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1.
Nat Cell Biol ; 22(4): 372-379, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32231306

RESUMEN

The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. In addition, progesterone bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. ddx21-deficient zebrafish show resistance to leflunomide-induced stress. At a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression signature and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.


Asunto(s)
ARN Helicasas DEAD-box/genética , Melanocitos/metabolismo , Cresta Neural/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Receptores de Progesterona/genética , Proteínas de Pez Cebra/genética , Animales , Línea Celular Tumoral , ARN Helicasas DEAD-box/metabolismo , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Humanos , Leflunamida/farmacología , Melanocitos/efectos de los fármacos , Melanocitos/patología , Cresta Neural/efectos de los fármacos , Cresta Neural/crecimiento & desarrollo , Nucleótidos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Progesterona/metabolismo , Unión Proteica , Receptores de Progesterona/metabolismo , Transducción de Señal , Estrés Fisiológico/genética , Elongación de la Transcripción Genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo
2.
Sheng Li Xue Bao ; 72(1): 105-114, 2020 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-32099988

RESUMEN

Embryo implantation is crucial for the establishment and maintenance of successful pregnancy and requires the synchronization between implantation-competent blastocyst and receptive uterus. In assisted reproductive technologies, recognition of uterine receptivity is the limiting factor for improving pregnancy rate. It has been previously reported that embryo implantation involves the activation and inactivation of numerous signaling molecules which may influence the proliferation and differentiation of uterine epithelial cells, epithelial polarity, luminal closure, embryo orientation, epithelial-stromal interactions, gland development, etc. Here we summarize the function of estrogen, progesterone, leukemia inhibitory factor (LIF), microRNA (miRNA), channel protein and signaling pathways in embryo implantation and explore their regulatory network to provide theoretical basis for the treatment of infertility and development of safe and efficient contraceptives.


Asunto(s)
Implantación del Embrión , Útero/fisiología , Blastocisto/fisiología , Estrógenos/fisiología , Femenino , Humanos , Factor Inhibidor de Leucemia/fisiología , MicroARNs/genética , Embarazo , Progesterona/fisiología , Transducción de Señal
3.
Life Sci ; 247: 117391, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32017871

RESUMEN

AIM: Although progesterone (P4) has a beneficial effect on the cardiovascular system, P4 actions on the coronary bed have not yet been fully elucidated. This study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in Wistar rats. MAIN METHODS: Eight-week-old adult rats were divided into Sham, Ovariectomized (OVX), Ovariectomized and progesterone treated (OVX P4). The OVX P4 group received daily doses of progesterone (2 mg/kg/day). Vascular reactivity was assessed by a modified Langendorff technique. The intensity of eNOS, Akt, and gp91phox protein expression was quantified by Western blotting. Superoxide anion (O2●-) and hydrogen peroxide (H2O2) production was measured by dihydroethidium and 2',7'-dichlorofluorescein, respectively. KEY FINDINGS: Treatment with P4 was able to prevent the reduction in baseline coronary perfusion pressure induced by ovariectomy. We observed that endothelium-dependent coronary vasodilation was reduced in the OVX group and potentiated in the OVX P4 group. Following the inhibition of the nitric oxide (NO) pathway, the bradykinin-induced relaxing response was potentiated in the OVX P4 group. With regard to the combined inhibition of NO and prostanoids pathways, the OVX P4 group showed a greater relaxing response, similar to what was found upon individual inhibition of NO. After the combined inhibition of NO, prostanoids and epoxyeicosatrienoic acids' pathways, the vasodilatory response induced by BK was abolished in all groups. SIGNIFICANCE: Treatment with P4 prevented oxidative stress induced by ovariectomy. These results suggest that progesterone has a beneficial action on the coronary vascular bed.


