RESUMO
Abstract Background: Thyroid hormone deficiency during fetal life could affect the cardiac function in later life. The mechanism underlying this action in fetal hypothyroidism (FH) in rats has not been elucidated thus far. Objective: The aim of this study is to evaluation the effect of FH on cardiac function in male rats and to determine the contribution of α-myosin heavy chain (MHC) and β-MHC isoforms. Methods: Six pregnant female rats were randomly divided into two groups: The hypothyroid group received water containing 6-propyl-2-thiouracil during gestation and the controls consumed tap water. The offspring of the rats were tested in adulthood. Hearts from the FH and control rats were isolated and perfused with langendroff setup for measuring hemodynamic parameters; also, the heart mRNA expressions of α- MHC and β-MHC were measured by qPCR. Results: Baseline LVDP (74.0 ± 3.1 vs. 92.5 ± 3.2 mmHg, p < 0.05) and heart rate (217 ± 11 vs. 273 ± 6 beat/min, p < 0.05) were lower in the FH rats than controls. Also, these results showed the same significance in ±dp/dt. In the FH rats, β-MHC expression was higher (201%) and α- MHC expression was lower (47%) than control. Conclusion: Thyroid hormone deficiency during fetal life could attenuate normal cardiac functions in adult rats, an effect at least in part due to the increased expression of β-MHC to α- MHC ratio in the heart.
Resumo Fundamento: Deficiência de hormônio da tireoide durante vida fetal pode afetar a função cardíaca no futuro. O mecanismo subjacente dessa ação em hipotireoidismo fetal (HF) em ratos ainda não tem explicação. Objetivo: O objetivo desse estudo é avaliar o efeito de HF na função cardíaca em ratos macho e determinar a contribuição da α-miosina de cadeia pesada (α-MCP) e de isoformas β-MCP. Métodos: Seis ratos fêmea gestantes foram aleatoriamente divididas em dois grupos. O grupo do hipotireoidismo recebeu água contendo 6-propil-2-tiouracil durante a gestação, e os ratos no grupo de controle receberam água de torneira. Os filhotes dos ratos foram testados quando atingiram idade adulta. O coração dos ratos HF e controle foram isolados e submetidos a perfusão pelo método de Langendorff para medição de parâmetros hemodinâmicos. Também foram medidas as expressões de mRNA do coração de α-MCP e β-MCP por qPCR. Resultados: PVED de base (74,0 ± 3,1 vs. 92,5 ± 3,2 mmHg, p < 0,05) e pressão arterial (217 ± 11 vs. 273 ± 6 batidas/min, p < 0,05) mostraram-se mais baixas em ratos HF do que em ratos controle. Além disso, esses resultados mostraram a mesma significância em ±dp/dt. Em ratos HF, a expressão de β-MCP foi mais alta (201%) e a de α-MCP foi mais baixa (47%) do que em ratos controle. Conclusão: Deficiência de hormônio da tireoide durante a vida fetal pode enfraquecer funções cardíacas normais em ratos adultos, efeito devido em parte à expressão aumentada de β-MCP em relação a α-MCP no coração.
