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2.
Food Chem Toxicol ; 135: 110897, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654709

RESUMO

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.


Assuntos
Cádmio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator Esteroidogênico 1/metabolismo , Testosterona/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Exposição Materna/efeitos adversos , MicroRNAs/metabolismo , Gravidez , Progesterona/metabolismo , Ratos Sprague-Dawley , Testículo/patologia
3.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875912

RESUMO

Changes in gonadotropin-releasing hormone (GnRH) release frequency from the brain help drive reproductive cycles. In polycystic ovary syndrome (PCOS), persistent high GnRH/luteinizing hormone (LH) frequency disrupts cycles and exacerbates hyperandrogenemia. Adult prenatally-androgenized (PNA) mice exhibit increased GnRH neuron firing rate, elevated ovarian androgens, and disrupted cycles, but before puberty, GnRH neuron activity is reduced in PNA mice compared with controls. We hypothesized that ovarian feedback mediates the age-dependent change in GnRH neuron firing rate in PNA vs control mice. Extracellular recordings of green fluorescent protein (GFP)-identified GnRH neurons were made 5 to 7 days after sham-surgery, ovariectomy (OVX), or, in adults, after OVX plus replacement of sub-male androgen levels with dihydrotestosterone implants (OVX + DHT). In 3-week-old mice, OVX did not affect GnRH neuron firing rate in either group. In adult controls, OVX increased GnRH neuron firing rate, which was further enhanced by DHT. In adult PNA mice, however, OVX decreased GnRH neuron firing rate, and DHT restored firing rate to sham-operated levels. In contrast to the differential effects of ovarian feedback on GnRH neuron firing rate, serum LH increased after OVX in both control and PNA mice and was not altered by DHT. Pituitary gene expression largely reflected changes expected with OVX, although in PNA but not control mice, DHT treatment increased Lhb expression. These results suggest prenatal androgen exposure programs marked changes in GnRH neuron regulation by homeostatic steroid feedback. PNA lowers GnRH neuron activity in low-steroid states (before puberty, OVX), and renders activity in adulthood dependent upon ongoing exposure to elevated ovarian androgens.


Assuntos
Androgênios/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/fisiologia , Ovário/metabolismo , Animais , Di-Hidrotestosterona/farmacologia , Eletrofisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ovariectomia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Maturidade Sexual/fisiologia
4.
Ecotoxicol Environ Saf ; 188: 109898, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31711775

RESUMO

Gamma-aminobutyric acid (GABA) plays a critical role in regulation of gonadotropin-releasing hormone (GnRH) through GABAA receptor (GABAAR). Nitric oxide (NO) production has correlation with GABA and regulates GnRH secretion. This study was performed to examine the mechanisms by which manganese (Mn) accelerate puberty onset involves GABAAR/NO pathway in the preoptic area-anterior hypothalamus (POA-AH) in immature female rats. First, female rats received daily dose of MnCl2 0 (saline), 2.5, 5 and 10 mg/kg b.w by oral gavage during postnatal day (PND) 21-32. Animals administered with 10 mg/kg MnCl2 exhibited earlier puberty onset age and advanced ovary and uterus development than these in saline-treatment group. Furthermore, we found that decrease of GABAAR result in elevated production of nitric oxide synthase1 (NOS1), NO and GnRH in the POA-AH. Second, we recorded the neuronal spikes alternation after perfusion with GABAAR inhibitor bicuculline (BIC), GABAAR agonist isoguvacine (isog), and MnCl2 from the POA-AH in acute brain slices of PND21 rats. Spontaneous firing revealed a powerful GABAAR-mediated action on immature POA-AH and confirm that MnCl2 has a significant effect on GABAAR. Third, we revealed that decrease in NOS1 and NO production by treatment with isog-alone or isog+MnCl2 contribute to the decrease of GnRH in the POA-AH and a delayed puberty onset age compared to treatment with MnCl2-alone. Together, these results suggested that excessive exposure to MnCl2 stimulates NO production through decreased GABAAR in the POA-AH to advance puberty onset in immature female rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloretos/toxicidade , Disruptores Endócrinos/toxicidade , Óxido Nítrico/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Maturidade Sexual/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Compostos de Manganês , Neurônios/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Área Pré-Óptica/crescimento & desenvolvimento , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Útero/diagnóstico por imagem , Útero/efeitos dos fármacos , Desmame
5.
Gen Comp Endocrinol ; 285: 113250, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445009