Asunto(s)
Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Progesterona/farmacología , Vasodilatación/efectos de los fármacos , Animales , Femenino , Peróxido de Hidrógeno/metabolismo , NADPH Oxidasa 2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ovariectomía , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Superóxidos/metabolismo
4.
Adv Exp Med Biol ; 1191: 523-541, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32002944

RESUMEN

Exposure therapy, a key treatment for anxiety disorders, can be modelled in the laboratory using Pavlovian fear extinction. Understanding the hormonal and neurobiological mechanisms underlying fear extinction in females, who are twice more likely than males to present with anxiety disorders, may aid in optimising exposure therapy outcomes in this population. This chapter will begin by discussing the role of the sex hormones, estradiol and progesterone, in fear extinction in females. We will also propose potential mechanisms by which these hormones may modulate fear extinction. The second half of this chapter will discuss the long-term hormonal, neurological and behavioural changes that arise from pregnancy and motherhood and how these changes may alter the features of fear extinction in females. Finally, we will discuss implications of this research for the treatment of anxiety disorders in women with and without prior reproductive experience.


Asunto(s)
Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/terapia , Ansiedad/metabolismo , Ansiedad/terapia , Estradiol/metabolismo , Progesterona/metabolismo , Reproducción , Ansiedad/psicología , Trastornos de Ansiedad/psicología , Extinción Psicológica , Miedo , Femenino , Humanos , Embarazo
5.
Zhonghua Fu Chan Ke Za Zhi ; 55(1): 9-14, 2020 Jan 25.
Artículo en Chino | MEDLINE | ID: mdl-32074767

RESUMEN

Objective: To explore and compare the preventive effect of using letrozole and gonadotropin-releasing hormone (GnRH) antagonist during luteal phase of patients at high risk for ovarian hyperstimulation syndrome (OHSS). Methods: A total of 99 infertile women undergoing in vitro fertilization and embryo transfer or intracytoplasmic sperm injection with high risk for OHSS were enrolled in this randomized controlled trial.The letrozole group (n=51) received letrozole of 7.5 mg daily for 3 days;the GnRH antagonist group (n=48) were given cetrorelix of 0.25 mg subcutaneously daily for 3 days. Both groups received support therapy combined with embryo cryopreservation. The incidence of OHSS was surveyed. And the serum concentration of estradiol, LH and progesterone on days 3, 5 and 8 after oocytes retrieval were measured. Results: There were no statistical differences in terms of baseline characteristics of patients and outcomes of controlled ovarian hyperstimulation between the two groups.The incidence of moderate and severe OHSS was found no significantly difference between letrozole group [11.8%(6/51)] and GnRH antagonist group [10.4%(5/48);P>0.05]. The estradiol concentration of the indicated days on days 3,5 and 8 after oocytes retrieval in letrozole group and GnRH antagonist group were (1 417±3 543) versus (15 210±9 921) pmol/L, (1 692±4 330) versus (18 680±11 567) pmol/L, (239±336) versus (3 582±5 427) pmol/L, respectively;compared with GnRH antagonist group, the estradiol level was significantly lower in the letrozole group (all P<0.01). The luteinizing hormone level in the letrozole group were (0.46±0.40), (0.56±0.55)and (0.67±0.58) U/L on days 3,5 and 8 after oocytes retrieval, which were significantly higher than those of GnRH antagonist group [(0.28±0.28), (0.30±0.19) and (0.45±0.37) U/L, respectively; all P<0.05]. There was no obvious differences on progesterone levels between letrozole group and GnRH antagonist group (all P>0.05),and on days 8 after oocytes retrieval,the level of progesterone in each group were significantly lower than those on day 3 and 5 after oocytes retrieval (P<0.05). Conclusion: Letrozole has the same efficiency as GnRH antagonist for the prevention of OHSS, faster and cheaper to use, but its efficacy seems not to be related to the suppression of steroidogenic during the luteal phase.


Asunto(s)
Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Infertilidad Femenina/terapia , Letrozol/uso terapéutico , Síndrome de Hiperestimulación Ovárica/prevención & control , Inducción de la Ovulación , Estradiol/sangre , Femenino , Fertilización In Vitro , Humanos , Fase Luteínica , Hormona Luteinizante/sangre , Progesterona/sangre
6.
BJOG ; 127(6): 757-767, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32003141

RESUMEN

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.


