small-molecule inhibitor that suppresses HIF-1α activity, blocked ovulation and triggered atresia in large follicles. On the other hand, PX-478 injection reduced oocyte quality via impairing the meiotic apparatus, showing a prominently defective spindle assembly and actin dynamics. Collectively, our findings unveiled a vascularization-independent effect of FSH on follicular growth, whereas follicular survival, ovulation, and oocyte development relies on FSH-mediated angiogenesis in the follicles.


Assuntos
Hormônio Foliculoestimulante/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/crescimento & desenvolvimento , Ovulação/metabolismo , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Feminino , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovulação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
PLoS One ; 15(3): e0229043, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182244

RESUMO

Oocyte in vitro maturation can be improved by mimicking the intra-follicular environment. Oocyte, cumulus cells, granulosa cells, and circulating factors act as meiotic regulators in follicles and maintain oocyte in the meiotic phase until oocyte becomes competent and ready to be ovulated. In a randomized experimental design, an ovine model was used to optimize the standard in vitro maturation media by Granulosa secreted factors. At first, the development capacity of oocyte derived from medium (>4 to 6 mm) and small (2 to ≤4 mm) size follicles was determined. Differential gene expression of granulosa secreted factors and their receptors were compared between the cumulus cells of the two groups. Then, the best time and concentration for arresting oocytes at the germinal vesicle stage by natriuretic peptide type C (CNP) were determined by nuclear staining in both groups. Oocyte quality was further confirmed by calcein uptake and gene expression. The developmental competence of cumulus oocyte complexes derived from small size follicles that were cultured in the presence of CNP in combination with amphiregulin (AREG) and prostaglandin E2 (PGE2) for 24 h was determined. Finally, embryo quality was specified by assessing expressions of NANOG, SOX2, CDX2, OCT4, and TET1. The cumulus oocyte complexes derived from small size follicles had a lower capacity to form blastocyst in comparison with cumulus oocyte complexes derived from medium size follicles. Prostaglandin E receptor 2 and prostaglandin-endoperoxide synthase 2 had significantly lower expression in cumulus cells derived from small size follicles in comparison with cumulus cells derived from medium size follicles. Natriuretic peptide type C increased the percentage of cumulus oocyte complexes arresting at the germinal vesicle stage in both oocytes derived from medium and small follicles. Gap junction communication was also improved in the presence of natriuretic peptide type C. In oocytes derived from small size follicles; best blastocyst rates were achieved by sequential exposure of cumulus oocyte complexes in [TCM+CNP (6 h), then cultured in TCM+AREG+PGE2 (18h)] and [TCM+CNP (6 h), then cultured in conventional IVM supplements+AREG+PGE2 (18h)]. Increased SOX2 expression was observed in [TCM+CNP (6 h), then cultured in TCM+AREG+PGE2 (18h)], while decreased OCT4 expression was observed in [TCM+CNP (6 h), then cultured in conventional IVM supplements+AREG+PGE2 (18h)]. It seems that the natriuretic peptide type C modulates meiotic progression, and oocyte development is probably mediated by amphiregulin and prostaglandin E2. These results may provide an alternative IVM method to optimize in vitro embryo production in sheep and subsequently for humans.


Assuntos
Meios de Cultura/farmacologia , Células do Cúmulo/citologia , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/citologia , Anfirregulina/farmacologia , Animais , Biomarcadores , Células Cultivadas , Meios de Cultura/química , Células do Cúmulo/metabolismo , Dinoprostona/farmacologia , Feminino , Fertilização In Vitro , Fluoresceínas/metabolismo , Meiose , Modelos Animais , Peptídeo Natriurético Tipo C/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Folículo Ovariano/efeitos dos fármacos , Ovinos
13.
Toxicol Appl Pharmacol ; 393: 114952, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165126