Assuntos
Animais , Masculino , Feminino , Gravidez , Peso Corporal/efeitos dos fármacos , Cadeias Pesadas de Miosina/metabolismo , Hipotireoidismo Congênito/metabolismo , Miocárdio/metabolismo , Propiltiouracila , Antitireóideos , Tiroxina/sangue , Tri-Iodotironina/sangue , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Wistar , Pressão Ventricular , DNA Complementar/metabolismo , Hipotireoidismo Congênito/induzido quimicamente , Hipotireoidismo Congênito/sangue , Modelos Animais de Doenças , Frequência CardíacaRESUMO
BACKGROUND: Thyroid hormone deficiency during fetal life could affect the cardiac function in later life. The mechanism underlying this action in fetal hypothyroidism (FH) in rats has not been elucidated thus far. OBJECTIVE: The aim of this study is to evaluation the effect of FH on cardiac function in male rats and to determine the contribution of α-myosin heavy chain (MHC) and ß-MHC isoforms. METHODS: Six pregnant female rats were randomly divided into two groups: The hypothyroid group received water containing 6-propyl-2-thiouracil during gestation and the controls consumed tap water. The offspring of the rats were tested in adulthood. Hearts from the FH and control rats were isolated and perfused with langendroff setup for measuring hemodynamic parameters; also, the heart mRNA expressions of α- MHC and ß-MHC were measured by qPCR. RESULTS: Baseline LVDP (74.0 ± 3.1 vs. 92.5 ± 3.2 mmHg, p < 0.05) and heart rate (217 ± 11 vs. 273 ± 6 beat/min, p < 0.05) were lower in the FH rats than controls. Also, these results showed the same significance in ±dp/dt. In the FH rats, ß-MHC expression was higher (201%) and α- MHC expression was lower (47%) than control. CONCLUSION: Thyroid hormone deficiency during fetal life could attenuate normal cardiac functions in adult rats, an effect at least in part due to the increased expression of ß-MHC to α- MHC ratio in the heart.
Assuntos
Peso Corporal/efeitos dos fármacos , Hipotireoidismo Congênito/metabolismo , Miocárdio/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Animais , Antitireóideos , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/induzido quimicamente , DNA Complementar/metabolismo , Modelos Animais de Doenças , Feminino , Frequência Cardíaca , Masculino , Gravidez , Propiltiouracila , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos Wistar , Tiroxina/sangue , Tri-Iodotironina/sangue , Pressão VentricularRESUMO
Developmental thyroid hormone (TH) deficiency leads to mental retardation and neurological deficits in humans. In this study, congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water during gestation and suckling period. This treatment induced hyperphosphorylation of neurofilaments, the neuronal intermediate filament (IF) proteins, of heavy, medium and low molecular weight (NF-H, NF-M and NF-L, respectively) without altering the phosphorylation level of astrocyte IF proteins, glial fibrillary acidic protein (GFAP) and vimentin in cerebral cortex of rats. NF-H was hyperphosphorylated on KSP repeats in the carboxy-terminal tail domain. Furthermore, the immunocontent of GFAP and NF subunits was down-regulated, while vimentin was unaltered both in tissue homogenate and in cytoskeletal fraction of hypothyroid animals. Moreover, we verified the immunocontent of astrocyte glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) as well as activation of mitogen-activated protein kinases (MAPKs) in hypothyroid rats. Results showed that hypothyroidism is associated with decreased GLAST and GLT-1 immunocontent. Additionally, we demonstrated increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation without altering Jun N-terminal kinase (JNK) and p38(MAPK) phosphorylation. However, total JNK levels were down-regulated. Taken together, these results suggest that the thyroid status could modulate the integrity of neuronal cytoskeleton acting on the endogenous NF-associated phosphorylating system and that such effect could be related to glutamate-induced excitotoxicity, as well as ERK1/2 and JNK modulation. These events could be somehow related to the neurological dysfunction described in hypothyroidism.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Hipotireoidismo Congênito/metabolismo , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Filamentos Intermediários/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Córtex Cerebral/metabolismo , Hipotireoidismo Congênito/induzido quimicamente , Hipotireoidismo Congênito/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas In Vitro , Masculino , Fosfatos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Propiltiouracila , Ligação Proteica/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos WistarRESUMO
Congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water from day 9 of gestation, and continually up to postnatal day 15. Structural alterations observed by light microscopy of seminiferous tubules and by transmission electron microscopy of Sertoli cells of treated animals were consistent with hypothyroid condition. Hypothyroidism was also associated with high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 levels. Furthermore, the phosphorylation and the immunoreactivity of cytoskeletal-associated vimentin were increased without altering vimentin expression, suggesting an accumulation of insoluble and phosphorylated vimentin. These alterations in intermediate filament dynamics could result in loss of Sertoli cell cytoskeletal integrity and be somewhat related to the deleterious effects of hypothyroidism in testis. In addition, the mitochondrial alterations observed could also be related to defective cytoskeletal dynamics implying in cell damage. Moreover, we observed decreased oxygen consumption and unaltered lipid peroxidation in hypothyroid testis. However, we demonstrated decreased enzymatic and non-enzymatic antioxidant defenses, supporting an increased mitochondrial reactive oxygen species (ROS) generation, contributing to biochemical changes in hypothyroid testis. In addition, the changes in the testis histoarchitecture could be ascribed to cytoskeletal alterations, decreased antioxidant defenses, and increased ROS generation, leading to oxidative stress in the organ.