Asunto(s)
Aborto Espontáneo/economía , Aborto Espontáneo/prevención & control , Progesterona/economía , Progestinas/economía , Hemorragia Uterina/tratamiento farmacológico , Aborto Espontáneo/etiología , Adolescente , Adulto , Análisis Costo-Beneficio , Método Doble Ciego , Femenino , Humanos , Nacimiento Vivo/economía , Embarazo , Progesterona/uso terapéutico , Progestinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medicina Estatal , Resultado del Tratamiento , Reino Unido , Hemorragia Uterina/complicaciones , Hemorragia Uterina/economía , Adulto Joven
8.
Curr Allergy Asthma Rep ; 20(1): 4, 2020 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-31993777

RESUMEN

PURPOSE OF REVIEW: Progestogen hypersensitivity (PH) is a condition which typically occurs in women in childbearing years with a spectrum of symptoms ranging from urticaria with or without angioedema, dermatitis to systemic anaphylaxis. Herein, a clinical case of PH is presented followed by a discussion on the evaluation, diagnosis, and management of PH. RECENT FINDINGS: Progestogen hypersensitivity (a.k.a. "autoimmune progesterone dermatitis") symptoms are associated with exogenous progestin exposure (e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. This condition can be difficult to recognize due to its heterogeneous clinical presentation. The mechanism of PH is believed to be primarily IgE-mediated; however, less commonly other immune responses may be involved. There is now a useful progesterone specific IgE immunoassay to assist in diagnosis and well-defined treatment algorithms that can be used to successfully manage PH. The epidemiology of PH is still poorly elucidated but is likely to be encountered by clinicians and especially allergists given the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone required to support pregnancy in IVF. Including PH in the differential diagnosis of women presenting with cyclic hypersensitivity will accelerate diagnosis and successful management of this condition.


Asunto(s)
Anafilaxia/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Dispositivos Intrauterinos Medicados/efectos adversos , Progesterona/efectos adversos , Progestinas/efectos adversos , Urticaria/inducido químicamente , Anafilaxia/diagnóstico , Anafilaxia/tratamiento farmacológico , Antialérgicos/uso terapéutico , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Dermatitis/diagnóstico , Dermatitis/tratamiento farmacológico , Desensibilización Inmunológica , Remoción de Dispositivos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina E/sangre , Omalizumab/uso terapéutico , Urticaria/diagnóstico , Urticaria/tratamiento farmacológico , Adulto Joven
9.
PLoS One ; 15(1): e0224874, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31995557

RESUMEN

Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20-24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34-1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20-2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study's a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Nacimiento Prematuro/tratamiento farmacológico , Progesterona/administración & dosificación , Vagina/efectos de los fármacos , Administración Intravaginal , Adulto , Medición de Longitud Cervical , Cuello del Útero/efectos de los fármacos , Cuello del Útero/fisiopatología , Cuello del Útero/virología , Estudios de Factibilidad , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Recién Nacido , Embarazo , Embarazo Múltiple , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/fisiopatología , Vagina/fisiopatología , Vagina/virología , Zambia/epidemiología
10.
Chemosphere ; 242: 125208, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31896193

RESUMEN

Female fecundity is finely regulated by hormonal signaling, representing a potential target for endocrine-disrupting chemicals. Among the chemicals of most concern are the perfluoroalkyl substances (PFAS), widely used in consumer goods, that are associated with adverse effects on reproductive health. In this context, the endometrium clearly represents an important fertility determining factor. The aim of this study was to investigate PFAS interference on hormonal endometrial regulation. This study was performed within a screening protocol to evaluate reproductive health in high schools. We studied a cohort of 146 exposed females aged 18-21 from the Veneto region in Italy, one of the four areas worldwide heavily polluted with PFAS, and 1080 non-exposed controls. In experiments on Ishikawa cells included UV-Vis spectroscopy, microarray analysis and qPCR. We report a significant dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity. The most differentially-expressed genes upon PFOA coincubation were ITGB8, KLF5, WNT11, SULT1E1, ALPPL2 and G0S2 (all p < 0.01). By qPCR, we confirmed an antagonistic effect of PFOA on all these genes, which was reversed at higher progesterone levels. Molecular interference of PFOA on progesterone was confirmed by an increase in the intensity of absorption spectra at 250 nm in a dose-dependent manner, but not in the presence of ß-estradiol. Age at menarche (+164 days, p = 0.006) and the frequency of girls with irregular periods (29.5% vs 21.5%, p = 0.022) were significantly higher in the exposed group. Our results are indicative of endocrine-disrupting activity of PFAS on progesterone-mediated endometrial function.