RESUMO

Di(2-ethylhexyl) phthalate (DEHP) is a phthalate commonly used for its plasticizing capabilities. Because of the wide production and use of DEHP, humans are exposed to DEHP on a daily basis. Diisononyl phthalate (DiNP) is often used as a DEHP replacement chemical, and because of the increased use of DiNP, humans are increasingly exposed to DiNP over time. Of concern is that DEHP and DiNP both exhibit endocrine disrupting capabilities, and little is known about how short-term exposure to either of these phthalates affects aspects of female reproduction. Thus, this study tested the hypothesis that short-term exposure to DEHP or DiNP during adulthood has long-lasting consequences on ovarian follicles and hormones in female mice. Female CD-1 mice aged 39-40 days were orally dosed with either vehicle control (corn oil), DEHP (20 µg/kg/day-200 mg/kg/day), or DiNP (20 µg/kg/day-200 mg/kg/day) for 10 days. Ovarian follicle populations, estradiol, testosterone, progesterone, follicle stimulating hormone (FSH), and inhibin B were analyzed at time points immediately post-dosing and 3, 6, and 9 months post-dosing. The results indicate that 10 days of exposure to DEHP and DiNP changed the distribution of ovarian follicle populations and sex steroid hormones at multiple time points, including the last time point, 9 months post-dosing. Further, FSH was increased at multiple doses up to 6 months post-dosing. Inhibin B was not affected by treatment. These data show that short-term exposure to either DEHP or DiNP has long-term consequences that persist long after cessation of exposure.


Assuntos
Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Folículo Ovariano/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Reprodução/efeitos dos fármacos , Androgênios/sangue , Animais , Estrogênios/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Hormônios/sangue , Camundongos
14.
Acta Vet Scand ; 62(1): 16, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164737

RESUMO

BACKGROUND: Oestrous synchronisation of cattle has been widely applied to accomplish simultaneous ovulation in animals and facilitate timed artificial insemination. The main aim of this study was to investigate the ovarian follicular growth and ovulatory response to oestrus and ovulation synchronisation in Norwegian Red heifers and cows. Oestrous cycles in 34 heifers and 10 cows from 4 herds were synchronised with two PGF2α analogue treatments 11 days apart, followed by GnRH analogue treatment for induction of ovulation. Thereafter, the ovaries were examined by ultrasonography at 3 h intervals until ovulation. RESULTS: The luteolytic effect of the PGF2α analogue was verified in 9 of 10 cows by progesterone contents in milk. Maximum physical activity of the cows occurred on average 69 h after PGF2α analogue treatment. An ovulatory response was recorded in 95.5% (42/44) of the animals. A significant difference in follicle size at ovulation was found between 2 of the herds. Animals with medium sized and large follicles and heifers aged > 16 months ovulated earlier than other animals. CONCLUSIONS: The applied sequence of treatments in the study was shown to be effective in synchronizing and inducing ovulation within a relatively narrow time interval in the Norwegian Red heifers and cows, consistent with findings in other cattle breeds.


Assuntos
Bovinos/fisiologia , Dinoprosta/farmacologia , Sincronização do Estro , Hormônio Liberador de Gonadotropina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação/veterinária , Animais , Cruzamento , Dinoprosta/administração & dosagem , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Folículo Ovariano/anatomia & histologia , Folículo Ovariano/diagnóstico por imagem
15.
Arch Gynecol Obstet ; 301(3): 845-850, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32112181

RESUMO

OBJECTIVE: To detect whether amlodipine could increase pre-ovulatory follicular blood flow, thus enhancing ovulation and creating a better chance of conception in women with PCOS. METHODS: 165 women were screened of which 124 were qualified and women were equally randomized to 62 receiving clomiphene citrate and amlodipine and 62 receiving clomiphene citrate and placebo. The primary outcome was to detect if amlodipine can improve pre-ovulatory follicle blood flow studied by colour and power Doppler Pulsatility index of ovarian arteries, with drug administration. The secondary outcomes were endometrial thickness and clinical pregnancy. RESULTS: The mean value of the ovarian arteries Pulsatility Index was significantly lower in the amlodipine group when compared to those of the placebo group (1.36 and 1.82, respectively, with P value 0.002). Mean endometrial thickness, for all women in both groups, on the day of detecting a mature follicle was significantly higher in the amlodipine group compared to the placebo group (8.99 and 7.0, respectively, with P value 0.003), and clinical pregnancy increased from 11% to 37% in the amlodipine group compared to the placebo group. CONCLUSION: Amlodipine improves ovarian blood flow and increases the chances of conception. TRIAL REGISTRATION: Pan African Clinical Trial Registry (http://www.pactr.org). Trial No: PAC TR201708002485292.


