Mechanisms of Resistance of Aquatic Vertebrate Populations to Mixtures

哈德逊河(HR)河口拥有多氯联苯、TCDD和重金属的超级基金站点。大西洋 来自HR的鳕鱼生物积累了这些污染物的高组织负担，有时达到创纪录的水平。 我们以鳕鱼为模型，评估这些污染物的生态影响，并研究 它们毒性的机械基础。来自HR各地的西鳕鱼对环境具有很强的抵抗力 在不同的分子和组织中，相应剂量的共面多氯联苯和TCDD，但不包括多环芳烃 包括生命早期毒性在内的终点与芳烃受体(AHR)途径介导的基因 表情。本次续签申请的总体目标是进一步描述抵抗的程度 并对其机制基础进行了研究。尽管，曾经有一段时间，来自 HR显示肝脏肿瘤的发生率显著升高，多氯联苯在这一过程中的作用是 从来没有经验性地解决过。在受控实验室研究中，我们将确定大马鱼的后代是否来自 与敏感人群相比，HR对肝肿瘤和相关的癌前病变具有抵抗力 端点，如癌前病变、K-ras激活、ROS修饰的碱基、笨重的DMA 暴露于多氯联苯和多环芳烃后的加合物。来自污染严重的地区的鱼，如超级基金网站， 通常同时暴露在芳香烃和金属污染物中。化学分析表明 这就是人力资源部的TomCod的情况。然而，人们对它们在体内的交互作用知之甚少。我们会 研究联合暴露于Gr VI对苯并[a]磷诱发的突变、DMA加合物和核苷酸的影响 K-ras癌基因的切除修复，它在环境暴露的和 经过化学处理的鱼。我们将讨论抵抗的机制基础。基因多态将会 被鉴定，并列举了它们在红鳕鱼AHR2、AHRR和ARNT1的频率 非抗性种群。那些表现出显著等位基因差异的基因将在 将量化配基结合、核转化和反式激活的分析。显示多个AHR 将存在于其他鱼类中，并将它们的结构和表达进行比较 敏感人群。将使用蛋白质组学来鉴定与AHR或DRE相关的新蛋白质 方法及其在HR种群和敏感种群中的表达比较。

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.