Biotransformation Gene-Environment Interactions in Coho Salmon Neurotoxicity

太平洋鲑鱼的数量在美国西部明显下降。尤其令人关切的是，鲑鱼接触某些杀虫剂和微量金属后，会出现亚致死性神经损伤。这些行为的影响包括捕食者检测和猎物选择的损失，改变生殖时间，以及失去归巢。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。抗胆碱酯酶农药也表现出类似于金属的神经行为功能障碍，肝脏生物转化酶亚型的表达可以影响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，生物化学和定量 神经行为学方法来评估肝脏和嗅觉生物转化途径在银鲑对神经毒性损伤的易感性中的作用。我们假设，第一阶段（如细胞色素P450，黄素单加氧酶）和第二阶段（谷胱甘肽S-转移酶/氧化防御）途径之间的平衡是一个关键的决定因素，coho鲑鱼，一个模型鲑鱼物种的生态相关的太平洋西北部的神经毒性损伤。我们的方法将是初步表征的高亲和力酶负责生物转化的毒死蜱和甲拌磷，两个有机磷，特别是 在鲑鱼伤害和指定ATSDR超级基金化学品的重要性。将鉴定在这些有机磷酸酯的脱烷基化和缀合中具有活性并防止氧化损伤的GST同种型。银鳕鱼肝细胞中的RNA沉默将用于评估保护免受毒死蜱损伤的关键鲑鱼生物转化基因。氧化应激在镉和铜诱导的嗅觉损伤中的作用将被建立，并且微阵列分析将与定量行为研究结合使用，以在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，如盐度驯化和共同暴露于金属对毒死蜱神经毒性的影响， 在体内的特点，以及居住在广盐性超基金走廊鲑鱼的影响， 将使用项目期间开发的强有力的分子和生物化学标志物评估神经毒性。预计这项研究的结果将显着扩展我们的理解的基因-环境相互作用在鲑鱼神经毒性的作用。

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.