Assuntos
Antioxidantes/metabolismo , Hipotireoidismo Congênito/metabolismo , Propiltiouracila , Testículo/metabolismo , Vimentina/metabolismo , Animais , Hipotireoidismo Congênito/induzido quimicamente , Hipotireoidismo Congênito/patologia , Citoesqueleto/metabolismo , Peroxidação de Lipídeos , Masculino , Mitocôndrias/metabolismo , Consumo de Oxigênio , Fosforilação , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Túbulos Seminíferos/metabolismo , Túbulos Seminíferos/patologia , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Testículo/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
INTRODUCTION: Amiodarone (AMD) is an antiarrhythmic agent which contains 37% of iodine. It can reach the fetus by transplacental passage and induce transient congenital hypothyroidism (TCH). We report two cases of TCH caused by gestational exposure to AMD, detected by the Newborn Screening Program for Congenital Hypothyroidism of the State of Paraná-Brazil. CLINICAL CASE 1 (C1): Neonatal TSH value was 78.2 mU/L (normal<15 mU/L). AMD had been given to the mother during pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests. Levothyroxin (L-T4) (50 microg/day) was started on the first visit, on the 14th day of life (dl). CLINICAL CASE 2 (C2): Neonatal TSH value was 134.0 mU/L. AMD had been given to the mother in the third trimester of pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests: L-T4 (50 microg/day) was started on the first visit, with 13 dl. FOLLOW-UP: TSH and T4 normalized on 51 dl (C1) and 36 dl (C2); L-T4 could be diminished gradually and stopped within 16 months (C1) and 10 months (C2). They were followed-up until 22 months (C1) and 16 months (C2) with normal thyroid function tests. Their growth and mental development, evaluated by the Cognitive Adaptive Test/Clinical Linguistic & Auditory Milestone Scale (CAT/CLAMS test), were normal. CONCLUSION: Evaluation of thyroid function and mental development should be performed if AMD is used during pregnancy. Treatment of TCH must be started as soon as the diagnosis is made.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Transtornos Cognitivos/etiologia , Hipotireoidismo Congênito/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Hipotireoidismo Congênito/psicologia , Feminino , Humanos , Recém-Nascido , Inteligência , Gravidez , Testes de Função Tireóidea , Glândula Tireoide/efeitos dos fármacosRESUMO
INTRODUÇÃO: A amiodarona (AMD) é uma droga antiarrítmica que contém 37 por cento de iodo. A AMD pode alcançar o feto por via transplacentária e causar hipotireoidismo congênito (HC) ou transitório (HCT). Relatamos dois casos de HCT em virtude de exposição gestacional à AMD, detectados pelo programa de triagem neonatal para HC no Estado do Paraná, Brasil. CASO CLÍNICO 1 (C1): TSH neonatal 78,2 mU/L (normal < 15 mU/L). A AMD foi utilizada durante toda a gestação em virtude de arritmia materna. As dosagens séricas iniciais confirmaram o HC; e na primeira consulta [aos 14 dias de vida (dv)], foi iniciada levotiroxina (L-T4), 50 µg/dia. CASO CLÍNICO 2 (C2): TSH neonatal 134 mU/L. A AMD foi utilizada no último trimestre da gestação em virtude de arritmia materna. As dosagens séricas iniciais confirmaram o HC; aos 13 dv, foi iniciada L-T4 50 µg/dia. ACOMPANHAMENTO: TSH e T4 estavam normais aos 51 dv (C1) e aos 36 dv (C2) sendo então gradativamente reduzida a dose da medicação e suspensa aos 16 meses (C1) e aos dez meses (C2). As pacientes foram acompanhadas até 22 meses (C1) e 16 meses (C2) com testes de função tireoidiana normais. O crescimento e o desenvolvimento neuropsicomotor (DNPM), avaliados pelo teste CAT/CLAMS, eram normais. CONCLUSÃO: As avaliações da função tireoidiana e do DNPM são necessários quando a AMD é utilizada na gestação. O tratamento do HCT deve ser instituído tão logo o diagnóstico seja realizado.
