Do organophosphates impair neurodevelopment through inhibition of endocannabinoid

描述（由申请人提供）：这是一份NIDA CEBRA R21申请，用于确定有机磷对神经发育的有害影响是否由于抑制内源性大麻素降解而引起。有机磷是一种有效且广泛使用的农药，改善了人类健康和作物产量。然而，关于有机磷酸盐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，有机磷酸盐还抑制其他酯酶，包括脂肪酸氨基水解酶（FAAH）和单酰基甘油脂肪酶（MGL）。FAAH和MGL是内源性大麻素降解中最重要的两种酶。值得注意的是，FAAH和MGL的抑制作用发生在体内可以实现的有机磷酸酯浓度下。有机磷是如何扰乱神经发育的？越来越多的证据表明，内源性大麻素系统在大脑发育中起着核心作用，包括神经祖细胞的增殖、神经元的迁移和神经回路的形成。我们发现内源性大麻素信号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目标，以确定有机磷酸酯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：目的1。围产期有机磷暴露是否会抑制发育中的大脑中eCB的降解，从而导致神经发育异常？目标2。围产期有机磷治疗会对成年动物产生行为改变吗？如果是这样，这些变化是由CB1信号在发育过程中介导的吗？成功完成这些目标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是有机磷酸盐对神经发育不利影响的基础。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的易感性。

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.