Biotransformation Gene-Environment Interactions in Coho Salmon Neurotoxicity

银鲑鱼神经毒性中的生物转化基因-环境相互作用

• 批准号: 7089374
• 负责人: EVAN P GALLAGHER
• 金额: $ 37.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089374
• 关键词: RNA interference; biomarker; biotransformation; cadmium; copper; cytochrome P450; environmental toxicology; gene environment interaction; glutathione transferase; liver cells; liver metabolism; microarray technology; neurotoxicology; olfactions; organophosphorus insecticide; oxidative stress; oxygenases; pesticide biological effect; toxin metabolism; trout /salmon

Pacific salmon populations have declined markedly in the Western United States. Of particular concern is the sublethal neurological injury 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. The salmon olfactory system is a sensitive target for copper and cadmium-induced peripheral neurotoxicity, and metal-induced oxidative stress may underlie olfactory injury. Neurobehavioral dysfunction similar to that observed for metals has also been demonstrated for anticholinesterase pesticides, and the expression of hepatic biotransformation enzyme isoforms can influence susceptibility to pesticide neurotoxicity. The goal of this new Superfund project is to use molecular, biochemical, and quantitative neurobehaviorial approaches to evaluate the role of hepatic and olfactory biotransformation pathways in susceptibility of coho salmon to neurotoxic injury. We hypothesize that the balance among phase I (e.g. cytochrome P450s, flavin monooxygenases) and phase II (glutathione S-transferase/oxidative defense) pathways is a key determinant of neurotoxic injury in coho salmon, a model salmonid species of ecological relevance to the Pacific Northwest. Our approach will be to initially characterize the high-affinity enzymes responsible for biotransformation of chlorpyrifos and phorate, two organophosphates of particular importance in salmon injury and designated ATSDR Superfund chemicals. GST isoforms that are active in the dealkylation and conjugation of these organophosphates and that protect against oxidative injury will be identified. RNA silencing in coho hepatocytes will be used to evaluate key salmon biotransformation genes that protect against chlorpyrifos injury. The role of oxidative stress in cadmium and copper-induced olfactory injury will be established, and microarray analysis will be used in conjunction with quantitative behavioral studies to functionally link gene expression with metal-induced olfactory injury. Environmental scenarios such as effects of salinity acclimation and co-exposure to metals on chlorpyrifos neurotoxicity will be characterized in vivo, and the effects of residence in a euryhaline Superfund corridor on salmon neurotoxicity will be assessed using robust molecular and biochemical markers developed during the project. It is anticipated that the results of this study will significantly extend our understanding of the role of gene-environment interactions in salmon neurotoxicity.

美国西部的太平洋鲑鱼数量明显减少。尤其令人担忧的是，暴露在某些杀虫剂和痕量金属中的鲑鱼的亚致死性神经损伤。这些行为影响包括失去对捕食者的检测和猎物的选择，改变繁殖时机，以及失去归宿。鲑鱼嗅觉系统是铜和镉诱导的周围神经毒性的敏感靶点，金属诱导的氧化应激可能是嗅觉损伤的基础。在抗胆碱酯酶农药中也发现了类似于金属的神经行为障碍，肝脏生物转化酶亚型的表达可以影响对农药神经毒性的敏感性。这个新的超级基金项目的目标是使用分子、生化和定量 神经行为学方法评估肝脏和嗅觉生物转化通路在鲑鱼神经毒性损伤易感性中的作用。我们推测，I期(如细胞色素P450、黄素单加氧酶)和II期(谷胱甘肽S转移酶/氧化防御)通路之间的平衡是Coho鲑鱼神经毒性损伤的关键决定因素。Coho鲑鱼是太平洋西北部的一种模式鲑鱼。我们的方法将是初步表征负责毒死蜱和甲膦生物转化的高亲和力酶，这两种有机磷是特别的。 三文鱼伤害的重要性和指定的ATSDR超级基金化学品。将确定在这些有机磷的脱烷基化和结合中活跃并保护其免受氧化损伤的GST亚型。Coho肝细胞中的RNA沉默将被用来评估保护毒死蜱免受伤害的关键三文鱼生物转化基因。氧化应激在镉和铜诱导的嗅觉损伤中的作用将被确定，微阵列分析将与定量行为研究相结合，从功能上将基因表达与金属诱导的嗅觉损伤联系起来。环境情景，如盐度适应和共暴露于金属对毒死蜱神经毒性的影响将是 在活体中的特征，以及在泛盐碱超级基金走廊居住对鲑鱼的影响 神经毒性将使用在项目期间开发的强大的分子和生化标记物进行评估。预计这项研究的结果将大大扩展我们对基因-环境相互作用在鲑鱼神经毒性中的作用的理解。