Desfechos nos desenvolvimentos cognitivo, somático e reprodutivo da exposição pré-natal e neonatal de ratos à betametasona”
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Data
2021-04-09
Autores
Figueiredo, Thamiris Moreira [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A betametasona (BM) é o fármaco de escolha para a corticoterapia antenatal em casos de risco de parto prematuro por induzir a maturação pulmonar e garantir a sobrevivência fetal pós-natal. No entanto, estudos deste grupo de pesquisa com exposição de ratos à BM no período gestacional crítico para o desenvolvimento do sistema genital evidenciam programação fetal e alterações na função e desenvolvimento reprodutivos em F1. Nosso objetivo foi investigar os efeitos da BM sobre o desenvolvimento sexual em período que corresponde à janela de exposição em humanos, além de avaliar os efeitos da exposição pré-natal à BM com ênfase nos desenvolvimentos sexual, cognitivo e somático de machos e fêmeas F1 e F2. Para o experimento neonatal, ratos machos e fêmeas (n=10/grupo) foram expostos por via subcutânea à solução NaCl 0,9 % (Controle) ou 0,1 mg/Kg de BM nos dias pós-natal (DPN) 1, 2 e 3. Além disso, para a exposição pré-natal, ratas prenhes (n=10/grupo) foram expostas à solução NaCl 0,9% (Controle) ou 0,1 mg/Kg de BM por via intramuscular nos dias gestacionais 12, 13, 18 e 19. No DPN 90, os ratos machos e fêmeas (F1) expostos in utero foram acasalados com animais não tratados para obtenção de F2 (prole de ratos machos) e F2’ (prole de ratos fêmeas). A exposição neonatal de ratos à BM reduziu o ganho de peso corpóreo em machos e fêmeas durante o tratamento e a qualidade espermática em machos, além de ter causado desregulação do ciclo estral e redução na concentração de LH em fêmeas na maturidade sexual. Nos ratos expostos in utero, houve redução do ganho de peso em F0 e do peso da prole F1. Além disso, a instalação da puberdade estava atrasada e o ciclo estral desregulado em fêmeas F1, assim como a qualidade espermática e o peso testicular em machos F1 estavam reduzidos. Houve atraso dos desenvolvimentos cognitivo e somático em F1, F2 e F2’. Nas proles F2 e F2’, houve redução do peso no dia do desmame e aumento da distância ano-genital em fêmeas F2’ no DPN 01. Conclui-se que a exposição pré-natal à BM causou disfunções nos desenvolvimentos cognitivo e somático em F1, F2 e F2’ e ambos os períodos de exposição alteraram a qualidade espermática, desregularam o ciclo estral e causaram programação do desenvolvimento reprodutivo e restrição do crescimento em machos e fêmeas F1. Portanto a exposição de ratos à BM no período neonatal, embora tenha efeitos menos evidentes sobre o sistema genital masculino e feminino, confirma resultados observados anteriormente após exposição pré-natal. Apesar da reconhecida importância da corticoterapia antenatal humana, os achados do presente estudo sinalizam e estimulam novos estudos a fim de minimizar possíveis efeitos adversos colaterais pós-natais.