RESUMO

Seasonally breeding animals initiate gonadal recrudescence when mechanisms that suppress reproduction give way to mechanisms that stimulate it. However, knowledge of mechanistic changes in hormonal regulation during this transition is limited. Further, most studies of reproductive timing have focused on males, despite the critical role of females in determining breeding phenology. Closely related populations that live in the same environment but differ in reproductive timing provide an opportunity to examine differences in mechanisms during the transition from the pre-reproductive to reproductive state. We studied closely related migrant and resident populations of dark-eyed juncos (Junco hyemalis) that reside in the same environment in spring but differ in breeding phenology. Residents initiate breeding earlier than migrants, which do not breed until after they have migrated. To directly study differences in the hypothalamic mechanisms of reproduction, we captured 16 migrant and 13 resident females from the field on March 25-April 11. We quantified expression of mRNA transcripts and show that resident females had higher abundance of gonadotropin-releasing hormone transcripts than migrant females, indicating greater reproductive development in resident than migrant females living in the same environment. We also found higher transcript abundance of estrogen receptor and androgen receptor in migrant than resident females, suggesting that negative feedback may delay reproductive development in migrant females until after they migrate. These differences in hypothalamic mechanisms may help to explain differences in reproductive timing in populations that differ in migratory strategy.


Assuntos
Migração Animal/fisiologia , Sistemas Neurossecretores/metabolismo , Estações do Ano , Aves Canoras/fisiologia , Simpatria/fisiologia , Animais , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Modelos Lineares , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Histochem Cell Biol ; 152(6): 423-437, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630211

RESUMO

Wide application of gonadotropin-releasing hormone (GnRH) agonists and antagonists for clinical purposes determines their effects on ovarian signaling pathways. Our study aimed to determine the localization, expression levels of Wnt signaling members in the pubertal and adult mouse ovary and the impact of GnRH antagonist cetrorelix on these signaling members. 0.5 mg/kg of cetrorelix was injected to 3-and 6-week-old mice for 2 weeks. At the end of injection, ovaries from 5 (5Ce)- to 8-week (8Ce)-old mice were embedded in paraffin for immunohistochemistry and homogenized for western blot to compare with control (5C-8C) and sham groups (5S-8S). WNT2 and WNT4 showed higher expression in thecal and stromal cells in adult mouse ovaries and only WNT4 expression was affected by cetrorelix. FZD1 was localized mainly in oocytes of pubertal ovaries and granulosa cells and oocytes of adult ovaries. FZD1 was reduced by cetrorelix in pubertal ovaries. FZD4 was abundantly localized in thecal and stromal cells of all groups and protein level was not affected by cetrorelix. LRP-6 was expressed mainly in oocytes and stromal cells of pubertal, oocytes of adult ovaries and its expression was reduced by cetrorelix in adult ovaries. CTNNB1 intensity in granulosa cells was the lowest in pubertal and the highest in adult ovaries and its expression was decreased by cetrorelix in adult ovaries. Cetrorelix affected the expression of specific members of the Wnt signaling depending on the developmental stage of mice, pointing out its possible interaction with gonadotropins during pubertal and adult stages.


Assuntos
Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/farmacologia , Oócitos/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/química , Camundongos , Camundongos Endogâmicos BALB C , Oócitos/metabolismo , Puberdade/metabolismo
7.
Chemosphere ; 234: 909-916, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31519099

