RESUMO
BACKGROUND: Studies on epididymal toxicology are scarce. Betamethasone (BM) is a glucocorticoid used in clinical practice for antenatal therapy. We previously reported changes to testicular morphology, altered sperm quality, and fertility in adult rats following intrauterine administration of BM. OBJECTIVES: Given that high levels of corticosteroids during gestation lead to fetal androgen depletion, and the essential role of testosterone during epididymal development, here we investigated epididymal morphology and physiology in the F1 and F2 male offspring of female rats treated with BM during gestation. MATERIALS AND METHODS: Pregnant rats were randomly divided into two experimental groups: control (saline vehicle, n = 11) and BM-treated group (0.1 mg/kg betamethasone 21-phosphate disodium, n = 13). Rats received an intramuscular injection of vehicle or BM on gestational days 12, 13, 18, and 19. This encompasses the beginning of the critical window of male rat reproductive tract development. A subset of three males from each litter (n = 5 litters/group) was used: One rat per litter was euthanized at puberty, one was euthanized at adulthood, while the others were mated with a non-treated female to obtain the F2 generation. The same protocol described for the F1 was applied for F2, except for the mating protocol. RESULTS: In both F1 and F2 generations, prenatal BM exposure resulted in delayed differentiation of the cauda epididymal epithelium, characterized by increased cribriform appearance on PND 45, and displayed weaker or non-detectable Cx43 immunostaining. Furthermore, in the F1 generation only, immunostaining of TP63, a transcription factor expressed in basal cells, appeared more intense with a greater number of TP63-positive cells observed in the cauda epididymis. In adults, the epithelial area was reduced in the F1 BM rats. The contractile activity of isolated epididymal ducts was comparable between groups. DISCUSSION AND CONCLUSION: Prenatal BM exposure leads to intergenerational impairment in the development and structure of the rat epididymis.
Assuntos
Betametasona/toxicidade , Epididimo/crescimento & desenvolvimento , Epididimo/fisiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Conexina 43/metabolismo , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Maturação do Esperma/efeitos dos fármacos , Testosterona/sangue , Proteínas Supressoras de Tumor/metabolismoRESUMO
Reproduction and fertility are regulated via hormones of the hypothalamic-pituitary-gonadal (HPG) axis. Control of this reproductive axis occurs at all levels, including the brain and pituitary, and allows for the promotion or inhibition of gonadal sex steroid secretion and function. In addition to guiding proper gonadal development and function, gonadal sex steroids also act in negative- and positive-feedback loops to regulate reproductive circuitry in the brain, including kisspeptin neurones, thereby modulating overall HPG axis status. Additional regulation is also provided by sex steroids made within the brain, including neuroprogestins. Furthermore, because reproduction and survival need to be coordinated and balanced, the HPG axis is able to modulate (and be modulated by) stress hormone signalling, including cortiscosterone, from the hypothalamic-pituitary-adrenal (HPA) axis. This review covers recent data related to the neural, hormonal and stress regulation of the HPG axis and emerging interactions between the HPG and HPA axes, focusing on actions at the level of the brain and pituitary.
Assuntos
Hormônios Hipotalâmicos/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Reprodução , Estresse Psicológico/fisiopatologia , Animais , Estrogênios/fisiologia , Feminino , Hormônio Liberador de Gonadotropina/fisiologia , Humanos , Kisspeptinas/fisiologia , Hormônio Luteinizante/fisiologia , Neuropeptídeos/fisiologiaRESUMO
Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1mg/kg, i.m.) at gestational days 12, 13, 18 and 19. Male and female offspring were killed at post-natal day 30 and the right atrium (RA) was isolated to in vitro evaluation of drug-induced chronotropic responses. Additionally, whole hearts were retrograde-perfused in a Langendorff apparatus and infarct size in response to in vitro ischemia/reperfusion (I/R) protocol was evaluated. Male and female progeny from BET-exposed pregnant rats had reduced birth weight, a hallmark of fetal programming. Male BET-progeny had increased basal RA rate, impaired chronotropic responses to noradrenaline and adenosine, and increased myocardial damage to I/R. Though a 12-fold reduction in the negative chronotropic responses to adenosine, the effects of non-metabolisable adenosine receptor agonists 5'-(N-ethylcarboxamido)adenosine or 2-Chloro-adenosine were not different between VEH- and BET-exposed male rats. BET-exposed female offspring presented no cardiac dysfunction. Prenatal BET exposure engenders male-specific impairment of sinoatrial node function and on myocardial ischemia tolerance resulting, at least in part, from an increased adenosine metabolism in the heart. In light of the importance of adenosine in the cardiac physiology our results suggest a link between reduced adenosinergic signaling and the cardiac dysfunctions observed in glucocorticoid-induced fetal programming.
Assuntos
Betametasona/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Nó Sinoatrial/efeitos dos fármacos , Animais , Betametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/toxicidade , Frequência Cardíaca/fisiologia , Masculino , Gravidez , Ratos , Traumatismo por Reperfusão , Fatores Sexuais , Nó Sinoatrial/fisiologiaRESUMO
OBJECTIVE: To evaluate Ki-67 antigen expression in the mammary epithelium of female rats in persistent estrus treated with raloxifene. MATERIALS AND METHODS: Forty-one Wistar-Hannover rats in persistent estrus induced by 1.25 mg of testosterone propionate were randomly divided into two groups: Group A (control, n = 21) in which the animals received only the vehicle (propylene glycol) and Group B (experimental, n = 20) in which the rats received 750 µg/day of raloxifene by gavage. After 21 days of treatment, all the animals were sacrificed and the first pair of abdominal-inguinal mammary glands was extirpated and fixed in 10% buffered formalin to investigate Ki-67 expression by immunohistochemistry. The data were analysed using Student's t-test (p < 0.05). RESULTS: The percentage of Ki-67-stained nuclei per 500 cells in the mammary epithelium was 42.33 ± 6.18 and 15.51 ± 3.71 [mean ± standard error of the mean (SEM)] in the control and experimental groups, respectively (p < 0.001). CONCLUSION: Raloxifene treatment significantly reduced Ki-67 expression in the mammary epithelium of rats in persistent estrus.
Assuntos
Estro/efeitos dos fármacos , Antígeno Ki-67/análise , Glândulas Mamárias Animais/química , Cloridrato de Raloxifeno/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Epitélio/química , Feminino , Ratos , Ratos WistarRESUMO
OBJECTIVE: The objective of this study was to evaluate the effects of raloxifene on the weight and epithelial thickness of the urethra of castrated female rats. METHODS: Forty castrated female rats were randomly separated into two groups: group I (control, n = 20) received only the vehicle, and group II (raloxifene, n = 20) received 750 microg/day of raloxifene for 30 days. On the 31st day, the animals were sacrificed and the urethras were removed for the study. A model for categorical data using the weighted minimum mean square error method and Student's t test were used for the data analysis (p < 0.05). RESULTS: The mean weights of the urethras in groups I and II were 22 +/- 1.6 mg and 24 +/- 1.7 mg, respectively (p = 0.371). There was an increase in the mean epithelial thickness of the distal segments in group II compared to group I (50.7 +/- 1.9 microm vs. 45.3 +/- 1.6 microm, respectively) (p < 0.04). No statistically significant difference was found in the mean epithelial thickness of the proximal urethra between the two groups (p = 0.187). CONCLUSION: Raloxifene administered to castrated female rats for 30 days increased the distal urethral epithelial thickness and did not alter the weight of the urethra.