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和重金属的超级基金站点。大西洋