Brain derived extracellular vesicles-mediated neurotoxicity of deltamethrin

摘要 流行病学研究发现，早期接触拟除虫菊酯是注意力缺陷的危险因素 多动症(ADHD)。因为报告的暴露风险在未观察到的不良影响水平内 (NOAEL)指南，环境中暴露于拟除虫菊酯可能是ADHD的主要原因被低估 以及其他一般人群的神经发育障碍。早期暴露于空气中的动物模型 拟除虫菊酯杀虫剂溴氰菊酯(DM)是一种在大脑中积聚的强大的高度亲脂分子， 通过破坏伏核中的多巴胺信号来概括ADHD样行为，伏隔核多巴胺信号是 与人类疾病有关的大脑区域。然而，DM对其他发育中的大脑的毒性机制 地区尚未确定。我们小组的初步研究表明，接触DM会扰乱大脑 衍生的细胞外小泡(BDEV)，参与细胞之间的通讯和调节 几种疾病的病理生理学。此外，早期接触DM会破坏大脑中的长时程增强。 海马体，这是一种潜在的学习和记忆形成现象，在儿童ADHD中被破坏。 基于这一前提，我们建议表征BDEV的生物发生改变及其在突触中的作用 早期接触DM引起的损伤(目标1)和确定BDEV是否源于DM早期 暴露足以诱导与海马区功能相关的DM突触和行为表型 在幼稚的动物身上(目标2)。这项研究的结果将为基于分子的 了解神经发育障碍的危险因素为治疗发展提供指导 防止暴露。

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.