Asunto(s)
Caprilatos/toxicidad , Disruptores Endocrinos/toxicidad , Contaminantes Ambientales/toxicidad , Fluorocarburos/toxicidad , Progesterona/metabolismo , Adolescente , Adulto , Implantación del Embrión , Endometrio , Estradiol/toxicidad , Femenino , Humanos , Italia , Reproducción , Sulfotransferasas , Adulto Joven
11.
Sci Total Environ ; 709: 136262, 2020 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-31905574

RESUMEN

Fish are exposed to progestins and steroid mixtures in contaminated waters but the ecotoxicological implications are not sufficiently known. Here we analyze effects of the new generation progestin dienogest (DNG) followed by investigating effects of mixtures of new generation progestins containing DNG, cyproterone acetate and drospirenone and the hormone progesterone. Furthermore, effects of this mixture were studied after adding 17ß-estradiol (E2) and clobetasol propionate (CLO) in zebrafish embryos and larvae at concentrations between 0.01 and 10 µg/L. DNG showed only very minor transcriptional alterations among the 24 assessed genes with downregulation of the fshb transcript only. The progestin mixture caused weak induction of the lhb, cyp2k22 and sult2st3 transcripts. Addition of E2 to the mixture caused strong induction vtg1, cyp19b, esr1 and lhb, as well as downregulation of fshb from 0.01 µg/L onwards. Besides altering the same transcripts, addition of CLO altered glucocorticoid regulated genes mmp-9, mmp-13, g6pca, fkbp5 and irg1l. While each steroid class exhibited its specific activity independently in the mixture, sult2st3 and cyp2k22 were regulated by both E2 and CLO. Furthermore, CLO alone and in mixtures decreased spontaneous muscle contractions, increased heartrate and induced edema. Our study highlights the prominent effects of E2 and CLO in environmental steroid mixtures, while new generation progestins show relatively low activity.


Asunto(s)
Pez Cebra , Animales , Progesterona , Progestinas , Esteroides , Contaminantes Químicos del Agua
12.
Endocrinology ; 161(1)2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31748790

RESUMEN

Decidualization, the process by which fibroblastic human endometrial stromal cells (HESC) differentiate into secretory decidual cells, is a critical event during the establishment of pregnancy. It is dependent on the steroid hormone progesterone acting through the nuclear progesterone receptor (PR). Previously, we identified insulin receptor substrate 2 (IRS2) as a factor that is directly regulated by PR during decidualization. IRS2 is an adaptor protein that functionally links receptor tyrosine kinases, such as insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R), and their downstream effectors. IRS2 expression was induced in HESC during in vitro decidualization and siRNA-mediated downregulation of IRS2 transcripts resulted in attenuation of this process. Further use of siRNAs targeted to IR or IGF1R transcripts showed that downregulation of IR, but not IGF1R, led to impaired decidualization. Loss of IRS2 transcripts in HESC suppressed phosphorylation of both ERK1/2 and AKT, downstream effectors of insulin signaling, which mediate gene expression associated with decidualization and regulate glucose uptake. Indeed, downregulation of IRS2 resulted in reduced expression and membrane localization of the glucose transporters GLUT1 and GLUT4, resulting in lowered glucose uptake during stromal decidualization. Collectively, these data suggest that the PR-regulated expression of IRS2 is necessary for proper insulin signaling for controlling gene expression and glucose utilization, which critically support the decidualization process to facilitate pregnancy. This study provides new insight into the mechanisms by which steroid hormone signaling intersects with insulin signaling in the uterus during decidualization, which has important implications for pregnancy complications associated with insulin resistance and infertility.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Decidua/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Progesterona/farmacología , Diferenciación Celular/genética , Células Cultivadas , Decidua/citología , Decidua/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Fosforilación/efectos de los fármacos , Embarazo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Células del Estroma/citología , Células del Estroma/metabolismo , Útero/citología , Útero/metabolismo
13.
Food Chem Toxicol ; 135: 110897, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31654709