Assuntos
Anlodipino/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Infertilidade Feminina/tratamento farmacológico , Folículo Ovariano/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Adulto , Anlodipino/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Clomifeno/farmacologia , Método Duplo-Cego , Feminino , Humanos , Síndrome do Ovário Policístico/complicações , Gravidez , Estudos Prospectivos
16.
Chemosphere ; 244: 125493, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32050327

RESUMO

Zearalenone (ZEA), as a contaminant commonly found in our daily diet, has been widely studied for its toxicity. However, the exact mechanism underlying ZEA induced reproduction disorders remains unclear. Our study aimed to elucidate the underlying relationship between aberrations in the gut microbiota and the degeneration of the ovarian reserve following exposure to ZEA. Four-week-old mice were treated with different doses (0, 20, 40 µg/kg bw/day) of ZEA for 2 weeks and it was found that the primordial follicles were dramatically decreased when compared to untreated controls. Moreover, we applied metagenomic shotgun sequencing to investigate the effects of ZEA exposure on the population composition and function of gut microbiota. The results showed that the abundance of three susceptible bacterial strains, parabacteroides, bacteroides and lachnospiraceae were increased in a dose-dependent manner after ZEA exposure, whereas the bacterial glycerophospholipid metabolism pathway was greatly suppressed. Of note, utilizing LC/MS we found lysophosphatidylcholines (LPCs), important metabolites in the process of glycerophospholipid metabolism, were markedly decreased in the plasma of the ZEA treated mice. In conclusion, our findings here provide evidences that the dysfunction in gut microbiome after ZEA exposure may affect the ovarian reserve.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Bactérias/efeitos dos fármacos , Feminino , Glicerofosfolipídeos/metabolismo , Lisofosfolipídeos/sangue , Camundongos , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos
17.
Reprod Domest Anim ; 55(4): 442-447, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31916295

RESUMO

We tested FSHp, eCG and FSHp + eCG to establish ovum pick-up (OPU) and in vitro maturation method in spotted paca. Eight healthy adult females were subjected to each of four treatments to stimulate ovarian follicular growth. All females were subjected to a hormonal protocol using a single dose of 45 mg of injectable progesterone and single intramuscular injection of 0.075 mg d-cloprostenol on day 6. Ovarian stimulation was carried out as follows: in Group TFE (FSHp and eCG), animals were treated with a single dose of 80 mg of FSHp and 200 IU of eCG intramuscularly on day 6 after the application of progesterone; in Group TF (FSHp), they were treated with a single dose of 80 mg of FSHp intramuscularly on day 6 after application of progesterone; in Group treatment eCG, they were treated with 200 IU of eCG intramuscularly on day 6 after application of progesterone; and in Group TC (saline solution), 1 ml of saline solution was administered to control does. The OPU was performed between 22 and 26 hr after gonadotropin treatments. All recovered oocytes were placed into maturation media and incubated for 24 hr. There were no differences among the mean number of observed follicles, aspirated follicles and oocytes recovered per treatment. Oocyte maturation rates did not differ among groups, except, TF and treatment eCG oocytes had greater maturation rates than TC oocytes. In this study, gonadotropin administration failed to superovulate treated does and increase oocyte retrieval efficiency. Despite the feasibility of the procedure, further studies are needed to develop and refine hormonal protocols for oocyte recovery and in vitro maturation in this species.


