Molecular and Behavioral Impacts of Developmental OP Neurotoxicity

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7. PROJECT SUMMARY/ABSTRACT Repeated developmental exposure to organophosphorus insecticides (OP) results in long term negative consequences in children including behavioral problems (ADHD) and decreased cognitive abilities and motor skills. Animal studies have also identified negative effects following repeated developmental exposure that persist into adulthood which include altered levels of the synaptic components of of multiple neurotransmitter systems and behavioral dysfunction. The classical action of OP insecticides is stimulation of the cholinergic system via the inhibition of brain cholinesterase (ChE). However, environmental exposures typically occur at levels of an OP that do not induce brain ChE inhibition suggesting a different mechanism of action. Unfortunately, very few studies have been conducted using exposure levels that did not inhibit brain ChE. Our previous work demonstrated that repeated developmental exposure to the OP insecticide chlorpyrifos (CPF), at levels that did not inhibit brain ChE, resulted in significant inhibition of fatty acid amide hydrolase (FAAH), accumulation of its substrate, the endocannabinoid anandamide (AEA), and altered emotional reactivity. Our preliminary data identified similar effects in adolescent rats exposed either to CPF or to a specific inhibitor of FAAH. These included increased adolescent exploratory/anxiolytic and social behaviors and altered transcriptome and proteome in the amygdala This suggests that inhibition of FAAH is responsible for many of the persistent effects induced by developmental OP exposure. This application's objective is to further characterize how OP-mediated developmental FAAH inhibition alters behavior and neurochemistry in adolescence. The observed increased exploratory/anxiolytic behavior suggests that developmental OP exposure could alter other behaviors including attention, impulsivity, and risk-related behavior which are behaviors reported to be altered in children exposed to OPs. This will be determined in Aim 1. The developmental inhibition of FAAH results in transcriptomic/proteomic changes suggesting altered synaptic components of the GABAergic and glutamatergic systems with tendency towards GABAergic signaling. The presence of this will be tested in Aim 2. Overall, these studies dive more deeply into this newly recognized mechanism by attempting to further dissect the components involved and establish a clearer understanding of the persistent outcomes that are directly connected to the binding of the OP to the target.