RESUMEN

The mechanisms of prenatal cadmium (Cd) exposure cause adverse effect transmission to future generations that remain unclear. In this study, pregnant SD rats were orally dosed with Cd (0, 0.5, 2.0, and 8.0 mg/kg/day) from gestation day 1 until birth. F1 female rats were mated with untreated males for F2 generation. In both generations, after prenatal Cd exposure, histopathological examinations showed testicular development disorder. A significant decrease in serum testosterone (T) was observed in the F1 rats, but a significant increase in serum T was observed in the F2 rats. Moreover, both the F1 and F2 rats had different patterns of mRNA and protein expression for testicular steroidogenic factor 1 (SF-1) and steroidogenic enzymes at postnatal days (PNDs) 21 and 56. We also found that rno-miR-328a-5 and rno-miR-10b-5p significantly changed and TargetScan software showed that both of these microRNAs targeted SF-1 and steroidogenic acute regulatory (StAR), respectively. Overall, the results indicate that prenatal Cd exposure causes male reproductive problems in a multigenerational manner. In addition, SF-1 signaling was disrupted and the expressions of microRNAs were affected, which may be an important target for Cd-induced reproductive toxicity in offspring.


Asunto(s)
Cadmio/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Transducción de Señal/efectos de los fármacos , Factor Esteroidogénico 1/metabolismo , Testosterona/metabolismo , Animales , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Exposición Materna/efectos adversos , MicroARNs/metabolismo , Embarazo , Progesterona/metabolismo , Ratas Sprague-Dawley , Testículo/patología
14.
Chemosphere ; 241: 125074, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31627108

RESUMEN

Perfluorooctane acid (PFOA), a persistent organic pollutant, is ubiquitously present in the environment and may detrimentally affect male reproductive health. In this study, mature human sperm were in vitro exposed to different concentrations of PFOA (0.25, 2.5 or 25 µg/ml) alone or in combination with progesterone (P4) to evaluate the toxicity and the potential mechanism of action. Exposure to high-dose PFOA (25 µg/ml) alone for 4 h caused a decline in capacity of human spermatozoa to penetrate synthetic mucus, with an increased production of reactive oxygen species (ROS). Furthermore, PFOA treatment (2.5 and 25 µg/ml) evoked a transient rise in intracellular calcium concentration [Ca2+]i by activating the sperm-specific CatSper channel. However, preincubation with PFOA (2.5-25 µg/ml) for 4 h significantly suppressed P4-stimulated extracellular Ca2+ influx in human spermatozoa. Moreover, PFOA pretreatment at all concentrations evaluated markedly compromised P4-induced acrosome reaction and sperm penetration into viscous medium. Taken together, these results suggest that PFOA exposure may impair human sperm function through inducing oxidative stress and disturbing P4-induced Ca2+ signaling.


Asunto(s)
Canales de Calcio/metabolismo , Fluorocarburos/toxicidad , Sustancias Peligrosas/toxicidad , Reacción Acrosómica , Calcio/metabolismo , Humanos , Masculino , Progesterona/farmacología , Espermatozoides/metabolismo
15.
Theriogenology ; 141: 98-104, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31536862

