Brain derived extracellular vesicles-mediated neurotoxicity of deltamethrin

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ABSTRACT Epidemiological studies identify early life exposure to pyrethroids as a threatening risk factor for attention-deficit hyperactivity disorder (ADHD). Because the reported risk of exposure is within no-observed-adverse-effect level (NOAEL) guidelines, environmental exposure to pyrethroids could be an underestimated leading cause of ADHD and other neurodevelopmental disorders in the general population. Animal models of early-life exposure to the pyrethroid pesticide deltamethrin (DM), a potent highly lipophilic molecule that accumulates in the brain, recapitulate ADHD-like behavior through disruption of dopamine signaling in the nucleus accumbens, one of the brain regions implicated in the human disease. Yet, the mechanism of toxicity of DM in other developing brain regions has not yet been determined. Preliminary work from our group indicates that DM exposure disrupts brain derived extracellular vesicles (BDEVs), molecules involved in communication between cells and regulating the pathophysiology of several diseases. Further, early-life exposure to DM disrupts long-term potentiation in the hippocampus, a phenomenon underlying learning and memory formation which is disrupted in childhood ADHD. Building on this premise, we propose to characterize the altered biogenesis of BDEVs and its role in synaptic injury induced by early-life exposure to DM (Aim 1) and to determine whether BDEVs derived from DM early-life exposure are sufficient to induce DM synaptic and behavioral phenotypes associated with hippocampal function in naïve animals (Aim 2). Outcomes of this study will provide new insights into the molecular-based understanding of risk factors for neurodevelopmental disorders providing guidance for therapeutic development against exposure.