RESUMO

T-2 toxin could impair male reproductive function. But, the toxicity mechanism is still unclear. In this study, male Kunming mice were orally administrated with T-2 toxin at the doses of 0, 0.5, 1 or 2 mg/kg body weight for 28 days. The fertility, body weight, reproductive organs volume, daily sperm production (DSP), and sperm malformation rate were detected. The expressions of testosterone (T) biosynthetic enzymes, luteinizing hormone (LH)-receptor, follicle stimulating hormone (FSH)-receptor and androgen binding protein (ABP) in testis were detected. The serum hormone level of gonadotropin-releasing hormone (GnRH), FSH, LH, T and progesterone (P), and the mRNA expression of GnRH, GnRH-receptor, LH and FSH were measured. These results demonstrated that T-2 toxin decreased body weight, reproductive organs volume and DSP, increased sperm malformation rate. T-2 toxin impaired fertility by decreasing the mating index, fertility index, numbers of implantation sites and viable fetuses, and increasing the number of animal with resorptions. Meantime, T-2 suppressed testicular function by inhibiting T biosynthesis and decreasing FSHR, LHR and ABP expression. Furthermore, the serum reproductive hormone contents and key factors expression of hypothalamic-pituitary-testis (HPT) axis were decreased by T-2 toxin. In summary, T-2 toxin impaired the male fertility by disrupting HPT axis and impairing testicular function.


Assuntos
Toxina T-2/toxicidade , Testículo/efeitos dos fármacos , Animais , Fertilidade , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/sangue , Masculino , Camundongos , Receptores do FSH/metabolismo , Receptores LHRH/metabolismo , Reprodução , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/sangue
8.
Endocrinology ; 160(11): 2543-2555, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504396

RESUMO

A defining characteristic of the hypothalamus-pituitary-gonad reproductive endocrine axis is the episodic secretion of the pituitary gonadotropin hormones LH and FSH by the anterior pituitary gonadotropes. Hormone secretion is dictated by pulsatile stimulation, with GnRH released by hypothalamic neurons that bind and activate the G protein-coupled GnRH receptor expressed by gonadotropes. Hormone secretion and synthesis of gonadotropins are influenced by the amplitude and frequency of GnRH stimulation; variation in either affects the proportion of LH and FSH secreted and the differential regulation of hormone subunit gene expression. Therefore, proper decoding of GnRH signals is essential for appropriate gonadotropin synthesis and secretion. The GnRH receptor robustly activates downstream signaling cascades to facilitate exocytosis and stimulate gene expression and protein synthesis. It is necessary to rapidly quench signaling to preserve sensitivity and adaptability to changing pulse patterns. Reactive oxygen species (ROS) generated by receptor-activated oxidases fulfill the role of rapid signaling intermediates that facilitate robust and transient signaling. However, excess ROS can be detrimental and, unchecked, can confuse signal interpretation. We demonstrate that sulfiredoxin (SRXN1), an ATP-dependent reductase, is essential for normal responses to GnRH receptor signaling and plays a central role in resolution of ROS induced by GnRH stimulation. SRXN1 expression is mitogen-activated protein kinase dependent, and knockdown reduces Lhb and Fshb glycoprotein hormone subunit mRNA and promoter activity. Loss of SRXN1 leads to increased basal and GnRH-stimulated ROS levels. We conclude that SRXN1 is essential for normal responses to GnRH stimulation and plays an important role in ROS management.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Peroxirredoxinas/metabolismo , Animais , Linhagem Celular , Sistema de Sinalização das MAP Quinases , Camundongos , NADPH Oxidases/metabolismo , Oxirredução
9.
Ecotoxicol Environ Saf ; 184: 109614, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31526925

RESUMO

Microcystin-leucine arginine (MC-LR) enters into gonadotropin-releasing hormone (GnRH) neurons and induces decline of serum GnRH levels resulting in male reproductive toxicity via hypothalamic-pituitary-testis axis. The organic anion transporting polypeptide 1a5 (Oatp1a5) is a critical transporter for the uptake of MC-LR by GnRH neurons. However, the underlying molecular mechanisms of the transport process are still elusive. In this study, we found that the transmembrane domains 2, 8, and 9 played important roles in transporting function of Oatp1a5. In addition, our data demonstrated that N-linked glycosylation was involved in the transport of MC-LR by Oatp1a5. Moreover, we showed that N-linked glycosylation sites Asn483 and Asn492 were vital for the transport function of Oatp1a5. In summary, the study furthered our understanding of mechanisms that the uptake of MC-LR by GnRH neurons and laid a theoretical foundation for preventing MC-LR from injuring male reproductive health.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Microcistinas/metabolismo , Neurônios/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Transporte Biológico Ativo , Linhagem Celular , Glicosilação , Mutação , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Domínios Proteicos
10.
Gene ; 721: 144106, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31499126