RESUMEN

The objective was to evaluate the association between postpartum health disorders, reproductive responses and pregnancy status in lactating multiparous cyclic Holstein cows. Cows were retrospectively categorized as healthy (n = 70) or sick (n = 60) based on postpartum health records and serum metabolites. Sick cows were further categorized as having metabolic (MET; n = 35), infectious (INF; n = 15), or both diseases (MET/INF; n = 10). Blood samples were collected on d 7 and 14 after calving to determine serum concentrations non-esterified fatty acids (NEFA), ß-hydroxybutyrate (BHB) and aspartate aminotransferase (AST), on d 0 (TAI), 8, 16, 18 and 20 after TAI to determine concentrations of progesterone (P4; d 0, 8, 16, 18 and 20) and prostaglandin F metabolite (PGFM; d 16, 18 and 20) and interferon-stimulated gene-15 (ISG15; d 16) relative mRNA expression. Cyclicity was determined by transrectal ultrasonography 30 d postpartum and cows were subjected to a GnRH-based TAI protocol (to classify cows bearing a visible CL as cyclic). Prediction of pregnancy status on d 16 after TAI was determined by ISG15 mRNA gene expression relative to ß actin and following, pregnancy was diagnosed by transrectal ultrasonography at 32 and 60 d after TAI. An interaction (P = 0.04) between occurrence of disease and pregnancy status was detected for the expression of ISG15 in blood, with healthy pregnant healthy cows having the greatest relative expression of ISG15. Postpartum health disorders were associated with reduced concentration (P < 0.05) of serum P4 post TAI. However, serum P4 concentrations at TAI were greater (P = 0.01) in sick cows (0.65 ±â€¯0.09, 0.86 ±â€¯0.13 and 0.75 ±â€¯0.10 ng/mL for MET, INF and MET/INF cows, respectively) compared with that in healthy cows (0.24 ±â€¯0.10 ng/mL). Serum concentrations of PGFM after TAI was reduced in healthy cows, regardless of pregnancy status. Pregnancy status on d 16 after TAI predicted by ISG15 mRNA expression and P/AI on d 32 and 60 after TAI based on ultrasonography, were negatively affected (P < 0.05) by occurrence of health disorders. Similarly, pregnancy loss from d 16 to 32 and d 16 to 60 after TAI was greater (P < 0.05) in sick cows compared to that in healthy cows. However, neither P/AI nor pregnancy loss were associated to the category of postpartum health disorder. Cows affected by postpartum health disorders had overall reduced P4 and greater PGFM serum concentrations after TAI, which were associated with reduced pregnancy success and enhanced pregnancy loss. Collectively, our findings support the hypothesis of a carryover effect of disease on reproductive responses, embryo survival and maintenance of pregnancy in lactating dairy cows independent of the category of postpartum health disorder.


Asunto(s)
Enfermedades de los Bovinos , Inseminación Artificial/veterinaria , Animales , Composición Corporal , Bovinos , Dinoprost/análogos & derivados , Dinoprost/sangre , Femenino , Lactancia , Periodo Posparto , Embarazo , Progesterona/sangre , Reproducción/fisiología , Estudios Retrospectivos
16.
Theriogenology ; 141: 202-210, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31606718

RESUMEN

The present study tested the hypothesis that administration of GnRH on day 5 of the estrous cycle in embryo transfer (ET) recipients would increase progesterone (P4) concentrations, embryo size, and improve fertility. Holstein and cross-bred Holstein heifers (n = 1562) were synchronized using a modified 5-day CIDR-Synch protocol as follows (All AM treatments): D-8, CIDR inserted; D-3, CIDR removed and PGF2α (500 µg cloprostenol) treatment; D-2, second PGF2α; D0, GnRH (G1, 100 µg gonadorelin acetate) to induce ovulation. On D5 in the afternoon, heifers were assigned in a completely randomized design to one of two treatments: Control (untreated) or GnRH (200 µg). Transfer of day 7 fresh IVP embryos was performed between D6 and D8 after G1. Data collected from each heifer included: embryo stage and quality, body condition score, technician performing ET, interval from G1 to ET, and number of previous transfers. All heifers were evaluated by transrectal ultrasonography on D5, D33, and D60 and a subset of heifers was scanned on D12 (n = 718; to determine ovulation to treatment) and another subset on D33 (n = 295; 16 s video to determine embryo and amniotic vesicle size). Serum P4 was determined from a subset of heifers on D12 (n = 467) and on D21 (n = 837) and pregnancy specific protein B (PSPB) on D28 (n = 843). Pregnancies per ET (P/ET) were analyzed by logistic regression and continuous outcomes by ANOVA. Ovulation to D5 GnRH, defined by the presence of an accessory CL on D12, was 83.9% (302/360) in GnRH-treated heifers vs. 3.3% (12/358) in Controls (P < 0.001). On D12, P4 was greater (P < 0.001) in GnRH-treated heifers (7.2 ±â€¯0.1 ng/ml) vs Controls (6.0 ±â€¯0.1 ng/ml). There was greater P/ET at D33 and D60 of pregnancy for Stage 7 than Stage 6 embryos. Treatment with GnRH did not alter P/ET with either embryo stage but decreased pregnancy loss between D33 and D60 in heifers receiving Stage 7 embryos. Presence of an accessory CL at the D33 pregnancy diagnosis was associated with a larger reduction in pregnancy loss from D33 to D60 in recipients of Stage 7 embryos (11.6 vs 27.6%). Although there was no GnRH effect on embryo size, the presence of an accessory CL was associated (P < 0.05) with larger amniotic vesicle volume in recipients of Stage 7 embryos. In addition, greater PSPB was linked to greater amniotic vesicle volume (P = 0.01) and to reduced pregnancy loss (P < 0.0001). In conclusion, treatment with GnRH on D5 caused ovulation and formation of an accessory CL, increased circulating P4, and reduced pregnancy loss in heifers receiving a Stage 7 but not a Stage 6 IVP embryo.


