RESUMO
Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.
Assuntos
Modelos Animais de Doenças , Hipotálamo , Camundongos Endogâmicos C57BL , Animais , Feminino , Camundongos , Hipotálamo/metabolismo , Ciclo Estral/fisiologia , Saúde Reprodutiva , Transtorno Autístico/metabolismo , Transtorno Autístico/genética , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/genética , Reprodução/fisiologia , Reprodução/genética , Progesterona/sangue , Progesterona/metabolismo , Estradiol/sangue , Estradiol/metabolismo , Masculino , Hormônios Esteroides Gonadais/metabolismo , Hormônios Esteroides Gonadais/sangueRESUMO
The neuropeptide kisspeptin (Kiss) is crucial in regulating the hypothalamic-pituitary-gonadal axis. It is produced by two main groups of neurons in the hypothalamus: the rostral periventricular region around the third ventricle and the arcuate nucleus. Kiss is the peptide product of the KiSS-1 gene and serves as the endogenous agonist for the GPR54 receptor. The Kiss/GPR54 system functions as a critical regulator of the reproductive system. Thus, we examined the effect of intracerebroventricular administration of 3 µg of Kiss to the right lateral ventricle of ovariectomized rats primed with a dose of 5 µg subcutaneous (sc) of estradiol benzoate (EB). Kiss treatment increased the lordosis quotient at all times tested. However, the lordosis reflex score was comparatively lower yet still significant compared to the control group. To investigate receptor specificity and downstream mechanisms on lordosis, we infused 10 µg of GPR54 receptor antagonist, Kiss-234, 5 µg of the progestin receptor antagonist, RU486, or 3 µg of antide, a gonadotropin-releasing hormone-1 (GnRH-1) receptor antagonist, to the right lateral ventricle 30 min before an infusion of 3 µg of Kiss. Results demonstrated a significant reduction in the facilitation of lordosis behavior by Kiss at 60 and 120 min when Kiss-234, RU486, or antide were administered. These findings suggest that Kiss stimulates lordosis expression by activating GPR54 receptors on GnRH neurons and that Kiss/GPR54 system is an essential intermediary by which progesterone activates GnRH.
Assuntos
Estradiol , Kisspeptinas , Receptores LHRH , Receptores de Progesterona , Comportamento Sexual Animal , Animais , Kisspeptinas/farmacologia , Kisspeptinas/metabolismo , Feminino , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Sexual Animal/fisiologia , Receptores LHRH/antagonistas & inibidores , Receptores LHRH/metabolismo , Ratos , Estradiol/farmacologia , Estradiol/análogos & derivados , Receptores de Progesterona/metabolismo , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/antagonistas & inibidores , Ovariectomia , Ratos Wistar , Progesterona/farmacologia , Antagonistas de Hormônios/farmacologia , Postura/fisiologia , Receptores de Kisspeptina-1/metabolismo , Mifepristona/farmacologiaRESUMO
Intracerebroventricular (ICV) administration of estradiol benzoate (E2B) and progesterone (P) induces intense lordosis behavior in ovariectomized rats primed peripherally with E2B. The present study tested the hypothesis that the Kisspeptin (Kiss) and melanin-concentrating hormone (MCH) pathways regulate female sexual behavior induced by these steroid hormones. In Experiment 1, we tested the relevance of the Kiss pathway by ICV infusion of its inhibitor, kiss-234, before administration of E2B or P in estrogen-primed rats. Lordosis induced by E2B alone or with the addition of P was reduced significantly at 30, 120, and 240 min. In Experiment 2, ICV infusion of MCH 30 min before E2B or P significantly reduced lordosis in rats primed with E2B alone. These data support the hypothesis that the Kiss and MCH pathways, which can release or modulate gonadotropin-releasing hormone (GnRH), are involved in E2B- and P-induced lordosis.
Assuntos
Lordose , Progesterona , Animais , Feminino , Ratos , Estradiol/farmacologia , Hormônio Liberador de Gonadotropina/farmacologia , Kisspeptinas/farmacologia , Lordose/induzido quimicamente , Ovariectomia , Progesterona/farmacologia , Comportamento Sexual Animal/fisiologiaRESUMO
In normal hormonal conditions, increased neuronal activity in the ventromedial hypothalamus (VMH) induces lordosis whereas activation of the preoptic area (POA) exerts an opposite effect. In the present work, we explored the effect of bilateral infusion of different doses of the apelin-13 (0.37, 0.75, 1.5, and 15 µg) in both brain areas on the expression of lordosis behavior. Lordosis quotient and lordosis reflex score were performed at 30, 120, and 240 min. Weak lordosis was observed following the 0.37 µg dose of apelin-13 at 30 min in the VMH of EB-primed rats; however, the rest of the doses induced significant lordosis relative to the control group. At 120 min, all doses induced lordosis behavior, while at 240 min, the highest dose of 15 µg did not induce significant differences. Interestingly, only the 0.75 µg infusion of apelin in the POA induced significant lordosis at 120 and 240 min. These results indicate that apelin-13 acts preferably in HVM and slightly in POA to initiate lordosis behavior in estrogen-primed rats.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Lordose , Área Pré-Óptica , Animais , Estradiol/farmacologia , Estrogênios/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lordose/induzido quimicamente , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/patologia , Progesterona/farmacologia , Ratos , Comportamento Sexual Animal/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
A dose-response study was made of the broad-spectrum gonadal steroid agonist tibolone (TBL) on lordosis behavior in estradiol benzoate (EB: 5 µg) primed rats. Doses of TBL (0, 1, 4, and 16 µg) were infused to the right lateral ventricle 2 h before testing. The highest dose increased lordosis quotients significantly at 240 min and 360 min following infusion. However, the intensity of lordosis was weak. In experiment 2, the TBL dose of 16 µg was selected to determine whether tamoxifen (TMX), RU486, or antide could modify the lordosis response to TBL. Infusions of the three compounds, before TBL, significantly attenuated the TBL-induced facilitation of lordosis. The results suggest that TBL stimulates lordosis by activating estrogen, progesterone, and may do so by downstream stimulation of GnRH release. The physiological role TBL plays in controlling lordosis behavior remains to be determined.