ARYL HYDROCARBON SIGNAL TRANSDUCTION MECHANISMS IN FISH

鱼类中芳基烃信号转导机制

• 批准号: 6043465
• 负责人: WADE H POWELL
• 金额: $ 3.84万
• 依托单位: WOODS HOLE OCEANOGRAPHIC INSTITUTION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6043465
• 关键词: aromatic hydrocarbon receptor; biological signal transduction; cycloalkene; molecular cloning; protein structure function; trout /salmon

The overall objective of this project is to understand the molecular mechanisms of the toxic effects of dioxin and other halogenated aromatic hydrocarbons (HAH) in fish, using the estuarine teleost Fundulus heteroclitus as a model system. These compounds are common pollutants which result from many manufacturing processes. Their effects, including tumor promotion, teratogenesis, immunosuppression, and wasting, are mediated through an intracellular receptor. Although the basic scheme of HAH signal transduction is thought to be conserved between vertebrate species, the wide interspecific range of HAH toxicity, the large variation in molecular mass of HAH receptors (AhR) in different species, and the recent discovery of multiple forms of AhR in F. heteroclitus suggest that key differences may exist Specific aims of this project are (1) to clone the aryl hydrocarbon receptor nuclear translocator (ARNT) gene or genes in this species, (2) to characterize interactions between ARNT(s), the multiple AhR forms, and their target DNA sequences, and (3) to identify tissue specific patterns of expression of AhR and ARNT genes which may govern their physiological roles. The study of HAH signal transduction in fish is important for the validation of fish as model systems for in vivo toxicological testing of compounds posing potential human hazards. Knowledge of the molecular mechanisms governing the metabolism and accumulation of HAH compounds in fish will also have important implications for the assessment of the safety of fish consumption by humans and the use of fish as biomarkers for pollutant exposure.

本项目的总体目标是了解分子 二恶英和其他卤代芳烃的毒性作用机理 碳氢化合物（HAH）在鱼，使用河口硬骨鱼底 heteroclitus作为一个模型系统。这些化合物是常见的污染物 这是由许多制造工艺造成的。其影响，包括 肿瘤促进、致畸、免疫抑制和消耗， 通过细胞内受体介导。虽然基本方案 HAH信号转导被认为是脊椎动物之间保守的 物种，广泛的种间范围的HAH毒性， 不同物种中HAH受体（AhR）分子量的变化， 以及最近在F.异口 这表明可能存在关键差异， (1)克隆芳香烃受体核转位蛋白（ARNT） 基因或基因在这个物种，（2）表征之间的相互作用 ARNT、多种AhR形式及其靶DNA序列，以及（3） 鉴定AhR和ARNT基因表达的组织特异性模式 这可能决定了它们的生理作用。HAH信号的研究 鱼类的转导对于验证鱼类作为模型是重要的 用于对可能造成毒性的化合物进行体内毒理学测试的系统 人类危害。关于控制这些蛋白质的分子机制的知识， 鱼体内的HAH化合物的代谢和积累也将 对鱼类安全评估的重要影响 人类消费和使用鱼类作为污染物生物标志物 exposure.