Asunto(s)
Aborto Veterinario/prevención & control , Blastocisto/fisiología , Bovinos , Transferencia de Embrión/veterinaria , Hormona Liberadora de Gonadotropina/farmacología , Ovulación/efectos de los fármacos , Animales , Dinoprost/administración & dosificación , Dinoprost/farmacología , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Ovulación/fisiología , Embarazo , Proteínas Gestacionales/sangre , Progesterona/sangre
17.
Gen Comp Endocrinol ; 285: 113273, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31525377

RESUMEN

There exists a surprising diversity in the physiology and endocrinology of pregnancy among mammals in both the source (luteal/placental) and metabolism of progesterone. To evaluate the possible diversity of steroid metabolism within toothed cetaceans, we investigated 5α-reduced progesterone metabolites and androgens in cyclic (luteal phase) and pregnant captive killer whales, belugas and bottlenose dolphins (n = 5/species) bled longitudinally in early, mid- and late pregnancy (0.16, 0.50 and 0.85 fractions of 535, 464 and 380 gestation days, respectively). Mid-luteal samples were also collected. Serum was analyzed by liquid chromatography tandem-mass spectrometry as previously validated for (among others) progesterone, 20αOH-progesterone (20αOHP), 5α-dihydroprogesterone (DHP), several additional 5α-reduced metabolites and androgens (dehydroepiandrosterone, androstenedione and testosterone). The predominant mid-luteal pregnanes were: progesterone, belugas; progesterone and 20αOHP, dolphins; allopregnanolone (3α-DHP) and progesterone, killer whales. Progesterone was 2-4-fold higher in early pregnancy than mid-luteal samples but decreased thereafter. The predominant metabolite, 3ß,20α-dihydroprogesterone (3ß,20α-DHP; 40-80 ng/ml) was higher in mid- and late-than early gestation in all 3 species. Concentrations of 20αOHP and 3ß,20α-DHP were similar at mid-gestation but 20αOHP declined in late-gestation in killer whales, and 20αOHP was lower than 3ß,20α-DHP in belugas and dolphins throughout gestation. Other 5α-reduced metabolites, DHP, 3α-DHP and 20α-DHP, were far lower throughout pregnancy (<10 ng/ml). DHP and 3α-DHP decreased from early to mid-gestation in belugas, but changed little in killer whales and dolphins. These data suggest that progesterone metabolism is relatively conserved among these cetacean species. As in equine pregnancies, 3ß,20α-DHP is the major metabolite, increasing at the expense of progesterone as pregnancy progresses. Androstenedione and testosterone also increased detectably in mid- to late-gestation in these species. The tissue source remains unknown, but progesterone metabolism during gestation in these cetaceans is similar to horses and, together with androgens, may be reliable biomarkers of pregnancy.


Asunto(s)
Ballena Beluga/sangre , Delfín Mular/sangre , Cromatografía Liquida/métodos , Esteroides/sangre , Espectrometría de Masas en Tándem/métodos , Orca/sangre , Animales , Femenino , Embarazo , Pregnanos/sangre , Progesterona/sangre , Progesterona/metabolismo
18.
Gen Comp Endocrinol ; 285: 113295, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31580883