Betamethasone (BM) is the drug of choice for antenatal corticosteroid therapy for women at risk of preterm delivery once it induces fetal lung maturation and enhances survival after birth. However, fetal programming and impaired reproductive function and development were reported by our group in F1 rats exposed to BM during the critical window of genital system development. Thus we aimed to investigate the effects of BM on sexual development in the neonatal period that corresponds to the exposure in humans and evaluate the effects of prenatal BM exposure, emphasizing the sexual, cognitive and somatic developments of male and female F1 and F2. Therefore male and female rats (n=10/group) were exposed subcutaneously to NaCl 0.9% solution (Control) or 0.1 mg/Kg BM at postnatal days (PND) 1, 2 and 3. For prenatal exposure, 20 pregnant rats (n=10/group) were exposed intramuscularly to NaCl 0.9% solution (Control) or 0.1 mg/kg BM at gestational days 12, 13, 18 and 19. At PND 90, F1 male and female rats exposed in utero were mated with untreated animals to obtain F2 (offspring of male rats) and F2’ (offspring of female rats). Neonatal exposure to BM decreased body weight gain in male and female rats. Also, the estrous cycle was deregulated and LH level was decreased in female rats. The sperm concentration in the caputcorpus of the epididymis was decreased, while the sperm transit time was increased in male rats as well as the sperm concentration in the cauda of the epididymis. Prenatal exposure to BM reduced body weight gain of F0 female rats and at birth of F1 offspring, decreased body weight at weaning of F2 and increased anogenital distance of F2’ female at PND01. Also, BM delayed puberty onset and deregulated the estrous cycle of F1 female rats. There were a decrease in sperm quality and testicular weight at sexual maturity of male rats. We also observed delayed physical and neurobehavioral development of F1, F2 and F2' male and female rats. Our results demonstrated that both neonatal and prenatal exposure to BM impaired body growth of male and female rats, impaired sperm quality and reproductive function and led to development programming, but only prenatal BM exposure led to dysfunctions in the cognitive and somatic developments in F1, F2 and F2’. Therefore, neonatal BM exposure corroborated results previously observed after prenatal exposure to this drug. Despite the recognized importance of human antenatal corticosteroid therapy, the findings of this study evidence and encourage further studies in order to minimize possible adverse postnatal effects.
Betamethasone (BM) is the drug of choice for antenatal corticosteroid therapy for women at risk of preterm delivery once it induces fetal lung maturation and enhances survival after birth. However, fetal programming and impaired reproductive function and development were reported by our group in F1 rats exposed to BM during the critical window of genital system development. Thus we aimed to investigate the effects of BM on sexual development in the neonatal period that corresponds to the exposure in humans and evaluate the effects of prenatal BM exposure, emphasizing the sexual, cognitive and somatic developments of male and female F1 and F2. Therefore male and female rats (n=10/group) were exposed subcutaneously to NaCl 0.9% solution (Control) or 0.1 mg/Kg BM at postnatal days (PND) 1, 2 and 3. For prenatal exposure, 20 pregnant rats (n=10/group) were exposed intramuscularly to NaCl 0.9% solution (Control) or 0.1 mg/kg BM at gestational days 12, 13, 18 and 19. At PND 90, F1 male and female rats exposed in utero were mated with untreated animals to obtain F2 (offspring of male rats) and F2’ (offspring of female rats). Neonatal exposure to BM decreased body weight gain in male and female rats. Also, the estrous cycle was deregulated and LH level was decreased in female rats. The sperm concentration in the caputcorpus of the epididymis was decreased, while the sperm transit time was increased in male rats as well as the sperm concentration in the cauda of the epididymis. Prenatal exposure to BM reduced body weight gain of F0 female rats and at birth of F1 offspring, decreased body weight at weaning of F2 and increased anogenital distance of F2’ female at PND01. Also, BM delayed puberty onset and deregulated the estrous cycle of F1 female rats. There were a decrease in sperm quality and testicular weight at sexual maturity of male rats. We also observed delayed physical and neurobehavioral development of F1, F2 and F2' male and female rats. Our results demonstrated that both neonatal and prenatal exposure to BM impaired body growth of male and female rats, impaired sperm quality and reproductive function and led to development programming, but only prenatal BM exposure led to dysfunctions in the cognitive and somatic developments in F1, F2 and F2’. Therefore, neonatal BM exposure corroborated results previously observed after prenatal exposure to this drug. Despite the recognized importance of human antenatal corticosteroid therapy, the findings of this study evidence and encourage further studies in order to minimize possible adverse postnatal effects.
Descrição
Palavras-chave
Betametasona, Programação fetal, Saúde reprodutiva, Desenvolvimento sexual