Altered transport and epigenomic changes in maneb-potentiated neurotoxicity

代森锰增强神经毒性的转运和表观基因组变化

• 批准号: 8425616
• 负责人: James R Roede
• 金额: $ 7.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425616
• 关键词: Acetylation; Acute; Adverse reactions; Affect; Amino Acid Transporter; Biological Assay; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Chemosensitization; Complex; Copper; Corpus striatum structure; Coupled; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA-Binding Proteins; DNMT3B gene; DNMT3a; Data; Deposition; Development; Disease; Dopamine; Drug effect disorder; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Epidemiology; Exposure to; Fostering; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Grant; Herbicides; High Pressure Liquid Chromatography; Histone Acetylation; Histone H3; In Vitro; Industrial fungicide; Ions; Iron; K-Series Research Career Programs; Knowledge; Long-Term Effects; Maneb; Mass Spectrum Analysis; Measures; Mediating; Mentors; Metabolism; Metals; Methods; Methylation; Modification; National Institute of Environmental Health Sciences; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neutral Amino Acid Transport Systems; Oxidative Stress; Paraquat; Parkinson Disease; Pesticides; Phase; Plasma; Plasmids; Play; Population; Predisposition; Preparation; Principal Investigator; Probability; Protons; RNA Sequences; Research; Risk; Role; Scientist; Small Interfering RNA; Substantia nigra structure; Sulfhydryl Compounds; Testing; Toxic effect; Training; Work; aldehyde dehydrogenase 1; base; career; design; divalent metal; dopaminergic neuron; environmental agent; epigenomics; histone modification; in vivo; in vivo Model; interest; meetings; neurotoxic; neurotoxicity; next generation; oxidation; pesticide exposure; programs; promoter; public health relevance; response; uptake

DESCRIPTION (provided by applicant): Repeated exposure to environmental agents, such as pesticides and metals, can alter gene expression patterns, potentially resulting in enhanced susceptibility to future toxic insults. With greater than 90% of Parkinson's disease (PD) cases considered idiopathic, epidemiology has indicated the involvement of pesticides in PD. Specifically, exposures to the herbicide paraquat (PQ) and the fungicide maneb (MB) are associated with a 75-80% increased risk of PD. Additionally, epigenomic changes in gene expression are postulated to play a role in neurodegenerative disorders like PD. The candidate's previous NIEHS funded research (F32 ES019821) demonstrated that MB-potentiation of PQ neurotoxicity was not simply due to enhanced oxidative stress, but a complex mechanism involving thiol-modification by MB and oxidation by PQ. Additional gene expression data show that MB significantly altered the expression of more genes compared to PQ. MB induced 4 different amino acid transporters and 2 metal transporters. Of particular interest, Ala-, Ser-, Cys- preferring transporter-1 (ASCT-1 (Slc1a4)) and proton coupled, divalent metal ion transporter (LSH (Slc11a1)) were induced greater than 2-fold by MB and PQ+MB compared to control. The working hypothesis for this K99/R00 Career Development Award proposal is that long-term exposure to MB potentiates PQ-mediated neurodegeneration of dopaminergic neurons caused by increased uptake of PQ due to modified amino acid transporter expression, metal-mediated oxidative stress and changes in the epigenome. To accomplish this, 4 specific aims (2 mentored, 2 independent) consisting of in vitro and in vivo models will be used. In Specific Aim 1 (K99 mentored phase), both in vitro and in vivo models will be employed to determine if potentiation of PQ neurotoxicity is due to MB-mediated induction of ASCT-1 and LSH. Specific Aim 2 (K99 mentored phase) will study if methylation of genes associated with dopamine metabolism is mechanistically involved in MB- potentiated PQ neurotoxicity. Research proposed in Specific Aim 3 (R00 independent phase) will explore alterations in histone H3 methylation and acetylation caused by long term pesticide exposure. Lastly, Specific Aim 4 (R00 independent phase) will investigate global alterations in the DNA methylome in response to long term pesticide exposure. This project is designed to further develop the candidate's research program and fulfill strategic goals of the NIEHS by connecting environmental influences to disease through the study of epigenomics and to train the next generation of environmental scientists. The proposed research will meet these goals and foster the development of an independent research career. Public Health Relevance: Pesticide exposure is believed to contribute to the development of Parkinson's disease, which affects 1% of the worldwide population. The candidate believes that effects occur due to a combination of pesticides, where one pesticide can enhance the toxicity of a second pesticide via increased transport and altered gene expression. This project is designed to test this hypothesis.

描述（由申请人提供）：反复接触环境药物（例如农药和金属）可以改变基因表达模式，从而可能增加对未来有毒损害的敏感性。帕金森氏病（PD）的90％被认为是特发性的病例，流行病学表明农药参与了PD。具体而言，对除草剂Paraquat（PQ）和杀菌剂MANEB（MB）的暴露与PD风险增加了75-80％。另外，假设基因表达的表观基因组变化在PD等神经退行性疾病中起作用。候选人以前的NIEHS资助研究（F32 ES019821）表明，PQ神经毒性的MB-统计不仅是由于增强的氧化应激，而且还引起了一种复杂的机制，涉及通过MB进行硫醇化和PQ进行氧化。其他基因表达数据表明，与PQ相比，MB显着改变了更多基因的表达。 MB诱导4种不同的氨基酸转运蛋白和2个金属转运蛋白。特别感兴趣的Ala-， 与对照相比，MB和PQ+MB诱导了Ser-，Cys-偏爱转运蛋白1（ASCT-1（SLC1A4））和质子耦合，二价金属离子转运蛋白（LSH（SLC11A1））的2倍以上。该K99/R00职业发展奖的工作假设是，长期暴露于MB增强PQ介导的多巴胺能神经元的神经退行性因素是由于氨基酸转运蛋白转运蛋白表达，金属介导的氧化应激和表皮镜的变化而引起的PQ引起的多巴胺能神经元的神经退行性。为此，将使用4个由体外和体内模型组成的特定目标（2个指导，2个独立）。在特定的目标1（K99指导阶段）中，将使用体外和体内模型来确定PQ神经毒性的增强是否是由于MB介导的ASCT-1和LSH的诱导。具体目标2（K99指导阶段）将研究与多巴胺代谢相关的基因的甲基化在机械上与MB-增强的PQ神经毒性有关。在特定目标3（R00独立阶段）中提出的研究将探索由长期农药暴露引起的组蛋白H3甲基化和乙酰化的改变。最后，特定的目标4（R00独立阶段）将对长期农药暴露的DNA甲基团进行全局变化。该项目旨在通过研究表观基因组学并培训下一代环境科学家，通过将环境影响与疾病联系起来，进一步开发候选人的研究计划并实现NIEH的战略目标。拟议的研究将符合这些目标，并促进独立研究职业的发展。 公共卫生相关性：据信农药暴露会导致帕金森氏病的发展，这影响了全球人口的1％。候选人认为，由于农药的结合而产生的影响，其中一种农药可以通过增加的转运和基因表达改变来增强第二农药的毒性。该项目旨在检验这一假设。