Assuntos
Cuniculidae/fisiologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Recuperação de Oócitos/veterinária , Animais , Cloprostenol/farmacologia , Feminino , Hormônio Foliculoestimulante/farmacologia , Gonadotropinas Equinas/farmacologia , Técnicas de Maturação in Vitro de Oócitos/métodos , Recuperação de Oócitos/métodos , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação/métodos , Indução da Ovulação/veterinária , Progesterona/farmacologia
18.
Sci Rep ; 10(1): 242, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937877

RESUMO

Phloroglucinol (1,3,5 tri-hydroxy-benzene) (PGL), a natural phenolic substance, is a peroxidase inhibitor and has anti-oxidant, anti-diabetic, anti-inflammatory, anti-thrombotic, radio-protective, spasmolytic and anti-cancer activities. PGL, as a medicine, is administered to patients to control the symptoms of irritable bowel syndrome and acute renal colic, in clinical trials. PGL, as a phenolic substance, can cause cytotoxic effects. Administration of PGL up to 300 mg/kg (bw) is well tolerated by animals, while in cell lines its toxicity is developed at concentrations above the dose of 10 µg/ml. Furthermore, it seems that tumor or immortalized cells are more susceptible to the toxic power of PGL, than normal cells. However, studies of its cytotoxic potency, at the cellular level, in complex, differentiated and meta-mitotic biological systems, are still missing. In the present work, we have investigated the toxic activity of PGL in somatic epithelial cells, constituting the follicular compartment of a developing egg-chamber (or, follicle), which directs the choriogenesis (i.e. chorion assembly) process, during late oogenesis of Drosophila melanogaster. Our results reveal that treatment of in vitro growing Drosophila follicles with PGL, at a concentration of 0.2 mM (or, 25.2 µg/ml), does not lead to follicle-cell toxicity, since the protein-synthesis program and developmental pattern of choriogenesis are normally completed. Likewise, the 1 mM dose of PGL was also characterized by lack of toxicity, since the chorionic proteins were physiologically synthesized and the chorion structure appeared unaffected, except for a short developmental delay, being observed. In contrast, concentrations of 10, 20 or 40 mM of PGL unveiled a dose-dependent, increasing, toxic effect, being initiated by interruption of protein synthesis and disassembly of cell-secretory machinery, and, next, followed by fragmentation of the granular endoplasmic reticulum (ER) into vesicles, and formation of autophagic vacuoles. Follicle cells enter into an apoptotic process, with autophagosomes and large vacuoles being formed in the cytoplasm, and nucleus showing protrusions, granular nucleolus and condensed chromatin. PGL, also, proved able to induce disruption of nuclear envelope, activation of nucleus autophagy (nucleophagy) and formation of a syncytium-like pattern being produced by fusion of plasma membranes of two or more individual follicle cells. Altogether, follicle cell-dependent choriogenesis in Drosophila has been herein presented as an excellent, powerful and reliable multi-cellular, differentiated, model biological (animal) system for drug-cytotoxicity assessment, with the versatile compound PGL serving as a characteristic paradigm. In conclusion, PGL is a substance that may act beneficially for a variety of pathological conditions and can be safely used for differentiated somatic -epithelial- cells at clinically low concentrations. At relatively high doses, it could potentially induce apoptotic and autophagic cell death, thus being likely exploited as a therapeutic agent against a number of pathologies, including human malignancies.


Assuntos
Córion/efeitos dos fármacos , Córion/crescimento & desenvolvimento , Drosophila melanogaster/embriologia , Floroglucinol/toxicidade , Animais , Relação Dose-Resposta a Droga , Drosophila melanogaster/efeitos dos fármacos , Feminino , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Testes de Toxicidade
19.
Theriogenology ; 143: 148-156, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31964484

