Disruption of the Endocannbinoid System as a Target in Developmental OP Toxicity

描述（由申请人提供）：在发育过程中反复暴露于有机磷杀虫剂（OP），如毒死蜱（CPF），会对儿童造成长期负面影响。动物研究也发现了持续到成年的负面影响，包括行为缺陷。正常的生理和行为需要在发育过程中严格控制适当功能通路的形成。对这些通路的产生、成熟和维持所必需的信号的破坏可能导致神经网络的异常形成。已经证明，在动物中，反复的发育性OP暴露会导致多种神经递质系统突触成分水平的改变，并改变成人的行为功能障碍。如此广泛的影响表明，暴露会引起许多神经递质系统功能的变化，从而导致毒理学效应。虽然OP杀虫剂的经典作用是通过抑制胆碱酯酶（ChE）来刺激胆碱能系统，但在发育过程中暴露于OP的负面影响是在诱导最低水平的ChE抑制的剂量下观察到的。我们的初步数据表明，在不抑制ChE的水平上反复暴露于CPF，会导致脂肪酸酰胺水解酶（FAAH）的显著抑制，其底物内源性大麻素anandamide的积累，并改变情绪反应。内源性大麻素系统在大脑的正常发育中很重要，已发表的文献报道，在发育过程中，通过FAAH抑制anandamide的不适当升高会改变内源性大麻素系统的正常成熟。综上所述，这表明在发育性CPF暴露期间FAAH的抑制可能导致内源性大麻素系统成熟/功能的改变。对人类来说，最具破坏性的毒理学效应是行为的破坏，内源性大麻素系统在调节某些行为，包括情绪、情绪和焦虑方面发挥着重要作用。已发表的文献表明，CPF的发育暴露会导致成人焦虑水平的改变。内源性大麻素功能的破坏可能是在发育性CPF暴露中观察到的焦虑水平改变的基础，也可能是发育性暴露于极低水平的OP诱导长期毒性的机制。为此，我们将研究发育性OP暴露对内源性大麻素信号功能的破坏。本应用的目的1将确定FAAH的发育抑制是否对CPF暴露后发生的行为改变负责。目的2将确定内源性大麻素系统的生化变化与CPF发育暴露后产生的行为变化之间的关系。总的来说，这些研究将确定FAAH抑制是否可能是发育性OP暴露期间受到影响的作用机制。

DESCRIPTION (provided by applicant): Repeated developmental exposure to organophosphorus insecticides (OP), such as chlorpyrifos (CPF), results in long term negative consequences in children. Animal studies have also identified negative effects which persist into adulthood including behavioral deficits. Normal physiology and behavior requires the tightly controlled formation of appropriate functional pathways during development. Disruption of the signals necessary for the creation, maturation, and maintenance of these pathways can lead to aberrant formation of neuronal networks. It has been demonstrated that in animals, repeated developmental OP exposure induces altered levels of synaptic components in multiple neurotransmitter systems and altered behavioral dysfunction in adults. Such widespread effects indicate that the exposure induces changes in the functioning of numerous neurotransmitter systems leading to the toxicological effects. Although the classical action of OP insecticides is stimulation of the cholinergic system via the inhibition of cholinesterase (ChE), negative effects of developmental OP exposure are observed at dosages that induce minimal levels of ChE inhibition. Our preliminary data indicate that repeated developmental exposure to CPF, at levels that do not inhibit ChE, results in significant inhibition of fatty acid amide hydrolase (FAAH), accumulation of its substrate, the endocannabinoid anandamide, and alters emotional reactivity. The endocannabinoid system is important in normal development of the brain and published literature reports that inappropriate elevation of anandamide via FAAH inhibition during development alters the normal maturation of the endocannabinoid system. Taken together, this suggests that inhibition of FAAH during developmental CPF exposure could result in altered maturation/function of the endocannabinoid system. In humans, the most devastating toxicological effect would be the disruption of behavior and the endocannabinoid system plays and important role in regulating certain behaviors including emotion, mood, and anxiety. Published literature indicates that developmental exposure to CPF results in altered anxiety levels in adults. Disruption of endocannabinoid function could be the basis for the reported altered anxiety levels observed with developmental CPF exposure and could be the mechanism by which developmental exposure to very low levels of an OP induce long term toxicity. For this application, we will investigate the disruption of function of the endocannabinoid signaling as a result of developmental OP exposure. Aim 1 of this application will determine if developmental inhibition of FAAH is responsible for the altered behavior that occurs following developmental CPF exposure. Aim 2 will determine the relationship between the biochemical changes in the endocannabinoid system and the resulting behavioral changes following developmental exposure to CPF. Overall, these studies will determine if FAAH inhibition is a possible mechanism of action that is impacted during developmental OP exposure.