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.

有机磷酸盐农药（OP）是全球范围内最广泛的农药之一 状态。在成年人中，OP被认为通过抑制酶的能力充当神经毒性。 乙酰胆碱酯酶（ACHE）。在发展中的生物体中，仍然尚不清楚运算引起的发育是否 神经毒性是ACHE抑制作用的结果。儿童队列研究的报告增加了妊娠 对农药的暴露引起了公共卫生的关注。当前的风险评估和管理策略可能不会 将ACHE抑制作用作为调节锚，保持最佳状态。该项目将检查关系 在深度和神经毒性的深度，跨产后和产后发展阶段之间。这 我们建议的总体假设是，农药暴露会改变啮齿动物的神经发育和行为 干扰临界过程中中枢神经系统的增殖，分化和凋亡的细胞途径 “易感性的窗户”，这些机制独立于ACHE抑制。在体外使用 神经发育阶段的特定模型在产后和产后发育时期，我们建议评估 操作诱导的氧化应激的作用及其对这些重要细胞途径的结果影响， CNS开发基础。具体目的是：（l）研究OP对神经突生长的直接影响， 神经元的增殖和神经发育特异性体外模型（人干细胞，小鼠）的生存力 神经元前体细胞和啮齿动物海马神经元）;（2）阐明了操作诱导的氧化作用的影响 压力和对神经发生的影响； （3）检查发育阶段的特定OP对增生和 分化基因表达途径； （4）研究对神经神经神经神经元通信的OP影响。 这些提出的实验将为操作诱导的机制提供重大的新见解 神经毒性和抑制在产前和产后神经发育过程中的作用。紧密工作 借助生物统计学，建模和风险表征设施核心，这些研究的结果将是 整合并转化为开发基于生物学和途径的模型，与风险评估有关 发展时期和跨物种。