GABAERGIC INSECTICIDE TOXICOLOGY

伽巴能杀虫剂毒理学

• 批准号: 6329456
• 负责人: JOHN E CASIDA
• 金额: $ 22.85万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329456
• 关键词: Drosophilidae; GABA receptor; animal tissue; binding sites; brain mapping; chemical structure function; chloride channels; chlorohydrocarbon insecticide; environmental toxicology; insecticide biological effect; ion channel blocker; laboratory mouse; laboratory rat; neurotoxins; photochemistry; protein localization; radiotracer; receptor binding; tissue /cell culture; toxicant screening

The long-term objective is to define the fundamental basis for the selective toxicity of insecticides acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. This is the target of major neurotoxic insecticides acting as both blockers and activators of the GABA-gated chloride channel. More than 5,000,000,000 pounds of these channel blockers have been used for pest control in the past 50 years and they range in chlorine content from 52-73%. The major channel blockers used at present, representing 6% of the insecticide market, are endosulfan and lindane and this market share will increase with expanded use of the newly-commercialized polyhalogenated fipronil. The activators such as avermectin and moxidectin are also used in ever increasing quantities as insecticides and anthelmintics. More specifically, the goal is to provide toxicological profiles and maps for the insecticide blocker site and the insecticide activator site by designing and using high-affinity radioligands (the insecticide itself or a closely-related model compound) and photoaffinity probes to study binding site interactions and localization in the brain and chloride channel. Emphasis will be placed on the discovery of differences between the GABA receptors of mammals and insects that confer preferential sensitivity to insecticides and safety to mammals. The proposal is to prepare suitable radioligands and photoaffinity probes and use them to localize the binding sites as to brain region, receptor subunit and specific derivatized amino acid(s) in the chloride channel of mammals (bovine) and insects (Drosophila); the chemistry to achieve this end comes largely from discoveries in this laboratory. The research also involves rat cerebellar granule cells in primary culture to study radioligand binding and chloride flux in intact cells, localization of radioligand binding in mouse brain slices following in vitro and in vivo exposure to unlabeled toxicants, and receptors derived from Sf9 cells transfected with cDNs of human GABAa receptor subunits.

长期目标是确定 作用于γ-氨基丁酸的杀虫剂的选择性毒性 (GABA) 哺乳动物和昆虫的受体。这是主要目标 神经毒性杀虫剂既可作为神经系统的阻滞剂，又可作为神经系统的激活剂 GABA 门控氯离子通道。 其中超过 5,000,000,000 磅 过去 50 年来，通道阻断剂一直用于害虫防治 它们的氯含量范围为 52-73%。主要渠道 目前使用的阻滞剂占杀虫剂市场的 6%， 硫丹和林丹的市场份额将随着规模的扩大而增加 使用新商业化的多卤氟虫腈。 这 激活剂如阿维菌素和莫昔克丁也被用于 作为杀虫剂和驱虫剂，用量不断增加。 更多的 具体来说，目标是提供毒理学概况和地图 杀虫剂阻断位点和杀虫剂激活位点 设计和使用高亲和力放射性配体（杀虫剂本身 或密切相关的模型化合物）和光亲和探针进行研究 大脑和氯化物中的结合位点相互作用和定位 渠道。重点将放在发现之间的差异 哺乳动物和昆虫的 GABA 受体赋予优先权 对杀虫剂的敏感性和对哺乳动物的安全性。 该提议是 制备合适的放射性配体和光亲和探针并使用它们 将结合位点定位于大脑区域、受体亚基和 哺乳动物氯通道中的特定衍生氨基酸 （牛）和昆虫（果蝇）；实现这一目标的化学反应 主要来自该实验室的发现。 研究还 涉及原代培养的大鼠小脑颗粒细胞进行研究 完整细胞中的放射性配体结合和氯离子通量，定位 体外和体内小鼠脑切片中放射性配体的结合 暴露于未标记的毒物和源自 Sf9 细胞的受体 转染人 GABAa 受体亚基的 cDN。