Project 4: Biotransformation Gene-Environment Interactions in Coho Salmon

项目 4：银鲑鱼的生物转化基因-环境相互作用

基本信息

批准号：
8065489
负责人：
EVAN P GALLAGHER
金额：
$ 29.39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-20 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8065489
关键词：
Affect Antioxidants Behavior Behavioral Biological Markers CYP3A4 gene Cadmium Carbamates Cell Respiration Chemical Exposure Chemicals Chlorpyrifos Cloning Complementary DNA Copper Coupled Cytochromes Data Detection Deterioration Environmental Risk Factor Enzymes Exposure to Fishes Flavins Fresh Water Funding GTP-Binding Proteins Gene Targeting Genes Gills Goals Habitats Homing Homing Behavior Immunohistochemistry In Situ Hybridization Individual Injury Link Liver Maintenance Marines Mediating Metabolic Biotransformation Metabolism Metals Microarray Analysis Mixed Function Oxygenases Modeling Movement Nervous System Trauma Neuropathy Neurotoxins Olfactory Pathways Oncorhynchus kisutch Organ Organophosphates Oxidative Stress Peripheral Nervous System Pesticides Phase Play Pollution Population Populations at Risk Proteins Proteomics Receptor Signaling Recombinant Proteins Regulation Reproduction Role Salmon Salmonidae Signal Transduction Signal Transduction Pathway Site Smell Perception Superfund Surface System Time Tissues Toxic effect Trace metal United States Water base body system environmental chemical gene environment interaction imprint life history migration neurobehavioral neurotoxic neurotoxicity olfactory receptor pollutant protein expression reproductive research study residence superfund site waterborne

项目摘要

Pacific salmon populations have declined markedly in the Western United States. Of particular concern has been sublethal neurological injury occurring in salmon exposed to certain pesticides and trace metals. These behavioral impacts include loss of predator detection and prey selection, altered reproductive timing and loss of homing. These aforementioned neurobehavioral effects observed in individuals are now linked to population impacts. The salmon olfactory system is a sensitive target for the neurotoxicity of environmental chemicals, including metals and pesticides commonly found in Superfund sites. However, little is known about the mechanisms of chemical olfactory neurotoxicity in fish. Studies from our first funding cycle have produced important findings that will be explored in detail in our competitive renewal. Specifically, we know that: 1) the olfactory tissues of salmon are important site of chemical biotransformation, and in particular, cytochrome P4503A and flavin monooxygenases (FMO) appear to mediate tissue- and compound-specific differences in organophosphate biotransformation with potential impacts on neurotoxicity, 2) the olfactory injury by a model superfund organophosphate chemical (chlorpyrifos) and metal (copper) involves disruption of olfactory signal transduction pathways. However, copper primarily impacts G-protein coupled olfactory receptor signaling, likely through oxidative stress, whereas chlorpyrifos activates genes involved in the inhibition of olfactory signal transduction, and 3) transcriptional signatures can help us identify unique gene targets relevant to mixtures, as well differentiating metal- and organophosphate-driven affects. Based upon our findings, the objectives of the competing renewal are to: 1) use cDNA cloning, recombinant protein expression, microarray analysis and enzymatic approaches to determine the role of olfactory CYP3A and flavin monooxygenases in organophosphate neurotoxicity in salmon during movement from freshwater to saltwater, 2) use in situ hybridization and immunohistochemistry analyses coupled with behavioral studies to understand the role of oxidative stress in copper and cadmium-mediated olfactory injury, 3) use proteomics approaches to identify and discriminate important olfactory protein targets of copper and chlorpyrifos, 4) use a suite of olfactory biomarkers generated from the aforementioned studies to assess sublethal olfactory neurotoxicity in salmon migrating through Superfund sites.

美国西部的太平洋鲑鱼数量显着下降。特别值得关注的是接触某些农药和微量金属的鲑鱼发生亚致死性神经损伤。这些行为影响包括捕食者检测和猎物选择的丧失、繁殖时间的改变和丧失归巢。在个体中观察到的上述神经行为效应现在与人口影响。鲑鱼嗅觉系统是环境神经毒性的敏感目标化学品，包括超级基金站点中常见的金属和农药。然而，鲜为人知关于鱼类化学嗅觉神经毒性的机制。我们第一个资助周期的研究表明得出了重要的发现，我们将在我们的竞争性更新中详细探讨这些发现。具体来说，我们知道认为： 1) 鲑鱼的嗅觉组织是化学生物转化的重要场所，特别是，细胞色素 P4503A 和黄素单加氧酶 (FMO) 似乎介导组织和化合物特异性有机磷生物转化的差异对神经毒性的潜在影响，2) 嗅觉模型超级基金有机磷化学品（毒死蜱）和金属（铜）造成的损伤涉及破坏嗅觉信号转导途径。然而，铜主要影响 G 蛋白偶联的嗅觉受体信号传导，可能是通过氧化应激，而毒死蜱则激活参与相关基因嗅觉信号转导的抑制，以及3）转录特征可以帮助我们识别独特的基因与混合物相关的目标，以及区分金属和有机磷酸盐驱动的影响。基于我们的发现，竞争性更新的目标是：1）利用cDNA克隆、重组蛋白表达、微阵列分析和酶法来确定嗅觉 CYP3A 和黄素单加氧酶对鲑鱼从淡水到淡水的迁移过程中有机磷神经毒性的影响盐水，2) 使用原位杂交和免疫组织化学分析以及行为研究了解氧化应激在铜和镉介导的嗅觉损伤中的作用，3) 使用蛋白质组学识别和区分铜和毒死蜱重要嗅觉蛋白靶标的方法，4) 使用由上述研究产生的一套嗅觉生物标志物，用于评估亚致死嗅觉通过超级基金地点迁徙的鲑鱼的神经毒性。