Project 3: Molecular Mechanisms

项目3：分子机制

• 批准号: 8309379
• 负责人: LUCIO G COSTA
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309379
• 关键词: Acetylcholinesterase; Adult; Affect; Apoptosis; Behavior; Biological; Biometry; Child; Chlorpyrifos; Cohort Studies; Communication; Core Facility; Development; Environmental Health; Enzymes; Exposure to; Gene Expression; Hippocampus (Brain); In Vitro; Insecticides; Life; Modeling; Molecular; Mus; Nervous system structure; Neuraxis; Neurites; Neuroglia; Neuronal Differentiation; Neurons; Neurotoxins; Organism; Organophosphates; Oxidative Stress; Oxygen; Pathway interactions; Pesticides; Predisposition; Public Health; Reporting; Research; Research Support; Risk; Risk Assessment; Risk Management; Rodent; Role; Series; Signal Pathway; Staging; Toxic effect; Translating; Washington; Work; analog; base; developmental neurotoxicity; human stem cells; in vitro Model; insight; nervous system development; neurodevelopment; neurogenesis; neurotoxicity; pesticide exposure; pesticide induced neurotoxicity; postnatal; precursor cell; prenatal; research study; toxicant

Organophosphates pesticides (OP) are among the most widely applied pesticides worldwide and in Washington state. In adults, OPs are recognized to act as neurotoxicants through their ability to inhibit the enzyme, acetylcholinesterase (AChE). In the developing organism it is still unknown whether OP-induced developmental neurotoxicity is a consequence of AChE inhibition. Increased reports from child cohort studies suggest gestational exposures to pesticides are of public health concern. Current risk assessment and management strategies may not be optimal with the use of AChE inhibition as a regulatory anchor. This project will examine the relationship between AChE inhibition and neurotoxicity in depth, across pre- and postnatal developmental life stages. The overall hypothesis of our proposal is that pesticide exposure alters neurodevelopment and behavior in rodents by interfering with cellular pathways controlling proliferation, differentiation and apoptosis in the CNS during critical "windows of susceptibility" and that these mechanisms are independent of AChE inhibition. Using in vitro neurodevelopmental-stage specific models for both pre and postnatal developmental periods, we propose to assess the role of OP-induced oxidative stress and its consequential impact on these important cellular pathways, which underlie CNS development. The specific aims are: (l)to investigate the direct effects of OPs on neurite outgrowth, neuronal proliferation and viability in neurodevelopment-stage specific in vitro models (human stem cells, mouse neuronal precursor cells, and rodent hippocampal neurons);(2)to elucidate the impacts of OP-induced oxidative stress and effects on neurogenesis; (3)to examine developmental stage specific OP impacts on proliferation and differentiation gene expression pathways; and(4) to investigate OP effects on glial-neuronal communication. These proposed experiments will provide significant new insight into the mechanisms of OP-induced neurotoxicity and the role of AChE inhibition during pre- and post-natal neurodevelopment. Working closely with the Biostatistics, Modeling and Risk Characterization Facility Core, results from these studies will be integrated and translated into developing biological and pathway based models relevant for risk assessment across developmental periods and across species.

有机磷农药（OP）是世界上和华盛顿使用最广泛的农药之一 状态在成年人中，OP被认为是神经毒物，通过其抑制酶的能力， 乙酰胆碱酯酶（AChE）。在发育中的生物体中，OP诱导的发育 神经毒性是乙酰胆碱酯酶抑制的结果。来自儿童队列研究的报告增加提示妊娠 接触除害剂会影响公众健康。目前的风险评估和管理战略可能不 使用乙酰胆碱酯酶抑制剂作为调节锚是最佳的。本项目将研究 AChE抑制和神经毒性之间的深度，在出生前和出生后的发育生命阶段。的 我们的建议的总体假设是，农药暴露改变啮齿动物的神经发育和行为， 干扰中枢神经系统在关键时期控制增殖、分化和凋亡的细胞途径 “窗口的敏感性”，这些机制是独立的AChE抑制。使用体外 神经发育阶段的具体模型，为产前和产后的发展时期，我们建议评估 OP诱导的氧化应激的作用及其对这些重要细胞途径的影响， 中枢神经系统发展的基础。具体目的是：（1）研究OP对神经突起生长的直接影响， 神经发育阶段特异性体外模型（人干细胞、小鼠 神经元前体细胞和啮齿动物海马神经元）;（2）阐明OP诱导的氧化损伤对神经元的影响。 应激和对神经发生的影响;（3）检查发育阶段特异性OP对增殖的影响， 分化基因表达途径;（4）研究OP对神经胶质细胞-神经元通讯的影响。 这些实验将为研究OP诱导的细胞凋亡机制提供新的思路。 神经毒性和AChE抑制在产前和产后神经发育过程中的作用。密切合作 与生物统计学，建模和风险表征设施核心，这些研究的结果将是 整合并转化为开发与风险评估相关的生物和途径模型， 不同的发育时期和不同的物种。