RESUMO

The modified prolonged gonadotropin-releasing hormone agonist (GnRH-a) protocol lessens the ovarian hyperstimulation syndrome (OHSS) effect and improves the clinical pregnancy rate of women with polycystic ovary syndrome (PCOS) compared with the standard long GnRH-a protocol. However, the molecular basis of this process needs to be elucidated. Sprague Dawley (SD) female rats with letrozole-induced PCOS were divided into GnRH-a and blank groups. Rats in the GnRH-a group were given triptorelin for 11 days, whereas those in blank group were given an equal volume of 0.9% NaCl. Meanwhile, the changes in estrus cycle, hormonal profile, ovary index, ovarian histopathology and body weight were measured. The expressions of anti-mullerian hormone (AMH), type II receptor of AMH (AMHRII), and FSH receptor (FSHR) were taken as the indicators of follicular sensitivity. Changes of follicular counting and differences in antral follicle diameter at each stage were evaluated. The number of follicles from primordial to antral stages increased during downregulation and the differences in antral follicle diameter were reduced in the GnRH-a group, whereas no significant difference was found in the blank group. The results of Western blotting and ELISA indicated that the level of AMH in ovarian total protein and serum had a similar dynamic change in the GnRH-a group. The results of immunohistochemistry showed that follicular AMH, AMHRII, and FSHR significantly decreased in the GnRH-a group. Prolonged GnRH-a protocol can improve synchronization and sensitivity of follicular development by balancing the expressions of AMH, AMHRII, and FSHR among follicles at all levels, thereby achieving better therapeutic effect.


Assuntos
Hormônio Antimülleriano/metabolismo , Regulação para Baixo/efeitos dos fármacos , Letrozol/efeitos adversos , Folículo Ovariano/metabolismo , Síndrome do Ovário Policístico , Animais , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Letrozol/farmacologia , Folículo Ovariano/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Sprague-Dawley , Receptores do FSH/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-31386905

RESUMO

Gonadotropin-releasing hormones (GnRH) regulate gonadal growth of teleosts. Benzo(a)pyrene (BaP) functions as a reproductive endocrine disruptor. Furthermore, endocrine regulation on brood pouch growth of Syngnathidaes is elusive. To better understand the role of GnRH in brood pouch growth and effects of BaP on reproductive endocrine in lined seahorse (Hippocampus erectus), gnrh2 and gnrh3 genes were identified. Results showed that lined seahorse GnRH2 and GnRH3 precursors included the conservative tripartite structure and their transcripts highly expressed in brain as other teleosts. Expression profiles of gnrh2 and gnrh3 transcripts were detected during brood pouch growth. Results indicated that brain gnrh2 transcripts remarkably increased at the middle-stage and late-stage of brood pouch growth, while brain gnrh3 transcripts significantly raised at the early-stage and middle-stage. These suggested that GnRH2 and GnRH3 regulated brood pouch growth at different stages. Short-term BaP exposure in lined seahorse was performed. Transcripts of gnrh2 and gnrh3 remarkably increased in females and males exposed to BaP. Besides, plasma 17-beta estradiol (E2) levels presented a reduced trend during female fish exposed to BaP. This revealed that BaP functioned as anti-estrogenic effects and it may result in high expression of gnrh mRNA. However, plasma 11-ketone testosterone (11-KT) levels showed an increased trend during male fish exposed to BaP. Taken together, these indicated interesting results of BaP on reproduction in each sex of seahorse. These observations contribute to provide novel information of regulation on brood pouch growth and effects of BaP on reproductive endocrine in Syngnathidaes.


