Role of two AHRs in dioxin sensitivity & resistance

两个 AHR 在二恶英敏感性中的作用

• 批准号: 6578800
• 负责人: MARK HAHN
• 金额: $ 13.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578800
• 关键词: aromatic hydrocarbon receptor; biomarker; dioxins; environmental exposure; environmental toxicology; fish; gene environment interaction; genetic susceptibility; hazardous substances; receptor expression; water pollution; zebrafish

The overall objective of the basic research proposed here is to understand mechanisms underlying differential sensitivity to the developmental toxicity of dioxins. We will address this objective by elucidating the differences in expression and functional characteristics of two distinct aryl hydrocarbon receptor (AHR1 and AHR2) and an AHR repressor during development using a fish models of dioxin sensitivity and resistance. In the previous grant period, we characterized a PHAH-resistant population of the estuarine teleost Fundulus heteroclitus and New Bedford Harbor, a Superfund site. We showed that these fish were approximately 15-fold less sensitive to TCDD and that this diminished sensitivity was heritable We also identified two distinct AHRs in this species, including a novel AHR form (AHR2) that has been identified in several other species of fish. The proposed research seeks to understand the role of these two AHRs, and related proteins, in differential PHAH sensitivity in this model of dioxin resistance Elucidating the molecular mechanisms underlying such innate or acquired resistance is important for understanding the response of animals to chronic PHAH exposure and identifying molecular markers of susceptibility associated with increased risk in populations and subpopulations of animals, including humans. The central hypothesis to be tested is that alterations in the expression and/or function of AHR1, AHR2, and/or AHRR underlie differential dioxin sensitivity. This hypothesis will be tested primarily in Fundulus, with parallel studies in zebrafish The studies will focus on developmental toxicity of TCDD, which is among the most sensitive effects of this compound in vertebrates. The specific aims of the project are: 1. To measure the developmental expression of AHR1 and AHR2 in embryos and larvae of dioxin sensitive and dioxin resistant fundulus and zebrafish. 2. To determine the effect of TCDD treatment of AHR1 and AHR2 expression in Fundulus and zebrafish embryos. 3. To determine the ligand-binding specificity of Fundulus AHR1 and AHR2. 4. To determine if Fundulus and zebrafish express a homolog (ortholog) of the AHR repressor (AHRR) recently cloned from mice. 5. To determine the DNA- binding specificity of Fundulus AHR1 and AHR2. 6. To assess functional interactions among AHR1, AHR2, and AhRR.

这里提出的基础研究的总体目标是了解对二恶英发育毒性的不同敏感性的机制。我们将通过使用鱼类二恶英敏感性和抗性模型，阐明两种不同的芳烃受体（AHR1和AHR2）和AHR抑制因子在发育过程中的表达和功能特征差异来解决这一目标。在之前的拨款期间，我们对河口硬骨鱼Fundulus heteroclitus和新贝德福德港（一个超级基金站点）的pha抗性种群进行了表征。我们发现这些鱼对TCDD的敏感性降低了大约15倍，并且这种降低的敏感性是可遗传的。我们还在该物种中发现了两种不同的AHR，包括一种在其他几种鱼类中发现的新型AHR形式（AHR2）。该研究旨在了解这两种ahr和相关蛋白在二恶英耐药模型中phh敏感性差异中的作用，阐明这种先天或获得性耐药的分子机制对于理解动物对慢性phh暴露的反应以及识别与动物种群和亚种群（包括人类）风险增加相关的易感性分子标记非常重要。待验证的中心假设是AHR1、AHR2和/或AHRR表达和/或功能的改变是二恶英敏感性差异的基础。这一假设将主要在Fundulus进行测试，同时在斑马鱼中进行平行研究。研究将重点关注TCDD的发育毒性，这是该化合物对脊椎动物最敏感的影响之一。该项目的具体目标是：1。测定二恶英敏感和抗性底斑鱼和斑马鱼胚胎和幼虫中AHR1和AHR2的发育表达。2. 探讨TCDD对斑马鱼和眼底胚胎中AHR1和AHR2表达的影响。3. 确定眼底AHR1和AHR2的配体结合特异性。4. 确定眼底和斑马鱼是否表达最近从小鼠克隆的AHR抑制因子（AHRR）的同源物（同源物）。5. 目的：测定眼底AHR1和AHR2的DNA结合特异性。6. 评估AHR1、AHR2和AhRR之间的功能相互作用。