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: 7476286
• 负责人: Isaac I Wirgin
• 金额: $ 19.12万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476286
• 关键词: 1 year old; 2 year old; Address; Adolescent; Adult; Age; Antibodies; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Bile fluid; Binding; Biological Assay; Breeding; CYP1A1 gene; Chemicals; Chromium; Collaborations; Cytochromes; DNA; DNA Adducts; Dioxins; Dose; Embryo; End Point; Enzymes; Exhibits; Exons; Exposure to; Fishes; Frequencies; Gene Expression; Gene Expression Alteration; Genes; Genetic Enhancer Element; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Heavy Metals; Hepatic; High Prevalence; Induced Mutation; K-ras Oncogene; Laboratories; Laboratory Study; Larva; Lesion; Life; Ligand Binding; Liver neoplasms; Locales; Low Prevalence; Mediating; Messenger RNA; Metals; Modeling; Molecular; Mutate; Mutation; Mutation Spectra; Nuclear; Nucleotide Excision Repair; Nucleotide Excision Repair Inhibition; Pathway interactions; Pattern; Peptides; Polychlorinated Biphenyls; Population; Prevalence; Primary carcinoma of the liver cells; Process; Promoter Regions; Proteins; Proteomics; Reactive Oxygen Species; Research Personnel; Resistance; Resistance development; Rivers; Role; Staging; Structure; Tetrachlorodibenzodioxin; Time; Tissues; Toxic effect; Transactivation; Transfection; Variant; adduct; base; chromium hexavalent ion; in vitro Assay; in vivo; interest; novel; pollutant; programs; receptor; resistance mechanism; response; superfund site; tumor

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) 河口包含多氯联苯、TCDD 和重金属超级基金站点。大西洋 HR 中的 tomcod 会在组织中积累大量这些污染物，有时甚至达到创纪录的水平。 我们使用tomcod作为模型来评估这些污染物的生态影响并研究 其毒性的机制基础。整个 HR 部门的 Tomcod 都具有很强的耐环境能力 共面 PCB 和 TCDD（但不包括 PAH）在各种分子和生物体中的相关剂量 终点包括早期生命阶段毒性和芳烃受体 (AHR) 途径介导的基因 表达。本次更新申请的总体目标是进一步描述阻力的程度 HR tomcod 群体并描述其机制基础。虽然，曾经，tomcod 从 HR 表现出肝肿瘤患病率显着升高，PCB 在此过程中的作用是 从未从经验上解决过。在受控实验室研究中，我们将确定 tomcod 的后代是否来自 与敏感人群相比，HR 对肝肿瘤和相关癌前病变具有抵抗力 终点，例如癌前病变、K-ras 激活、ROS 修饰碱基、大容量 DMA 接触 PCB 和 PAH 后形成加合物。来自高度污染地区的鱼，例如超级基金地点， 通常同时暴露于芳香烃和金属污染物。化学分析表明 HR给的tomcod就是这样。然而，人们对它们在体内的相互作用作用知之甚少。我们将 研究同时暴露于 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，该基因在暴露于环境和 经过化学处理的鱼。将解决耐药性的机制基础。基因多态性将 被表征，并且它们的频率在 Tomcod 中的 AHR2、AHRR 和 ARNT1 处枚举，来自 HR 和 无抵抗力的人群。那些表现出显着等位基因差异的将在以下方面进行功能评估 定量配体结合、核转化和反式激活的测定。显示多个 AHR 将分离出存在于其他鱼类中的蛋白，并比较 HR 和 HR 之间的结构和表达。 敏感人群。将使用蛋白质组学来鉴定与 AHR 或 DRE 相关的新型蛋白质 方法及其在来自 HR 和易感人群的 tomcod 之间的表达比较。