RESUMO
Activated charcoal (AC) is a potential candidate antidote against dioxins. However, it is difficult to take AC as a supplement on a daily basis, because its long-term ingestion causes side effects such as constipation and deficiency of fat-soluble essential nutrients and hypocholesterolemia. Alginate-coated AC, termed Health Carbon (HC), was developed to decrease the side effects of AC, but its pharmacological effects, including side effects, remains unclear. Here, we show that HC enhanced fecal excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and decreased some side effects of unmodified AC, such as hypocholesterolemia, in male mice. Basal diet mixed with HC or unmodified AC at various concentrations was fed to mice for 16 days following a single intraperitoneal administration of [3H]TCDD. Both HC and unmodified AC at 3% or more significantly increased fecal excretion of [3H]TCDD in comparison with the control basal diet. Consistent with this, [3H]TCDD radioactivity in the liver-a major TCDD storage organ-was markedly decreased by HC at concentrations of 3% and 10%. In an examination of potential side effects, unmodified AC at 10% or more caused significant body weight reduction and at 20% caused significant hypocholesterolemia. In contrast, HC caused weight gain reduction only at a concentration of 20%, and there was no evidence of hypocholesterolemia at any dietary HC concentration. HC not only retains the ability of AC to enhance fecal excretion of TCDD but also reduces some of the side effects of AC.
Assuntos
Alginatos , Antídotos/efeitos adversos , Antídotos/farmacologia , Carvão Vegetal/efeitos adversos , Carvão Vegetal/farmacologia , Fezes , Dibenzodioxinas Policloradas/metabolismo , Administração Oral , Alginatos/administração & dosagem , Animais , Antídotos/administração & dosagem , Carvão Vegetal/administração & dosagem , Colesterol/sangue , Constipação Intestinal/induzido quimicamente , Masculino , Camundongos Endogâmicos , Redução de PesoRESUMO
Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development.
Assuntos
Etanol/efeitos adversos , Desenvolvimento Fetal/efeitos dos fármacos , Troca Materno-Fetal , Veículos Farmacêuticos/efeitos adversos , Óleos de Plantas/efeitos adversos , Desenvolvimento Sexual/efeitos dos fármacos , Animais , Óleo de Milho/administração & dosagem , Óleo de Milho/efeitos adversos , Etanol/administração & dosagem , Feminino , Peso Fetal/efeitos dos fármacos , Injeções Subcutâneas , Masculino , Camundongos Endogâmicos ICR , Veículos Farmacêuticos/administração & dosagem , Placentação/efeitos dos fármacos , Óleos de Plantas/administração & dosagem , Gravidez , Distribuição Aleatória , Reprodutibilidade dos Testes , Óleo de Gergelim/administração & dosagem , Óleo de Gergelim/efeitos adversos , Caracteres Sexuais , Processos de Determinação Sexual/efeitos dos fármacos , Testes de Toxicidade/métodos , Anormalidades Urogenitais/induzido quimicamente , Anormalidades Urogenitais/embriologia , Anormalidades Urogenitais/patologiaRESUMO
Retinoid X receptor (RXR) is a nuclear receptor that plays important and multiple roles in mammalian development and homeostasis. We previously reported that, in human choriocarcinoma cells, tributyltin chloride and triphenyltin hydroxide, which are typical environmental contaminants and cause masculinization in female mollusks, are potent stimulators of human chorionic gonadotropin production and aromatase activity, which play key endocrine functions in maintaining pregnancy and fetal development. However, the molecular mechanism through which these compounds stimulate these endocrine functions remains unclear. Our current study shows that trialkyltin compounds, including tributyltin chloride and triphenyltin hydroxide, function as RXR agonists. Trialkyltins directly bind to the ligand-binding domain of RXR with high affinity and function as transcriptional activators. Unlike the natural RXR ligand, 9-cis-retinoic acid, the activity of trialkyltins is RXR specific and does not activate the retinoic acid receptor pathway. In addition, trialkyltins activate RXR to stimulate the expression of a luciferase reporter gene containing the human placental promoter I.1 sequence of aromatase, suggesting that trialkyltins stimulate human placental endocrine functions through RXR-dependent signaling pathways. Therefore, our results suggest that activation of RXR may be a novel mechanism by which trialkyltins alter human endocrine functions.