Dieldrin-induced differential gene methylation and parkinsonian toxicity

狄氏剂诱导的差异基因甲基化和帕金森毒性

• 批准号: 10115257
• 负责人: Alison Bernstein
• 金额: $ 59.23万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-21 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115257
• 关键词: 3-Dimensional; Adult; Affect; Biological; Biological Assay; Brain; Candidate Disease Gene; Cell Culture Techniques; Corpus striatum structure; DNA Modification Process; DNMT3a; Data; Development; Dieldrin; Disease; Disease susceptibility; Dopamine; Elderly; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Etiology; Exposure to; Functional disorder; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; HDAC9 gene; High Pressure Liquid Chromatography; Immunohistochemistry; In Situ; In Vitro; Individual; Inherited; Injections; Knowledge; Link; Luciferases; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Methods; Methylation; Mission; Modeling; Modification; Mus; Mutation; NR4A2 gene; National Institute of Environmental Health Sciences; Neurites; Neurons; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Periodicity; Phenotype; Play; Predisposition; Presynaptic Terminals; Radioactive; Risk; Risk Factors; Role; Scanning; Sequencing By Hybridizations; Site-Directed Mutagenesis; Specificity; System; Testing; Toxic Environmental Substances; Toxic effect; Western Blotting; alpha synuclein; base; cell type; cytotoxicity; dopaminergic neuron; epidemiology study; epigenome; experimental study; genome-wide; genomic locus; in vivo; in vivo Model; laser capture microdissection; male; methylation pattern; motor behavior; mouse model; neurotransmission; nigrostriatal pathway; novel; offspring; organochlorine pesticide; pesticide exposure; response; sex; synaptic function; synucleinopathy; tool; toxicant; transcriptome sequencing; uptake

Project Summary The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in new data from our NIEHS-funded R21, α-synuclein (α-syn) preformed fibrils (PFFs). The epigenome is a potential mediator of this relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In line with this idea, we recently identified sex-specific differential methylation patterns in response to developmental dieldrin exposure. We hypothesize that dieldrin-induced epigenetic modifications during development cause changes in gene expression and phenotype that persist into adulthood, altering the sensitivity to parkinsonian insults and contributing to the development of PD. To test this hypothesis, we will determine cell-type specific DNA modifications and expression profiles of previously identified candidate genes in the dieldrin model (Aim 1); analyze the function of synaptic terminals in our novel dieldrin/PFF two-hit model (Aim 2); and determine if dieldrin or altered expression of candidate genes affects susceptibility to α-syn PFFs in a dopaminergic neuron cell culture model (Aim 3). The long-term goal of these experiments is to determine whether dieldrin-associated differentially methylated genes play a functional role in the biological response to parkinsonian toxicity. Completion of these aims will further the mission of NIEHS to increase our understanding of how the environment affects people in order to promote healthier lives, with a specific project goal of connecting exposures with functional changes in gene expression, neuronal phenotype, and PD susceptibility. The experiments proposed here will help to establish a biological mechanism linking developmental exposure to late life disease. This project will also expand our repertoire of tools for interrogating the function of epigenetic changes by establishing an in vitro experimental paradigm to connect specific epigenetic mechanisms with parkinsonian toxicity. With our in vivo model that combines developmental exposure with adult PFF injections, we will have a set of experimental systems in place that will allow us to test a wide variety of exposures, as well as combinations of exposures, both in vivo and in vitro. Together, this suite of tools will enable us to explore the mechanisms by which PD- related exposures alter neuronal vulnerability in PD, furthering the goal of NIEHS to understand how combined exposures affect disease pathogenesis and individual susceptibility.

项目摘要 大多数帕金森氏病（PD）病例不是由遗传的单基因突变和 疾病病因涉及遗传因素和环境因素的结合。流行病学研究表明 这种农药暴露，特别是对二氧化物蛋白等有机氯农药的暴露，增加了零星的风险 PD。在PD易感性提高的模型中，发育过程中暴露于狄氏素的小鼠表明男性特异性 增加对成年人对多巴胺能毒物MPTP的敏感性，在我们的新数据中 NIEHS资助的R21，α-突触核蛋白（α-Syn）预先形成的原纤维（PFF）。表观基因组是这种潜在的中介者 发育暴露，神经元脆弱性和成人疾病之间的关系。排队 有了这个想法，我们最近确定了针对发育的性别特异性差异化甲基化模式 Dieldrin暴露。我们假设在发育过程中，狄菲尔蛋白诱导的表观遗传修饰 导致基因表达和表型的变化，这种变化持续到成年，改变了灵敏度 向帕金森氏症侮辱和为PD的发展做出贡献。 为了检验这一假设，我们将确定细胞类型的特异性DNA修饰和表达曲线 先前鉴定的dieldrin模型中的候选基因（AIM 1）；分析突触终端的功能 我们的新型Dieldrin/PFF两次打击模型（AIM 2）；并确定dieldrin或候选基因表达的改变 在多巴胺能神经元细胞培养模型中影响对α-Syn PFF的敏感性（AIM 3）。长期目标 这些实验是确定与狄菲尔蛋白相关的甲基化基因是否发挥作用 对帕金森毒性的生物反应中的功能作用。 这些目标的完成将进一步促进NIEHS的使命，以提高我们对环境的理解 影响人们以促进更健康的生活，具体的项目目标是将风险接触与 基因表达，神经元表型和PD敏感性的功能变化。提出了实验 这里将有助于建立一种将发育暴露与​​晚期生命疾病联系起来的生物学机制。这个项目 还将扩大我们通过建立一个工具的工具曲目来询问表观遗传变化的功能 体外实验范式将特定的表观遗传机制与帕金森氏毒性联系起来。与我们一起 将发育暴露与​​成人PFF注射结合的体内模型，我们将有一组实验 已经到位的系统将使我们能够测试各种暴露以及暴露的组合， 体内和体外。这套工具共同使我们能够探索PD-的机制 相关暴露会改变PD中的神经元脆弱性，进一步发展NIEHS的目标以了解如何合并 暴露会影响疾病的发病机理和个体敏感性。