Organophosphate-Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain

: The overall goal of this project is to determine the underlying mechanisms for the neurological symptoms associated with Gulf War Illness. The central hypothesis is that subthreshold exposures to organophosphates-OPs (defined as exposures not associated with acute signs of toxicity) may have adversely affected axonal transport and/or myelin integrity in affected individuals. We are studying two OPs, a representative insecticide that was used in the first gulf war, chlorpyrifos (CPF), and a representative, nerve agent, diisopropylfluorophosphate (DFP) in rats. The first two years of this proposal have been primarily dedicated to Specific Aim #1: which has been designed to evaluate OP effects on axonal transport in the living rat brain using manganese-enhanced magnetic resonance imaging (MEMRI) of the optic nerve axonal projections from the retina to the superior colliculus. The following procedures have been conducted to date (N=6): 1) baseline MRI scans; 2) daily injections of vehicle or chlorpyrifos (3.0-18.0 mg/kg) x 14 days; 2) a second MRI scan on the day following the last drug injection; 3) a third scan after a 4 week (OP-free) washout period. For each animal, a separate 6 hour and 24 hour scan was performed after Mn2+ eye injection. For this work a manuscript is currently under review for publication. In this work we also evaluated the effects of an acute (single) exposure to CPF. We have also completed the MR scanning portion for the DFP study and a preliminary analysis indicates similar results (persistent impairments of axonal transport). The experiments for specific aim #2 (devoted to the evaluation of OP-related effects on myelin with diffusion tensor imaging-(DTI) and histology are currently underway.