Mechanisms of Resistance of Aquatic Vertebrate Populations to Mixtures

水生脊椎动物种群对混合物的抵抗机制

• 批准号: 7228676
• 负责人: Isaac I Wirgin
• 金额: $ 20万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228676
• 关键词: DNA damage; DNA repair; alleles; animal breeding; aquatic biology; aquatic organism; aromatic hydrocarbon receptor; binding sites; bioassay; dioxins; fish; free radical oxygen; genetic polymorphism; guanine nucleotide binding protein; halobiphenyl /halotriphenyl compound; hazardous substances; heavy metals; immunity; intermolecular interaction; ligands; liver neoplasms; protein isoforms; protein localization; proteomics; reporter genes; waste disposal; water environment

The Hudson River (HR) Estuary contains Superfund sites for PCBs, TCDD, and heavy metals. Atlantic tomcod from the HR bioaccumulate high tissue burdens of these contaminants, sometimes to record levels. We have used tomcod as a model to evaluate the ecological effects of these pollutants and to study the mechanistic bases of their toxicities. Tomcod from throughout the HR are highly resistant to environmentally relevant doses of coplanar PCBs and TCDD, but not PAHs, at a variety of molecular and organismic endpoints including early life stage toxicities and aryl hydrocarbon receptor (AHR) pathway-mediated gene expression. The overall objectives of this renewal application are to further describe the extent of resistance n the HR tomcod population and to characterize its mechanistic basis. Although, at one time, tomcod from the HR exhibited remarkably elevated prevalences of hepatic tumors, the role of PCBs in this process was never empirically addressed. In controlled laboratory studies, we will determine if tomcod offspring from the HR, compared to those from sensitive populations, are resistant to hepatic neoplasia and related preneoplastic endpoints such as preneoplastic lesions, K-ras activation, ROS modified bases, bulky DMA adducts after exposure to PCBs and PAHs. Fish from highly contaminated locales, such as Superfund sites, are usually co-exposed to aromatic hydrocarbon and metal contaminants. Chemical analyses indicate that this is the case for tomcod from the HR. Yet, little is known of their interactive effects in vivo. We will investigate the effects of co-exposure to Gr VI on B[a]P-induced mutations, DMA adducts, and nucleotide excision repair at the K-ras oncogene which is frequently mutated in environmentally-exposed and chemically-treated fishes. The mechanistic basis of resistance will be addressed. Genetic polymorphisms will be characterized and their frequencies enumerated at AHR2, AHRR, and ARNT1 in tomcod from the HR and non-resistant populations. Those which show significant allelic differences will be functionally evaluated in assays which will quantify ligand binding, nuclear transformation, and transactivation. Multiple AHRs shown to exist in other fishes will be isolated and their structure and expression compared between the HR and sensitive populations. Novel proteins associated with AHRs or DREs will be identified using a proteomics approach and their expression compared between tomcod from the HR and susceptible populations.

哈德逊河（HR）河口包含用于PCB，TCDD和重金属的超级基金站点。大西洋 来自人力资源生物积累的这些污染物的高组织负担有时，有时会记录水平。 我们已经使用tomcod作为模型来评估这些污染物的生态效应并研究 其毒性的机械基础。整个人力资源的tomcod对环境具有很高的抵抗力 在各种分子和有机体上，相关剂量的共面PCB和TCDD，而不是PAHS 终点，包括早期生命阶段毒性和芳基烃受体（AHR）途径介导的基因 表达。该更新应用的总体目标是进一步描述阻力的程度 n HR tomcod人群并表征其机械基础。虽然一次是从 人力资源表现出肝肿瘤患病率的升高，PCB在此过程中的作用是 从未经验解决。在对照实验室研究中，我们将确定是否来自 与敏感人群相比，人力资源对肝肿瘤具有抗性 终点，例如肿瘤性病变，K-RAS激活，ROS修饰碱，庞大的DMA 暴露于PCB和PAHS后的加合物。来自高度受污染的地区的鱼，例如超级基金地点， 通常共同暴露于芳族烃和金属污染物。化学分析表明 人力资源的Tomcod就是这种情况。然而，对它们在体内的互动效果知之甚少。我们将 研究共曝光对GR VI对B [A] P诱导的突变，DMA加合物和核苷酸的影响 K-Ras癌基因的切除修复，该维修经常在环境暴露和 化学处理的鱼类。电阻的机械基础将被解决。遗传多态性会 在HR中，在AHR2，AHRR和ARNT1上列举的频率和频率是从HR和 非抗性人群。那些显示出明显等位基因差异的人将在功能上评估 可以量化配体结合，核转化和反式激活的测定。显示多个AHR 将存在于其他鱼类中，并在人力资源和人力资源之间进行比较 敏感人群。将使用蛋白质组学确定与AHR或DRE相关的新型蛋白质 与人力资源和易感人群中的tomcod相比，接近及其表达。