INTRODUCTION: Amiodarone (AMD) is an antiarrhythmic agent which contains 37 percent of iodine. It can reach the fetus by transplacental passage and induce transient congenital hypothyroidism (TCH). We report two cases of TCH caused by gestational exposure to AMD, detected by the Newborn Screening Program for Congenital Hypothyroidism of the State of Paraná - Brazil. CLINICAL CASE 1 (C1): Neonatal TSH value was 78,2mU/L (normal < 15 mU/L). AMD had been given to the mother during pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests. Levothyroxin (L-T4) (50µg/day) was started on the first visit, on the 14th day of life (dl). CLINICAL CASE 2 (C2): Neonatal TSH value was 134,0 mU/L. AMD had been given to the mother in the third trimester of pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests: L-T4 (50µg/day) was started on the first visit, with 13 dl. FOLLOW-UP: TSH and T4 normalized on 51 dl (C1) and 36 dl (C2); L-T4 could be diminished gradually and stopped within 16 months (C1) and 10 months (C2). They were followed-up until 22 months (C1) and 16 months (C2) with normal thyroid function tests. Their growth and mental development, evaluated by the Cognitive Adaptive Test/Clinical Linguistic & Auditory Milestone Scale (CAT/CLAMS test), were normal. CONCLUSION: Evaluation of thyroid function and mental development should be performed if AMD is used during pregnancy. Treatment of TCH must be started as soon as the diagnosis is made.
Assuntos
Feminino , Humanos , Recém-Nascido , Gravidez , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Transtornos Cognitivos/etiologia , Hipotireoidismo Congênito/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Hipotireoidismo Congênito/psicologia , Inteligência , Testes de Função Tireóidea , Glândula Tireoide/efeitos dos fármacosRESUMO
The aim of this study was to investigate the potential relationship between hypothyroidism and delta-aminolevulinate dehydratase (delta-ALA-D) activity in rat blood and liver. Experimental hypothyroidism was induced in weanling rats by exposing their mothers to propylthiouracil (PTU) diluted in tap water (0.05% w/ v), ad libitum, during the lactational period (PTU group). Control (euthyroid) group included weanling rats whose mothers received just tap water, ad libitum, during the lactational period. Reverted-hypothyroid group (PTU + 3,3',5-triiodo-L-thyronine [T(3)]) included weanling rats whose mothers were exposed to PTU similarly to those in the hypothyroid group, but pups received daily subcutaneous injections of T(3) (20 microg/kg, from Postnatal Days 2-20). After the treatment, serum T(3) levels were drastically decreased (around 70%) in the PTU group, and this phenomenon was almost reverted by exogenous T(3). PTU decreased blood delta-ALA-D activity by 75%, and T(3) treatment prevented such phenomena. Erythrocytes and hemoglobin levels were increased by 10% in PTU-treated animals and higher increments (around 25%) were observed in these parameters when exogenous T(3) was coadministered. Dithiothreitol did not change blood delta-ALA-D activity of PTU-exposed animals when present in the reaction medium, suggesting no involvement of the enzyme's essential thiol groups in PTU-induced delta-ALA-D inhibition. PTU did not affect blood delta-ALA-D activity in vitro. These results are the first to show a correlation between hypothyroidism and decreased delta-ALA-D activity and point to this enzyme as a potential molecule involved with hypothyroidism-related hematological changes.