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

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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.