AH RECEPTOR IN NONMAMMALIAN SPECIES

Ah受体是一种配体激活的转录因子， 细胞色素P4501 A1（CYP 1A 1）在哺乳动物中的表达， 介导2，3，7，8-四氯二苯并-对- 二恶英（TCDD）和相关的平面卤代芳烃。 的 本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，特别是鱼类。 存在和性质 在某些分类群体中，Ah受体的表达可以决定 这些群体中的动物对TCDD毒性的敏感性。 信息 TCDD在非哺乳动物物种中的作用机制是必要的， 对这些物质的存在所构成的风险进行有意义的评估 环境中的化合物。 学习《啊 受体在遗传多样性物种是重要的， 建立TCDD作用机制的基本特性， 用于验证非传统物种在毒理学中的使用。 一 系统发育的方法也可以提高我们对 Ah受体的根本意义，提供线索， 原始生理功能，其“内源性”配体的鉴定， 以及基因调控系统的进化。 在拟议的研究中， 将确定鱼中Ah受体的分子特性， 并将比较和优化几种配体结合测定法。 鱼Ah受体向其DNA结合形式的转化将是 研究，及其与二恶英反应元件侧翼的相互作用， 鱼CYP 1A 1基因将被表征。 广泛的温度耐受性 将被用来解剖和分离 参与Ah受体转化的分子事件。 的 将获得硬骨鱼的Ah受体cDNA序列， 板鳃类鱼类使用聚合酶链反应， 将评价Ah受体结构的进化保守性。 鱼Ah受体序列将允许生产探针用于 在Ah受体调节和进化的研究中。 系统发育 将通过研究确定Ah受体的分布 不同的脊椎动物和无脊椎动物物种的存在啊 受体及相关基因。 进一步的研究将确定细胞- 和Ah受体在鱼中的组织特异性表达，使用配体- 结合分析、信使RNA扩增和原位杂交 鱼类特异性Ah受体探针。 Ah的发育规律 还将测定受体表达。 的结果予以 研究将提供一个更好的理解的基本 Ah受体的意义及其在TCDD作用机制中的作用 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.