RESUMO

Selection of a single dominant follicle is morphologically manifested by diameter deviation between the future dominant follicle (F1) and the future largest subordinate follicle (F2). Conventional deviation is defined as F2≥7 mm when F1 reaches ∼8.5 mm whereas, undersized deviation is if F2<7 mm when F1 reaches ∼8.5 mm. Greater frequency of undersized deviation has been temporally associated with greater circulating progesterone (P4) and greater FSH but reduced LH in observational studies. Experiment 1 was conducted to directly test if elevating P4 increased the likelihood of undersized deviation and altered circulating concentrations of LH and FSH. Experiment 2 was conducted to test if increasing LH action by treatment with exogenous porcine LH or human chorionic gonadotropin (hCG) in the presence of elevated P4, would stimulate growth of F2 and increase the likelihood of conventional deviation. Ovaries were evaluated by ultrasound and blood samples collected every 12 h after development of a new wave following follicle ablation on D6 (D0 = ovulation). Data were normalized to F1≥7.5 mm and compared using SAS software. In experiment 1 (n = 20), the CL was regressed by prostaglandin F2α treatment and heifers were randomized on D6 into control (no P4 treatment) or P4 treatment (75 mg every 12 h for 5.5 d) beginning when F1 reached ∼3 mm (P4-3 mm group) or ∼6 mm (P4-6 mm group). The P4 treatment significantly increased the frequency of undersized deviation from 0% (controls) to 54%, decreased LH by 44%, and increased FSH by 32%. In experiment 2 (n = 27) heifers were randomized on D6 into control (saline) or treatment with the LH analogs - pLH (1.25 mg porcine LH/12 h) or hCG (160 IU initially and subsequently 96 IU/24 h). Treatment with LH analogs significantly increased P4 (control, 4.6 ±â€¯0.3 ng/mL; pLH, 6.6 ±â€¯0.4 ng/mL; and hCG, 8.9 ±â€¯0.4 ng/mL) and decreased FSH (control, 0.46 ±â€¯0.03 ng/mL; combined-pLH/hCG, 0.34 ±â€¯0.02 ng/mL). However, F1 and F2 diameter and frequency of conventional (37%) and undersized (48%) deviations were similar between the control and combined-pLH/hCG groups. In conclusion, elevated P4 was directly linked to undersized deviation but the P4 effect on decreasing F2 diameter occurred independently of the P4 effects on FSH and LH concentrations.


Assuntos
Bovinos/fisiologia , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Folículo Ovariano/efeitos dos fármacos , Progesterona/farmacologia , Animais , Bovinos/sangue , Bovinos/metabolismo , Feminino
20.
Acta Histochem ; 122(2): 151484, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31902536

RESUMO

The aim of this study was to evaluate whether the addition of synthetic polymers to the vitrification solution affected follicular morphology and development and the expression of Ki-67, Aquaporin 3 (AQP3) and cleaved Caspase-3 proteins in ovarian tissue of the caprine species. Caprine ovaries were fragmented and two fragments were immediately fixed (Fresh Control) for morphological evaluation, while other two were in vitro cultured for 7 days (Cultured Control) and fixed as well. The remaining fragments were distributed in two different vitrification groups: Vitrified and Vitrified/Cultured. Each group was composed of 4 different treatments: 1) Sucrose (SUC); 2) SuperCool X-1000 0.2 % (X-1000); 3) SuperCool Z-1000 0.4 % (Z-1000) or 4) with polyvinylpyrrolidone K-12 0.2 % (PVP). Also, Fresh Control, Cultured Control, SUC and X-1000 were destined to immunohistochemical detection of Ki-67, AQP3 and cleaved Caspase-3 proteins. Morphologically, the treatment with X-1000 showed no significant difference with the Fresh Control group and was superior to the other treatments. After the cleaved caspase-3 analysis, X-1000 showed the lowest percentages of strong immunostaining while Cultured Control showed the highest. Also, a positive correlation was found between the percentages of degenerated follicles and the percentages of strong staining intensity follicles. Regarding the AQP3 analysis, the highest percentages of strong AQP3 staining intensity were found in X-1000. In conclusion, we have demonstrated that the addition of the synthetic polymer SuperCool X-1000 to the vitrification solution improved the current vitrification protocol of caprine ovarian tissue.


Assuntos
Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Polímeros/farmacologia , Animais , Criopreservação/métodos , Feminino , Cabras , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/metabolismo , Oócitos/metabolismo , Ovário/metabolismo , Técnicas de Cultura de Tecidos/métodos , Vitrificação
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