Assuntos
Benzo(a)pireno/farmacologia , Estradiol/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Gônadas/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Smegmamorpha/metabolismo , Testosterona/análogos & derivados , Animais , Feminino , Masculino , Ácido Pirrolidonocarboxílico/metabolismo , RNA Mensageiro/metabolismo , Reprodução/fisiologia , Testosterona/metabolismo
12.
Endocrinology ; 160(11): 2529-2542, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415088

RESUMO

Prenatal testosterone (T)-treated female sheep display reproductive deficits similar to women with polycystic ovarian syndrome (PCOS), including an increase in LH pulse frequency due to actions of the central GnRH pulse generator. In this study, we used multiple-label immunocytochemistry to investigate the possibility of changes in the γ-aminobutyric acid (GABA) neurotransmitter system at two key components of the GnRH pulse generator in prenatal T-treated sheep: kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus, and GnRH neurons in the preoptic area (POA) and mediobasal hypothalamus (MBH). We observed a significant decrease and increase, respectively, in the number of GABAergic synapses onto POA and MBH GnRH neurons in prenatal T-treated ewes; additionally, there was a significant increase in the number of GABAergic inputs onto KNDy neurons. To determine the actions of GABA on GnRH and KNDy neurons, we examined colocalization with the chloride transporters NKCC1 and KCC2, which indicate stimulatory or inhibitory activation of neurons by GABA, respectively. Most GnRH neurons in both POA and MBH colocalized NKCC1 cotransporter whereas none contained the KCC2 cotransporter. Most KNDy neurons colocalized either NKCC1 or KCC2, and 28% of the KNDy population contained NKCC1 alone. Therefore, we suggest that, as in the mouse, GABA in the sheep is stimulatory to GnRH neurons, as well as to a subset of KNDy neurons. Increased numbers of stimulatory GABAergic inputs to both MBH GnRH and KNDy neurons in prenatal T-treated animals may contribute to alterations in steroid feedback control and increased GnRH/LH pulse frequency seen in this animal model of PCOS.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiopatologia , Neurônios GABAérgicos/fisiologia , Hormônio Liberador de Gonadotropina/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Área Pré-Óptica/fisiopatologia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Modelos Animais de Doenças , Dinorfinas/metabolismo , Feminino , Kisspeptinas/metabolismo , Neurocinina B/metabolismo , Síndrome do Ovário Policístico/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Área Pré-Óptica/metabolismo , Ovinos , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Simportadores/metabolismo , Testosterona
13.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430847

RESUMO

An increasing body of recent experimental data confirms the impact of neurohormones on fetal development and function of different body systems. The synthesis of many neurohormones starts in fetal tissues before the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems are formed, and their high levels are detected in the bloodstream. Here, we studied the role of gonadotropin-releasing hormone (GnRH) in rat thymus development and tried to reveal possible mechanisms underlying the GnRH effects in early development. Western blotting and reverse transcription-polymerase chain reaction allowed us to identify receptor for GnRH in the fetal thymus with peak expression on embryonic days 17-18 (ED17-18). Blocking the receptors in utero on ED17 by a GnRH antagonist suppressed the concanavalin A-induced proliferative response of T cells in adults. GnRH (10-7 M) increased mRNA expression of interleukin (IL)-4, IL-10, IL-1ß, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) in the thymus of 18-day fetuses after an ex vivo culture for 24 h. The increased mRNA levels of the cytokines in the thymus were accompanied by increased numbers of CD4+ T helpers. Overall, the data obtained confirm the regulatory or morphogenetic effect of GnRH on fetal thymus development mediated by synthesis of thymic cytokines.


Assuntos
Citocinas/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Timo/embriologia , Animais , Diferenciação Celular , Feminino , Ratos , Ratos Wistar , Receptores LHRH/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo/metabolismo
14.
Photochem Photobiol Sci ; 18(10): 2509-2520, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31432859

