Neurotoxicology of deltamethrin in the developing brain

发育中大脑中溴氰菊酯的神经毒理学

• 批准号: 10271267
• 负责人: Thomas Arthur Green
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-28 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271267
• 关键词: Action Potentials; Affect; Agriculture; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain region; Categories; Cells; Complement; Corpus striatum structure; Deterioration; Development; Dopamine; Electrophysiology (science); Environmental Exposure; Exposure to; Functional disorder; Gas Chromatography; General Population; Guidelines; Household; Human; Hyperactivity; Image; Immunohistochemistry; Impulsivity; Injections; Insecta; Interneuron function; Interneurons; Lactation; Life; Lifestyle-related condition; Mammals; Mass Fragmentography; Mass Spectrum Analysis; Methods; Modeling; Molecular; Motor Activity; Mus; Neurodevelopmental Disorder; Neurons; Neurotoxins; No-Observed-Adverse-Effect Level; Nucleus Accumbens; Outcome Study; Output; Parvalbumins; Pathway interactions; Pattern; Pesticides; Pregnancy; Preparation; Process; Property; Protein Isoforms; Proteins; Reporting; Risk; Risk Factors; Rodent Model; Schools; Signal Transduction; Slice; Social Behavior; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Synapses; Testing; Toxic Environmental Substances; Toxic effect; United States Environmental Protection Agency; Viral Vector; autism spectrum disorder; base; behavioral phenotyping; behavioral study; brain tissue; cell type; course development; cross reactivity; decamethrin; designer receptors exclusively activated by designer drugs; early life exposure; endophenotype; epidemiology study; gamma-Aminobutyric Acid; human disease; in vivo; insight; interdisciplinary approach; mouse model; neuronal excitability; neuroregulation; neurotoxicity; neurotoxicology; novel; patch clamp; pyrethroid; relating to nervous system; response; tandem mass spectrometry; 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 neurotoxin that acts on the insect voltage- gated Na+ (Nav) channel, recapitulates ADHD-like behavior through disruption of dopamine signaling in the nucleus accumbens (NAc), the brain region implicated in the human disease. Yet, the mechanism of toxicity of DM in the developing brain has not yet been determined. Recent studies from our group provide evidence for cross reactivity of DM with the mammalian Nav1.1 channel, an isoform expressed in fast-spiking parvalbumin (PV) inhibitory interneurons during development. These cells exert a powerful inhibitory control over the output of the NAc, which, if disrupted, leads to dopamine dysfunction with effects on locomotor activity, attention, and impulsivity, endophenotypes that characterize ADHD. In supporting studies conducted in an early-life DM exposure animal model we show regional accumulation of DM and loss in GABA in the NAc/striatum and demonstrate disruption of PV interneuron firing in the same brain region accompanied by ADHD-like behaviors. Building on this premise, we propose molecular (Aim 1), functional (Aim 2) and behavioral (Aim 3) studies to test the hypothesis that the primary mechanism of DM toxicity in the developing brain is to disrupt PV interneuron function leading to loss of local inhibitory control in the NAc and behavioral phenotypes common to ADHD. 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.

抽象的 流行病学研究发现，生命早期接触拟除虫菊酯是引起注意的威胁性危险因素。 缺陷多动障碍（ADHD）。因为报告的暴露风险在未观察到的不利范围内 根据影响水平 (NOAEL) 指南，拟除虫菊酯的环境暴露可能被低估了 一般人群中 ADHD 和其他神经发育障碍的原因。早期生命的动物模型 接触拟除虫菊酯农药溴氰菊酯 (DM)，这是一种强效神经毒素，作用于昆虫电压 - 门控 Na+ (Nav) 通道，通过破坏大脑中的多巴胺信号传导来重现 ADHD 样行为 伏核（NAc），与人类疾病有关的大脑区域。然而，其毒性机制 发育中大脑中的 DM 尚未确定。我们小组最近的研究提供了证据 DM 与哺乳动物 Nav1.1 通道（一种在快速尖峰小白蛋白中表达的亚型）的交叉反应性 (PV) 发育过程中的抑制性中间神经元。这些细胞对输出施加强大的抑制控制 NAc 的功能，如果被破坏，会导致多巴胺功能障碍，从而影响运动活动、注意力和 冲动，多动症特征的内表型。支持在早期 DM 中进行的研究 暴露动物模型中，我们显示了 NAc/纹状体中 DM 的区域积累和 GABA 的损失，以及 证明同一大脑区域的 PV 中间神经元放电中断，并伴有 ADHD 样行为。 在此前提下，我们提出分子（目标 1）、功能（目标 2）和行为（目标 3）研究 检验以下假设：发育中大脑中 DM 毒性的主要机制是破坏 PV 中间神经元功能导致 NAc 局部抑制控制丧失和常见的行为表型 多动症。这项研究的结果将为基于分子的风险因素理解提供新的见解 对于神经发育障碍，为针对暴露的治疗开发提供指导。