Molecular and Behavioral Impacts of Developmental OP Neurotoxicity

7.项目摘要/摘要 反复暴露于有机磷杀虫剂(OP)会导致长期的负面影响 儿童的后果包括行为问题(ADHD)和认知能力下降 运动技能。动物研究也发现了反复发育后的负面影响 持续到成年期的暴露，包括多个神经元突触成分水平的变化 神经递质系统和行为功能障碍。有机磷杀虫剂的经典作用是刺激 通过抑制脑胆碱酯酶(ChE)而影响胆碱能系统。然而，环境 暴露通常发生在不会引起大脑ChE抑制的OP水平，这表明 作用机制。不幸的是，使用暴露水平进行的研究很少。 而不是抑制脑胆碱酯酶。我们之前的工作表明，反复发育过程中暴露于OP 在不抑制大脑胆碱酯酶的水平上，杀虫剂毒死蜱(CPF)能显著抑制脂肪。 酸酰胺水解酶(FAAH)，其底物的积累，内源性大麻酰胺(AEA)，以及 改变了情绪反应。我们的初步数据在暴露于以下两种环境的青春期大鼠中发现了类似的影响 对CPF或对FAAH的特定抑制剂。这些包括青少年探索性/焦虑症增加和 社会行为和杏仁核转录组和蛋白质组的改变这表明抑制 FAAH是许多由发育性OP暴露引起的持续性影响的原因。这 应用程序的目标是进一步表征OP介导的发育FAAH抑制是如何改变的 青春期的行为和神经化学。观察到的探索/缓解焦虑行为的增加 提示发育中的OP暴露可以改变其他行为，包括注意力、冲动和 风险相关行为--据报道，暴露于有机磷农药的儿童的行为会发生改变。这将是 FAAH的发育抑制导致转录/蛋白质组学变化 提示GABA能和谷氨酸能系统突触成分有改变的倾向 朝向GABA能信号。这一点的存在将在目标2中进行测试。总体而言，这些研究更深入 通过尝试进一步剖析所涉及的组件和 建立对与约束直接相关的持久结果的更清晰的理解 把行动传给目标。

7. PROJECT SUMMARY/ABSTRACT Repeated developmental exposure to organophosphorus insecticides (OP) results in long term negative consequences in children including behavioral problems (ADHD) and decreased cognitive abilities and motor skills. Animal studies have also identified negative effects following repeated developmental exposure that persist into adulthood which include altered levels of the synaptic components of of multiple neurotransmitter systems and behavioral dysfunction. The classical action of OP insecticides is stimulation of the cholinergic system via the inhibition of brain cholinesterase (ChE). However, environmental exposures typically occur at levels of an OP that do not induce brain ChE inhibition suggesting a different mechanism of action. Unfortunately, very few studies have been conducted using exposure levels that did not inhibit brain ChE. Our previous work demonstrated that repeated developmental exposure to the OP insecticide chlorpyrifos (CPF), at levels that did not inhibit brain ChE, resulted in significant inhibition of fatty acid amide hydrolase (FAAH), accumulation of its substrate, the endocannabinoid anandamide (AEA), and altered emotional reactivity. Our preliminary data identified similar effects in adolescent rats exposed either to CPF or to a specific inhibitor of FAAH. These included increased adolescent exploratory/anxiolytic and social behaviors and altered transcriptome and proteome in the amygdala This suggests that inhibition of FAAH is responsible for many of the persistent effects induced by developmental OP exposure. This application's objective is to further characterize how OP-mediated developmental FAAH inhibition alters behavior and neurochemistry in adolescence. The observed increased exploratory/anxiolytic behavior suggests that developmental OP exposure could alter other behaviors including attention, impulsivity, and risk-related behavior which are behaviors reported to be altered in children exposed to OPs. This will be determined in Aim 1. The developmental inhibition of FAAH results in transcriptomic/proteomic changes suggesting altered synaptic components of the GABAergic and glutamatergic systems with tendency towards GABAergic signaling. The presence of this will be tested in Aim 2. Overall, these studies dive more deeply into this newly recognized mechanism by attempting to further dissect the components involved and establish a clearer understanding of the persistent outcomes that are directly connected to the binding of the OP to the target.