RESUMO

We investigated changes in behavior, physiology and selected brain regions during the development of vernal migration and reproduction phenotypes in migratory redheaded buntings. We monitored 24 h activity-rest pattern and measured food intake, fat deposition, and body mass of buntings exposed for 12 weeks to short (SP, 8L : 16D) and long (LP, 13L : 11D) photoperiods at 22 ± 2 °C temperature. Under LP, not SP, buntings exhibited a photostimulated spring migration phenotype (hyperphagia, fat deposition and body mass gain). However, there were sex differences in the development of vernal migration, as shown by faster and earlier induction of Zugunruhe (nocturnal migratory restlessness) in males than in females. In the next experiment, increasing photoperiods over 12 weeks following the vernal equinox induced behavioural and physiological changes associated with vernal migration phenotypes in both male and female buntings, but in a sex-dependent manner. In a subsequent experiment over 8 weeks corresponding to the spring migration period we found an increased expression of CART, not NPY, in INc, and decreased expression of GnRH-I in POA in the brain by week 6 of the observation under increasing photoperiods. There was also an increased expression of doublecortin (a marker of neuronal incorporation) in the olfactory bulb and song control nuclei (Area X and HVC, higher vocal centre) in male birds. These results demonstrate changes in the brain peptides and neuronal recruitment along with changes in the behaviour and physiology, and give insights into the concurrent photoperiodic induction of the seasonal response at multiple levels in migratory songbirds.


Assuntos
Migração Animal/fisiologia , Neurônios/metabolismo , Passeriformes/fisiologia , Animais , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fotoperíodo , Estações do Ano
15.
Anim Reprod Sci ; 208: 106102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405485

RESUMO

In the present study, there was testing of the hypothesis that a centrally administered dopamine (DA) derivative, salsolinol, could affect pulsatile luteinizing hormone (LH) secretion in seasonally anestrous sheep by affecting the neuronal components of the estradiol (E2) negative feedback. In two experiments performed during early spring (increasing day length - March/April), salsolinol or Ringer-Locke solution (control) were administered into the third brain ventricle (IIIv): 1) in several injections for three consecutive days; and 2) in several hour-long infusions. In addition to determining the LH concentration (in both experiments), the abundances of gonadotropin-releasing hormone (GnRH) and kisspeptin mRNA were examined in the hypothalamus and LHß subunit mRNA in the pituitary (Experiment 1). In Experiment 2, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in perfusates collected from the infundibular nucleus/median eminence (IN/ME) by the push-pull method. In both experiments, salsolinol increased both LH pulse frequency (P < 0.05) and plasma LH concentration (P < 0.001) compared to controls. The injected salsolinol also increased (P < 0.05) the abundance of GnRH mRNA in the mediobasal hypothalamus and kisspeptin mRNA in the arcuate nucleus. The two doses of infused salsolinol decreased DA to undetectable concentrations and DOPAC concentration by 60% in perfusates collected from the IN/ME. In conclusion, exogenous salsolinol functioning centrally stimulates pulsatile LH secretion in sheep during seasonal anestrus. It is suggested that salsolinol may have this effect by reducing the activity of the hypothalamic neuroendocrine dopaminergic system, which results in an increase in both kisspeptin and GnRH neurons activity.


Assuntos
Dopamina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Isoquinolinas/farmacologia , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Ovinos/fisiologia , Anestro , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo , RNA Mensageiro , Estações do Ano
16.
Int J Mol Sci ; 20(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404950

RESUMO

Chemerin (CHEM) may act as an important link integrating energy homeostasis and reproductive functions of females, and its actions are mediated by three receptors: chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). The aim of the current study was to compare the expression of CHEM and its receptor (CHEM system) mRNAs (quantitative real-time PCR) and proteins (Western blotting and fluorescent immunohistochemistry) in the selected areas of the porcine hypothalamus responsible for gonadotropin-releasing hormone production and secretion: the mediobasal hypothalamus, preoptic area and stalk median eminence during the oestrous cycle and early pregnancy. Moreover, plasma CHEM concentrations were determined using ELISA. The expression of CHEM system has been demonstrated in the porcine hypothalamus throughout the luteal phase and follicular phase of the oestrous cycle, and during early pregnancy from days 10 to 28. Plasma CHEM levels and concentrations of transcripts and proteins of CHEM system components in the hypothalamus fluctuated throughout pregnancy and the oestrous cycle. Our study was the first experiment to demonstrate the presence of CHEM system mRNAs and proteins in the porcine hypothalamus and the correlations between the expression levels and physiological hormonal milieu related to the oestrous cycle and early pregnancy.