RESUMEN

Life history transitions and hormones are known to interact and influence many aspects of animal physiology and behavior. The South-American tegu lizard (Salvator merianae) exhibits a profound seasonal shift in metabolism and body temperature, characterized by high daily activity during warmer months, including reproductive endothermy in spring, and metabolic suppression during hibernation in winter. This makes S. merianae an interesting subject for studies of interrelationships between endocrinology and seasonal changes in physiology/behavior. We investigated how plasma concentrations of hormones involved in regulation of energy metabolism (thyroid hormones T4 and T3; corticosterone) and reproduction (testosterone in males and estrogen/progesterone in females) correlate with activity and body temperature (Tb) across the annual cycle of captive held S. merianae in semi-natural conditions. In our initial model, thyroid hormones and corticosterone showed a positive relationship with activity and Tb with independent of sex: T3 positively correlated with activity and Tb, while T4 and corticosterone correlated positively with changes in Tb only. This suggests that thyroid hormones and glucocorticoids may be involved in metabolic transitions of annual cycle events. When accounting for sex-steroid hormones, our sex separated models showed a positive relationship between testosterone and Tb in males and progesterone and activity in females. Coupling seasonal endocrine measures with activity and Tb may expand our understanding of the relationship between animal's physiology and its environment. Manipulative experiments are required in order to unveil the directionality of influences existing among abiotic factors and the hormonal signaling of annual cyclicity in physiology/behavior.


Asunto(s)
Temperatura Corporal , Hormonas/metabolismo , Lagartos/fisiología , Animales , Corticosterona/sangre , Sistema Endocrino/metabolismo , Metabolismo Energético , Femenino , Glucocorticoides/metabolismo , Masculino , Progesterona/metabolismo , Estaciones del Año , Testosterona/metabolismo , Hormonas Tiroideas/metabolismo
19.
Ecotoxicol Environ Saf ; 187: 109879, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31677567

RESUMEN

Cadmium (Cd) is a major environmental pollutant. Maternal Cd exposure throughout pregnancy caused fetal growth restriction (FGR). However, the pivotal time window of Cd-evoked FGR and its mechanism are unknown. Here, we will establish a murine model to explore the effects of maternal Cd exposure at different stages of gestation on fetal growth and placental progesterone biosynthesis. Pregnant mice were randomly divided into four groups. For Cd groups, mice were given with CdCl2 (150 mg/L) through drinking water at early (GD0-GD6), middle (GD7-GD12) and late (GD13-GD17) gestation, respectively. The controls received reverses osmosis (RO) water. Results showed that maternal cadmium exposure only in late gestation lowered fetal weight and length. Correspondingly, placental Cd level in late gestational Cd exposure is the highest among three different gestational stages. Although gestational Cd exposure had few adverse effects in the weight and diameter of mouse placenta, placental vascular development, as determined by H&E staining and cluster of differentiation-34 (CD-34) immunostaining, was impaired in mice exposed to Cd during late pregnancy. Additionally, late gestational exposure to cadmium markedly reduced progesterone level in maternal serum and placenta. In line, the expression of key progesterone synthetases, including steroidogenic acute regulatory protein (StAR) and 3ß-hydroxyl steroid dehydrogenase (3ß-HSD), was obviously downregulated in placenta from mice was exposed Cd during late pregnancy. These data suggest that maternal Cd exposure during late pregnancy, but not early and middle pregnancy, induces fetal growth restriction partially via inhibiting placental progesterone synthesis.


Asunto(s)
Cadmio/toxicidad , Contaminantes Ambientales/toxicidad , Retardo del Crecimiento Fetal/inducido químicamente , Exposición Materna/efectos adversos , Placenta/efectos de los fármacos , Progesterona/biosíntesis , Animales , Cadmio/sangre , Regulación hacia Abajo , Contaminantes Ambientales/sangre , Femenino , Edad Gestacional , Humanos , Ratones , Placenta/metabolismo , Embarazo , Resultado del Embarazo , Progesterona/antagonistas & inhibidores , Distribución Aleatoria
20.
J Sci Food Agric ; 100(1): 92-101, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31435952

RESUMEN

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.


Asunto(s)
Ostreidae/química , Péptidos/administración & dosificación , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Sustancias Protectoras/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Femenino , Galactosa/efectos adversos , Humanos , Hormona Luteinizante/metabolismo , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/metabolismo , Progesterona/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo
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