Chronic Low Level Exposure to Organophosphates

Purpose: The purpose of the work reviewed in this abstract was to evaluate potential treatment strategies against the negative effects of the highly toxic class of chemicals, the organophosphates (OPs), on a fundamental process in neurons, axonal transport (AXT). ---
Methodology: Using a time-lapse imaging technique, we evaluated OP effects on fast AXT of fluorescent membrane-bound organelles in cultured primary cortical neurons from rats. We also developed a manganese-enhanced magnetic resonance imaging (MEMRI) method for real-time measurements of AXT rates in mice in the olfactory system over a single scanning session. Both methods were used to evaluate therapeutic strategies designed to enhance AXT rates. ---
Findings: Our previous neuronal culture and animal experiments indicated that exposures to OPs of different classes (e.g., insecticide and nerve agent) can lead to impairments of AXT, a potential mechanism of the long-term neurological impairments observed in humans exposed to OPs.  Subsequent in vitro phenotypic screening studies indicated that some currently prescribed drugs (lithium chloride, methylene blue) with multi-target pharmacological activity could have potential as repurposed drugs for OP-related neurological impairments as a result of their ability to attenuate the deleterious effects of OPs on AXT. We have also developed an MEMRI method where real-time measurements of AXT rates can be determined in living mice in the olfactory system over a single scanning session. Using this method, we determined that AXT rates were slower in aged vs young mice. In aged mice, the microtubule stabilizing compound Epothilone D was associated with significant improvements in AXT rates. The conclusion of these studies was that our new MEMRI method is sensitive to the negative effects of aging on AXT as well as microtubule-focused therapeutic strategies for improving AXT. Future studies will focus on OP effects/therapeutic strategies using this method. ---
Research Limitations: All of the studies described in this report were conducted in vitro or in animal models. ---
Practical Implications: Our studies further suggest that impairments of AXT may underlie the long term deleterious neurologic effects that have been associated with OPs. Moreover, we have identified compounds that could potentially be used to attenuate the negative effects of OPs on AXT. ---
Value and Originality: The value of the methodology we have developed for assessing the effects OPs on AXT lies in its potential for elucidating novel therapeutic targets and treatment strategies against OP toxicity. The results could have therapeutic implications for conditions that have been associated with repeated OP exposures, such as Gulf War Illness and Aerotoxic Syndrome.