Assuntos
Quimiocinas/análise , Ciclo Estral , Hipotálamo/metabolismo , Receptores de Quimiocinas/análise , Animais , Quimiocinas/sangue , Quimiocinas/genética , Feminino , Expressão Gênica , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/química , Gravidez , Receptores de Quimiocinas/genética , Suínos
17.
Elife ; 82019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291191

RESUMO

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.


Assuntos
Hormônio Antimülleriano/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hipogonadismo/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Hormônio Antimülleriano/genética , Axônios/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Células COS , Movimento Celular , Feminino , Fertilidade , Feto/metabolismo , Heterozigoto , Humanos , Mutação com Perda de Função , Hormônio Luteinizante/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Bulbo Olfatório/metabolismo , Linhagem , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Adulto Jovem
18.
Ecotoxicol Environ Saf ; 181: 362-369, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31212184

RESUMO

DEHP is reported to cause precocious puberty of females in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of sexual precocity. Prepubertal female rats were treated with DEHP for 4 weeks. Key organs were analyzed in control conditions and after exposure to 0.2, 1, and 5 mg/kg/day DEHP in pubertal female rats. To determine the role of the IGF-1/PI3K/Akt/mTOR signaling pathway in DEHP-induced female precocious puberty, 36 rats were treated with 5 mg/kg/day DEHP to establish a model of female precocious puberty. And we investigated the expression of genes and proteins related to IGF-1 pathway in rat hypothalamus after treatment with inhibitors. In the present study, we observed that DEHP treatment resulted in earlier vaginal opening time, higher number of Nissl bodies in the hypothalamus neurons, lower apoptosis of hypothalamic cells, higher IGF-1 and GnRH levels in the serum and hypothalamus. DEHP could also upregulated the expression of IGF-1/PI3K/Akt/mTOR pathway and GnRH in the hypothalamus of adolescent female rats, and inhibition of IGF-1R and mTOR in hypothalamus could block the activation of Kiss-1, GPR54, and GnRH by DEHP. In summary, our study suggested that DEHP might activate the hypothalamic GnRH neurons prematurely through the IGF-1 signaling pathway and promote GnRH release, leading to the initiation of female sexual development. Our results provide a new molecular mechanism underlying reproductive and developmental toxicity in pubertal female rats induced by DEHP.


Assuntos
Dietilexilftalato/toxicidade , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Puberdade Precoce/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Puberdade Precoce/enzimologia , Puberdade Precoce/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
19.
Anat Histol Embryol ; 48(5): 415-420, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31241795

RESUMO

We examined the distribution of the orexin-like peptides in the pituitary and median eminence of the flat-tailed house gecko (Hemidactylus platyurus) using immunohistochemistry. Orexin-B-like, but not orexin-A-like, immunoreactivity was detected in the pituitary, specifically in the pars intermedia, and these cells corresponded to alpha-melanocyte-stimulating hormone (αMSH)-producing cells. Orexin-B and αMSH secreted from pars intermedia may modulate secretion of adenohypophyseal cells in the pars distalis. In the median eminence, orexin-B-immunoreactive puncta and fibres were observed, and these structures corresponded to gonadotropin-releasing hormone (GnRH)-immunoreactive puncta and fibres. Orexin-B secreted from GnRH-containing neurons in the hypothalamus may affect thyrotropin-releasing hormone-containing neurons resulting in modulation of αMSH secretion of melanotrophs in the pars intermedia.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Lagartos , Orexinas/metabolismo , Hipófise , alfa-MSH/metabolismo , Animais , Imuno-Histoquímica , Eminência Mediana/citologia , Eminência Mediana/metabolismo , Neurônios/metabolismo , Hipófise/citologia , Hipófise/metabolismo
20.
Med Hypotheses ; 128: 54-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203909

RESUMO

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Gonadotropinas/metabolismo , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Adamantano/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Hipogonadismo/terapia , Camundongos , Modelos Biológicos , Modelos Teóricos , Neuropeptídeos/metabolismo , Ratos , Receptores de Kisspeptina-1/metabolismo , Receptores de Neuropeptídeos/metabolismo
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