Brain derived extracellular vesicles-mediated neurotoxicity of deltamethrin

溴氰菊酯脑源性细胞外囊泡介导的神经毒性

• 批准号: 10679858
• 负责人: Fernanda Laezza
• 金额: $ 42.34万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679858
• 关键词: Actins; Agriculture; Animal Model; Animals; Anti-Inflammatory Agents; Anxiety; Apoptotic; Attention; Attention deficit hyperactivity disorder; Attenuated; Behavior; Binding; Biogenesis; Brain; Brain Injuries; Brain region; Categories; Cell Communication; Cell membrane; Cells; Cellular Structures; Child; Childhood; Communication; Complex; Control Animal; Dendritic Spines; Development; Disease; Dopamine; Early identification; Electron Microscopy; Electrophysiology (science); Endosomes; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Exposure to; Frequencies; Functional disorder; Funding Mechanisms; Gene Targeting; General Population; Goals; Guidelines; Hippocampus; Household; Impairment; Injury; Knowledge; Learning; Life; Link; Lipids; Long-Term Potentiation; Measures; Mediating; Memory; Memory impairment; Modeling; Molecular; Nature; Neurodevelopmental Disorder; Neurons; No-Observed-Adverse-Effect Level; Nucleus Accumbens; Organ; Outcome; Outcome Study; Pathway interactions; Patients; Pattern; Pesticides; Phospholipids; Psychopathology; Reporting; Research; Risk; Risk Behaviors; Risk Factors; Role; Schools; Signal Transduction; Solid; Sorting; Symptoms; Synapses; Synaptic Potentials; Synaptic plasticity; Testing; Toxic Environmental Substances; Toxic effect; United States Environmental Protection Agency; Western Blotting; Work; autism spectrum disorder; behavioral phenotyping; confocal imaging; cytokine; decamethrin; early life exposure; epidemiology study; exosome; extracellular vesicles; human disease; in vitro Model; in vivo; insight; interdisciplinary approach; lipophilicity; microvesicles; mouse model; nanovesicle; neurotoxicity; novel; novel therapeutics; pyrethroid; response; therapeutic development; voltage

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.

摘要 流行病学研究确定生命早期暴露于拟除虫菊酯是注意力缺陷的一个危险因素 多动症（ADHD）。因为报告的暴露风险在无明显不良作用水平内 （NOAEL）指南，拟除虫菊酯的环境暴露可能是ADHD的一个被低估的主要原因 和其他神经发育障碍的患者。生命早期暴露于 拟除虫菊酯杀虫剂溴氰菊酯（DM）是一种在大脑中积累的强效高度亲脂性分子， 通过破坏多巴胺信号传导来重现ADHD样行为，多巴胺信号传导是 与人类疾病有关的大脑区域然而，DM在其他发育脑中的毒性机制 地区尚未确定。我们小组的初步工作表明，DM暴露会扰乱大脑 衍生的细胞外囊泡（BDEV），参与细胞之间的通讯和调节细胞增殖的分子。 几种疾病的病理生理学。此外，生命早期暴露于DM会破坏大脑皮层的长时程增强。 海马体，一种在儿童多动症中被破坏的学习和记忆形成的基础现象。 在此前提下，我们提出了BDEV的生物发生改变及其在突触中的作用， 早期生活暴露于DM诱导的损伤（目的1），并确定BDEV是否来源于DM早期生活 暴露足以诱导与海马功能相关的DM突触和行为表型 在幼稚动物中（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，为治疗开发提供指导 防止暴露。