Do organophosphates impair neurodevelopment through inhibition of endocannabinoid

有机磷酸酯是否通过抑制内源性大麻素损害神经发育

基本信息

批准号：
7919106
负责人：
HUI-CHEN LU
金额：
$ 20.57万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919106
关键词：
Acetylcholine Acetylcholinesterase Address Adult Affect Anxiety Behavior Behavioral Behavioral Assay Biological Assay Brain CNR1 gene Child Chlorpyrifos Chronic Complex Data Development Discipline of Nursing Dose Drug usage Elderly Embryo Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Exposure to Fatty Acids Gender Health Health Benefit Human Hydrolase Impairment Insecticides Knockout Mice Lead Learning Logic Mass Spectrum Analysis Measures Mediating Monoacylglycerol Lipases Mus Muscle fasciculation National Institute of Drug Abuse Nervous system structure Neurons Newborn Infant Organophosphates Pattern Perinatal Pesticides Pharmaceutical Preparations Play Predisposition Process Public Health Receptor Signaling Role Signal Transduction System Testing Tissues Toxic effect Work axonal pathfinding base behavior change cannabinoid receptor esterase fetal improved in utero in vivo mature animal migration morris water maze nerve stem cell nervous system development neural circuit neurodevelopment neurogenesis novel preference pregnant public health relevance research study toxic organophosphate insecticide exposure

项目摘要

DESCRIPTION (provided by applicant): This is a NIDA CEBRA R21 application to determine if the deleterious effects of organophosphates on neurodevelopment are due to inhibition of endocannabinoid degradation. Organophosphates are effective and widely used pesticides that have improved human health and crop yields. However, one concerning chronic toxicity of organophosphates is their deleterious effect on neurodevelopment, which can occur independent of acetylcholinesterase (AChE) inhibition. In addition to AChE, organophosphates inhibit other esterases, including fatty acid amino hydrolase (FAAH) and monoacylglycerol lipase (MGL). FAAH and MGL are the two most important enzymes for the degradation of endocannabinoids. Significantly, inhibition of FAAH and MGL occurs at organophosphate concentrations that can be achieved in vivo. How might organophosphates perturb neurodevelopment? Emerging evidence has established that the endocannabinoid system plays a central role in brain development including in the proliferation of neural progenitors, neuronal migration and neural circuit formation. We have found that pharmacological blockade of endocannabinoid signaling and degradation disrupts these processes. In the proposed work we will complete two specific aims to determine if organophosphate inhibition of endocannabinoid degradation leads to abnormalities in neurodevelopment and later behavior: Aim 1. Does perinatal organophosphate exposure inhibits eCB degradation in the developing brain to cause abnormal neurodevelopment? Aim 2. Will perinatal organophosphate treatment produce behavioral changes in adult animals? If so, are these changes mediated by CB1 signaling during development? Successful completion of these aims will enable us to determine if inhibition of eCB degradation and enhanced cannabinoid receptor signaling underlie the adverse neurodevelopmental effects of organophosphates. Furthermore they will help us understand the role of FAAH and MGL in orchestrating the complex task of assembling the nervous system. Finally, they will tell us if perturbation of MGL and FAAH function during development predisposes to later behavioral abnormalities and susceptibility to drug use. PUBLIC HEALTH RELEVANCE: Commonly used organophosphate pesticides can cause abnormalities in nervous system development. This proposal will test the hypothesis that organophosphate pesticides impair degradation of endogenous cannabinoids in the fetal and newborn brain and that this leads to anatomical and behavioral deficits in later life. The results of this study could have significant public health benefits for children exposed in utero to organophosphate pesticides.

描述（由申请人提供）：这是 NIDA CEBRA R21 申请，旨在确定有机磷酸酯对神经发育的有害影响是否是由于抑制内源性大麻素降解所致。有机磷酸酯是有效且广泛使用的农药，可以改善人类健康和农作物产量。然而，有机磷酸酯的慢性毒性之一是它们对神经发育的有害影响，这种影响可以独立于乙酰胆碱酯酶（AChE）抑制而发生。除乙酰胆碱酯酶外，有机磷酸酯还可抑制其他酯酶，包括脂肪酸氨基水解酶 (FAAH) 和单酰甘油脂肪酶 (MGL)。 FAAH 和 MGL 是降解内源性大麻素的两种最重要的酶。值得注意的是，FAAH 和 MGL 的抑制发生在体内可达到的有机磷酸盐浓度下。有机磷酸酯如何干扰神经发育？新的证据表明，内源性大麻素系统在大脑发育中发挥着核心作用，包括神经祖细胞的增殖、神经元迁移和神经回路形成。我们发现内源性大麻素信号传导和降解的药理学阻断会破坏这些过程。在拟议的工作中，我们将完成两个具体目标，以确定有机磷酸盐抑制内源性大麻素降解是否会导致神经发育和后期行为异常：目标 1. 围产期有机磷酸盐暴露是否会抑制发育中大脑中的 eCB 降解，从而导致神经发育异常？目标 2. 围产期有机磷酸盐治疗是否会导致成年动物行为发生变化？如果是这样，这些变化是在发育过程中由 CB1 信号传导介导的吗？成功完成这些目标将使我们能够确定抑制 eCB 降解和增强大麻素受体信号传导是否是有机磷酸酯对神经发育产生不良影响的基础。此外，它们将帮助我们了解 FAAH 和 MGL 在协调组装神经系统的复杂任务中的作用。最后，他们将告诉我们发育过程中 MGL 和 FAAH 功能的扰动是否会导致以后的行为异常和对药物使用的敏感性。公众健康相关性：常用的有机磷农药可导致神经系统发育异常。该提案将检验以下假设：有机磷农药会损害胎儿和新生儿大脑中内源性大麻素的降解，从而导致以后生活中的解剖和行为缺陷。这项研究的结果可能对子宫内接触有机磷农药的儿童产生重大的公共健康益处。