AH RECEPTOR IN NON-MAMMALIAN SPECIES

AH受体是一种配体激活的转录因子，控制 细胞色素P4501A1(CYP1A1)在哺乳动物中的表达 介导2，3，7，8-四氯二苯并对苯二酚的大部分毒性作用. 二恶英(TCDD)和相关的平面卤代芳香烃。这个 这项研究的总体目标是表征结构， Ah受体的功能、调节和进化关系 在非哺乳动物物种中，尤其是鱼中。它的存在和性质 在某些分类类群中的ah受体可以决定 这些组中的动物对TCDD毒性的敏感性。信息 研究TCDD在非哺乳动物物种中的作用机制是必要的 对这些病毒的存在所构成的风险进行有意义的评估 环境中的化合物。通过学习《啊》学到的知识 在系统发育不同的物种中受体对 建立TCDD作用机制的基本属性和 用于验证非传统物种在毒理学中的使用。一个 系统发育学方法也可能加强我们对 Ah受体的基本意义，为其提供线索 原始的生理功能，其内源性配体的识别， 以及基因调控系统的进化。在拟议的研究中， 将确定鱼类中AH受体的分子特性， 并对几种配体结合分析方法进行比较和优化。 鱼的ah受体向其DNA结合形式的转化将是 以及它与二恶英反应元件的相互作用 将对鱼类细胞色素P1A1基因进行特征分析。宽广的耐温性 将被利用来解剖和分离 参与AH受体转化的分子事件。这个 将获得硬骨鱼和硬骨鱼的ah受体cDNA序列 使用聚合酶链式反应的弹簧鱼，以及 阿受体结构的进化保守性将被评估。 FISH AH受体序列将允许生产用于使用的探针 在阿受体调节和进化的研究中。系统发育学 将通过调查确定ah受体的分布 多样的脊椎动物和无脊椎动物物种的存在 受体及相关基因。更多的研究将确定细胞- 和组织特异性表达的ah受体在鱼类中，使用配体- 结合分析、信使RNA扩增和原位杂交 到鱼类特异的AH受体探针。阿的发育规律 受体的表达也将被确定。这些研究的结果 研究将使我们更好地理解 AH受体的意义及其在TCDD发病机制中的作用 毒性。

The Ah receptor is a ligand-activated transcription factor that controls the expression of cytochrome P4501A1 (CYP1A1) in mammals and is thought to mediate most of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) and related planar halogenated aromatic hydrocarbons. The overall objective of this research is to characterize the structure, function, regulation, and evolutionary relationships of the Ah receptor in non-mammalian species, particularly fish. The presence and properties of the Ah receptor in certain taxonomic groups could determine the susceptibility of animals in those groups to TCDD toxicity. Information on the mechanism of TCDD action in non-mammalian species is necessary for a meaningful assessment of the risk posed by the presence of these compounds in the environment. The knowledge gained by studying the Ah receptor in phylogenetically diverse species is important for establishing the fundamental properties of TCDD's mechanism of action and for validating the use of non-traditional species in toxicology. A phylogenetic approach may also enhance our understanding of the fundamental significance of the Ah receptor, providing clues to its original physiologic function, the identify of its "endogenous" ligand, and the evolution of gene regulatory systems. In the proposed studies, the molecular properties of the Ah receptor in fish will be determined, and several ligand-binding assays will be compared and optimized. Transformation of the fish Ah receptor to its DNA-binding form will be examined, and its interaction with dioxin-response elements flanking the fish CYP1A1 gene will be characterized. The broad temperature tolerance of poikilothermic vertebrates will be exploited to dissect and dissociate the molecular events involved in Ah receptor transformation. The sequences of Ah receptor cDNAs will be obtained for teleost and elasmobranch fish using the polymerase chain reaction, and the evolutionary conservation of Ah receptor structure will be evaluated. Fish Ah receptor sequences will permit the production of probes for use in studies of Ah receptor regulation and evolution. The phylogenetic distribution of the Ah receptor will be established by investigating diverse vertebrate and invertebrate species for the presence of the Ah receptor and related genes. Additional studies will determine the cell- and tissue-specific expression of the Ah receptor in fish, using ligand- binding assays, amplification of messenger RNA, and in situ hybridization to fish-specific Ah receptor probes. The developmental regulation of Ah receptor expression will also be determined. The results of these studies will provide a greater understanding of the fundamental significance of the Ah receptor and its role in the mechanism of TCDD toxicity.