Novel Mechanisms of Pesticide-Induced Neurotoxicity

农药引起的神经毒性的新机制

基本信息

批准号：
9906057
负责人：
Anumantha Gounder Kanthasamy
金额：
$ 33.37万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906057
关键词：
1-Methyl-4-phenylpyridinium Acetylation Address Animal Disease Models Animal Model Animals Apoptotic Attenuated Autopsy Brain Brain Diseases CREBBP gene Cell Culture Techniques Cell Death Cells ChIP-seq Chronic Complex Data Dieldrin Disease Dopaminergic Cell Dose Environmental Exposure Enzymes Epigenetic Process Etiology Event Exposure to Expression Profiling Functional disorder Gene Expression Genes Goals Histologic Histone Acetylation Histone Deacetylase Histone H3 Histone H4 Histones Homeostasis Human Impairment Link Lysine Maps Mitochondria Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurologic Symptoms Neurons Neurotransmitters Oxidative Stress Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Pattern Pesticides Process Protein Isoforms Proteins Public Health Research Research Proposals Risk Role Rotenone Signal Transduction Site Slice System Time Tissues Transgenic Animals Transgenic Mice Transgenic Organisms Ubiquitin Work brain tissue chromatin remodeling dopaminergic neuron gain of function genome-wide histone acetyltransferase histone modification inhibitor/antagonist knock-down mitochondrial dysfunction mitopark mouse mouse model multicatalytic endopeptidase complex mutant neurochemistry neurotoxic neurotoxicity neurotoxicology nigrostriatal system novel novel strategies pesticide exposure pesticide induced neurotoxicity toxicant

项目摘要

Abstract Environmental exposure to neurotoxic pesticides has been increasingly recognized as a key etiological factor of sporadic Parkinson’s disease (PD). Despite the established link, deciphering the neurotoxicological mechanisms associated with chronic pesticide exposure and its role in the etiopathogenesis of PD has been challenging. Thus, our research proposal intends to explore a novel paradigm in environmental neurotoxicology by studying the acetylation of histone proteins during pesticide exposure using animal models of pesticide neurotoxicity. Among various classes of pesticides, exposure to mitochondria-impairing neurotoxic pesticides, e.g., rotenone, has been linked to the etiology of PD. Mechanistically, exposure to rotenone and another related pesticide, pyridaben, inhibits mitochondrial complex-1 and impairs proteasomal function in neuronal cells. Dopaminergic neurons have been shown to be highly vulnerable to rotenone-induced neurotoxicity. While studying proteasomal dysfunction in mitochondria-impairing pesticide-induced neurotoxicity, we unexpectedly discovered that rotenone- and pyridaben-induced proteasomal inhibition resulted in the accumulation of the major histone acetyltransferase enzyme CBP (CREB-binding protein), which further contributed to acetylation of histones H3 and H4 to promote apoptotic cell death in dopaminergic neurons. Since hyperacetylation of histones is emerging as a key molecular mechanism capable of producing long-term changes in gene expression profiles due to chromatin remodeling, we propose to explore this novel mechanism in the molecular events underlying nigral dopaminergic neuronal damage in chronic mitochondria- impairing pesticide-induced neurotoxicity models. This work will be accomplished by pursuing the following specific objectives: i) Map the hyperacetylation sites of core histones H3 and H4 in dopaminergic neuronal cultures following mitochondria-inhibiting neurotoxic pesticide exposure, ii) Characterize cellular mechanisms of pesticide-induced hyperacetylation of histones H3 and H4 by examining the contributions of various isoforms of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and iii) Determine histone acetylation pattern in chronic rotenone or pyridaben animal models of pesticide neurotoxicity as well as in a progressive mitochondrial dysfunction-induced transgenic mouse model of PD, confirm the changes in acetylation patterns and HAT/HDAC homeostasis in human PD brain tissues, and define the functional significance of histone hyperacetylation-dependent signaling relevant to neurotoxic pesticide-induced neuronal degeneration. Cellular, molecular and neurochemical approaches will be used to delineate these objectives. Collectively, the proposed study represents a novel approach in pesticide neurotoxicological research since the work will provide a comprehensive understanding of the histone hyperacetylation mechanisms pertaining to environmentally- induced nigral dopaminergic neuronal toxicity as it relates to the etiopathogenesis of environmentally-linked PD.

抽象的环境暴露于神经毒性农药已越来越被认为是关键的病因零星帕金森氏病（PD）的因素。尽管建立了链接，但破译了神经毒理学与慢性农药暴露有关的机制及其在PD的疗法发生中的作用一直是具有挑战性的。这是我们的研究建议打算探索环境中的新型范式神经毒理学通过使用动物模型研究农药暴露期间组蛋白的乙酰化。在各种农药中，暴露于线粒体受损的神经毒性农药，例如烤面包酮，已与PD的病因有关。从机械上讲，暴露于烤面包酮和另一个相关的农药吡啶本抑制线粒体复合物1，并损害蛋白酶体功能神经元细胞。多巴胺能神经元已显示出高度容易受到rotorone诱导的神经毒性。同时研究线粒体受损农药诱导的蛋白酶体功能障碍神经毒性，我们意外地发现rotorone-和吡啶本诱导的蛋白酶体抑制导致主要组蛋白乙酰转移酶CBP（CREB结合蛋白）的积累这进一步有助于组蛋白H3和H4的乙酰化以促进多巴胺能细胞死亡神经元。由于组蛋白的高乙酰化是一种能够产生的关键分子机制由于染色质重塑而引起的基因表达谱的长期变化，我们建议探索这一新颖慢性线粒体中ni骨多巴胺能神经元损伤的分子事件的机制损害农药引起的神经毒性模型。这项工作将通过追求以下内容来完成特定目标：i）在多巴胺能神经元中绘制核心组蛋白H3和H4的高乙酰化位点线粒体抑制神经毒性农药暴露后的培养物，ii）表征细胞机制通过检查各种同工型的贡献组蛋白乙酰基转移酶（帽子）和组蛋白脱乙酰基酶（HDAC）和III）确定组蛋白乙酰化慢性葡萄干酮或吡啶替酮神经毒性的模型以及渐进式的模型线粒体功能障碍诱导的PD的转基因小鼠模型，确认乙酰化模式的变化人类PD脑组织中的HAT/HDAC稳态，并定义组蛋白的功能意义与神经毒性农药诱导的神经元变性有关的高乙酰化依赖性信号传导。细胞分子和神经化学方法将用于描述这些目标。共同提议研究代表了农药神经毒理学研究的一种新方法，因为该工作将提供对与环境有关的组蛋白高乙酰化机制的全面理解与环境链接的PD的疗法发生有关，诱导的ni骨多巴胺能神经元毒性。