RESUMO
Stress signals during fetal or early postnatal periods may disorganize reproductive axis development at different levels. This study was aimed to test the hypothesis that prenatal immunological stress induced by bacterial endotoxin, lipopolysaccharide (LPS), has impact on structure and function of the reproductive system in female offspring. Adult female Wistar rats were divided into two groups, a control group (n = 5) and a LPS group (n = 12). Rats were injected with LPS 50 µg/kg body or 0.9% saline intraperitoneally on the 12th day of pregnancy. After birth the female pups (n = 20 in each group) were divided into four groups: (group 1) 0.9% saline prenatally, sesame oil (vehicle) postnatally; (group 2) LPS prenatally, sesame oil postnatally; (group 3) LPS prenatally, fulvestrant postnatally; (group 4) LPS prenatally, flutamide postnatally. Pups were injected subcutaneously into the neck with fulvestrant (estrogen receptor antagonist), 1.5 mg/kg in sesame oil, from postnatal day (PND) 5 to PND14; or flutamide (androgen receptor antagonist), 20 mg/kg in sesame oil, from PND14 to PND30. Rats of the control group were injected with sesame oil during the same time period. Parameters were evaluated by ELISA (serum estradiol and testosterone) and ovarian histology. The main findings were: (1) prenatal stress during the critical period resulted in delayed vaginal opening, decreased body weight and serum concentrations of sex steroids, and significant disorders in ovarian development; (2) postnatal estradiol and testosterone antagonist treatments decreased follicular atresia through increasing the number of healthy follicles and restored endogenous steroid production. Lay summaryImmunological stress, caused by simulating infection through exposure to a bacterial toxin (LPS), during a critical period of fetal development in laboratory rats results in delayed reproductive maturity, decreased body weight and decreased secretion of sex steroids in female offspring, and abnormalities in the ovaries like those in polycystic ovarian syndrome. These prenatally toxin-induced sexual disorders in females could be corrected by estradiol/testosterone antagonists during the postnatal period.
Assuntos
Estradiol/imunologia , Estradiol/fisiologia , Genitália/imunologia , Lipopolissacarídeos/farmacologia , Testosterona/fisiologia , Animais , Feminino , Lipopolissacarídeos/imunologia , Masculino , Síndrome do Ovário Policístico/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Estresse Psicológico/imunologia , Testosterona/antagonistas & inibidores , Testosterona/sangueRESUMO
The effect of bacterial lipopolysaccharide endotoxin (LPS), immune system activator, on differentiation and migration of gonadotropin-releasing, hormone producing neurons in rat embryogenesis has been studied. Intraperitoneal introduction of LPS (18 jg/kg) to pregnant rats on the 12th day of pregnancy led to 50% decrease in total number of GRH-neurons in the forebrain of 17-day-old embryos and 17% decrease in 19-day-old embryos. At the same time, the number of GRH-neurons in the nasal area of the head of 17- and 19-day-old embryos increased by 40 and 50%, respectively, whereas it increased by 20% in olfactory bulbs of 17-day-old embryos and did not changed in olfactory bulbs of 19-day-old embryos. Neither the total number of neurons nor their distribution patterns were affected by the introduction of LPS into pregnant rats on the 15th day of pregnancy. Singular localization of GRH-neurons in embryo forebrain was observed after LPS administration, whereas the neurons were located by groups of 3-4 cells in rostral areas. Therefore, at the early stages of pregnancy, LPS was shown to suppress initial stages of differentiation and migration of GRH producing neurons. The effects observed in our study may be mediated by LPS-induced, proinflammatory cytokines.
Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Lipopolissacarídeos/farmacologia , Neurônios/metabolismo , Bulbo Olfatório/embriologia , Prosencéfalo/embriologia , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Neurônios/efeitos dos fármacos , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Gravidez , Prosencéfalo/citologia , Prosencéfalo/metabolismo , Ratos , Ratos WistarRESUMO
Different aspects of the reciprocal regulatory influence of systems producing the immune and gonadotropin-releasing hormone (GnRH) in pre- and postnatal ontogeny are discussed in this review. GnRH is a neurohormone synthesized by a small population of neurons located in the anterior hypothalamus, which regulates the secretion of gonadotropines in the anterior lobe of the pituitary gland and they finally regulate the synthesis of sex steroids. Particular attention is given to analysis of the data involving the role of thymus peptides and cytokines in GnRH-system regulation in the normal condition and in the case of inflammation development caused by endotoxines in adult animals. The main prospects of the studies involving the influence of proinflammatory cytokines on GnRH-neuron migration and differentiation in prenatal ontogenesis are also discussed.