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

• 批准号: 8033244
• 负责人: HUI-CHEN LU
• 金额: $ 18.64万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033244
• 关键词: Acetylcholine; Acetylcholinesterase; Address; Adult; Affect; Anxiety; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; CNR1 gene; Cannabinoids; 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

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应用程序，用于确定有机磷酸盐对神经发育的有害影响是否是由于内源性大麻素降解的抑制。有机磷是一种有效且广泛使用的杀虫剂，可以改善人类健康和作物产量。然而，有机磷的慢性毒性之一是它们对神经发育的有害影响，这种影响可能不依赖于乙酰胆碱酯酶（AChE）抑制而发生。除了乙酰胆碱酯酶，有机磷酸酯还抑制其他酯酶，包括脂肪酸氨基水解酶（FAAH）和单酰基甘油脂肪酶（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的抑制发生在可以在体内实现的有机磷酸盐浓度下。有机磷酸盐是如何扰乱神经发育的？新出现的证据已经确定，内源性大麻素系统在大脑发育中起着核心作用，包括在神经祖细胞的增殖、神经元迁移和神经回路形成中。我们已经发现，内源性大麻素信号传导和降解的药理学阻断破坏了这些过程。在拟议的工作中，我们将完成两个具体的目标，以确定内源性大麻素降解的有机磷酸盐抑制是否会导致神经发育和后来的行为异常：目标1。围产期有机磷暴露是否会抑制发育中大脑中eCB的降解，从而导致神经发育异常？目标二。围产期有机磷治疗是否会引起成年动物的行为变化？如果是这样的话，这些变化是由CB1信号在发育过程中介导的吗？这些目标的成功完成将使我们能够确定是否抑制eCB降解和增强大麻素受体信号传导是有机磷酸酯对神经发育的不良影响的基础。此外，他们将帮助我们了解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，在发育过程中MGL和FAAH功能的扰动是否会导致后来的行为异常和对药物使用的敏感性。 公共卫生相关性：常用的有机磷农药可导致神经系统发育异常。该提案将测试有机磷农药损害胎儿和新生儿大脑内源性大麻素降解的假设，这会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暴露于有机磷农药的儿童具有显着的公共卫生益处。