Project 3: Mitochondrial and cellular mechanisms of neurotoxicity of Superfund chemical co-exposures

项目 3：Superfund 化学品共同暴露神经毒性的线粒体和细胞机制

基本信息

批准号：
10353153
负责人：
Joel Newman Meyer
金额：
$ 28.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10353153
关键词：
Affect Architecture Aromatic Polycyclic Hydrocarbons Behavior Behavioral Bioenergetics Cadmium Caenorhabditis elegans Cell physiology Cells Chemical Exposure Chemicals Collaborations Complement Complex Complex Mixtures Development Economic Models Elderly Embryo Environmental Pollution Epigenetic Process Exposure to Female Fishes Future Hazardous Chemicals Homeostasis Human In Vitro Individual Intervention Laboratories Lead Life Maps Measures Mediating Mission Mitochondria Modeling Modification Molecular Molecular Target Morphology Nerve Degeneration Nervous system structure Neurons Neurotoxins Outcome Oxidation-Reduction Pathway interactions Pattern Persons Pharmacology Physiological Policies Predisposition Production Rattus Regulation Research Secondary to Sex Differences Stress Structure Superfund System Testing Time Toxic effect Universities Variant Work adverse outcome biological adaptation to stress cell type cost developmental neurotoxicity early life exposure environmental justice experimental study follow-up improved in vivo macromolecule male mitochondrial dysfunction nerve stem cell neurodevelopment neurogenesis neurotoxic neurotoxicity novel pollutant remediation resilience sex superfund chemical superfund site tool toxicant

项目摘要

Abstract In ongoing work by this Project, we have found that developmental exposures to mitochondrial toxicants cause neurotoxic outcomes in Caenorhabditis elegans, including morphological alterations in neurons, altered behavior, and, in the long term, increased susceptibility to neurodegeneration. In line with the EPA, we describe all of these as “developmental neurotoxicity (DNT),” because they result from exposures that occur during development. Two important and overarching mechanisms of DNT are 1) changes to neurogenesis resulting in altered cell fate, morphology, and connectivity (“hardwiring”), and 2) persistent changes to the function of neurons that appear to be morphologically normal (epigenetic “programming”). Distinguishing these is challenging; we propose a novel and powerful way to assess each possibility. We will begin with an in vivo yet relatively high-throughput and economic model, C. elegans. C. elegans offers an additional, key benefit: developmental neurogenesis is normally invariant, permitting clear identification of variation in hardwiring as well as behavioral and stress-responsive changes without morphological alteration (programming). Work in C. elegans will be followed by testing in human neuronal stem cells (hNSCs) that permit human-relevant DNT testing, plus the opportunity to identify sex-specific differences and epigenetic modifications. Relatively few chemicals have been rigorously evaluated for DNT. The paucity of information is even more pronounced for chemical co-exposures, despite the fact that combined exposures are the reality. This lack of testing of mixtures results partly from regulatory policy, and partly from technical challenges in laboratory testing of co-exposures. Our combined in vivo-in vitro approach will permit us to rigorously test for DNT resulting from both complex environmental mixtures, and from defined combinations of individual Superfund chemicals that we will evaluate for non-additive effects. We will test the effects of the prototypical developmental neurotoxicants Pb, Cd, and polycyclic aromatic hydrocarbons, singly and in combinations dictated by known environmental concentrations. We will compare our outcomes in C. elegans and hNSCs, to those obtained by other Projects in fish, rats, and people. Demonstration that C. elegans can be reliably used to investigate mixture DNT will add a powerful new model for testing and regulation of environmental mixtures. Finally, we will test the degree to which mitochondrial dysfunction, key to neurodevelopment, drives DNT by these prototypical chemicals. These chemicals have multiple molecular targets, including but not limited to different mitochondrial macromolecules. The fact that these chemicals individually all affect mitochondria and neurons, but by different mechanisms, is why we predict synergistic interactions. However, while mitochondria are known targets of these chemicals, the extent to which mitochondrial toxicity drives their DNT is not known. Our work will establish the contribution of mitochondrial dysfunction in single and combined chemical DNT, informing development of adverse outcome pathways and intervention efforts.

抽象的在该项目正在进行的工作中，我们发现对线粒体有毒物质的发育暴露会导致秀丽隐杆线虫的神经毒性结局，包括神经元的形态改变，改变了行为，从长远来看，增加了对神经退行性的敏感性。与EPA一致，我们描述所有这些都是“发育神经毒性（DNT）”，因为它们是由于在发展。 DNT的两个重要和总体机制是1）神经发生的变化，导致改变了细胞命运，形态和连通性（“硬线”），2）持续变化在形态上正常的神经元（表观遗传“编程”）。区分这些是具有挑战性的;我们提出了一种新颖而有力的方法来评估每种可能性。我们将从一个体内开始秀丽隐杆线虫提供了额外的关键好处：发育神经发生通常是不变的，也可以清楚地识别硬线变化作为行为和应力响应性的变化而没有形态学改变（编程）。在C. 秀丽隐杆线将在人类神经元干细胞（HNSC）中进行测试，该干细胞允许与人相关的DNT 测试，以及确定性别特定差异和表观遗传修饰的机会。对DNT进行了严格评估的相对较少的化学物质。信息的匮乏甚至更多对于化学共同曝光而言，宣布合并暴露是现实的事实。这种缺乏混合物的测试部分是由监管政策导致的，部分是由实验室测试中的技术挑战共同曝光。我们合并的体内体外方法将使我们能够严格测试复杂的环境混合物，以及来自我们的单个超级基金化学物质的明确组合将评估非添加效应。我们将测试原型发育神经毒性的影响 PB，CD和多环芳烃烃，单独，由已知环境决定的组合浓度。我们将将我们在秀丽隐杆线虫和HNSC中的结果与其他项目获得的结果进行比较鱼，老鼠和人。演示秀丽隐杆线虫可以可靠地用于研究混合物DNT会增加测试和调节环境混合物的强大新模型。最后，我们将测试线粒体功能障碍的程度，神经发育的关键，驱动DNT 这些原型化学物质。这些化学物质具有多个分子靶标，包括但不限于不同的线粒体大分子。这些化学物质单独影响线粒体和神经元，但通过不同的机制，这就是为什么我们预测协同相互作用的原因。但是，线粒体是这些化学物质的已知靶标，是未知的线粒体毒性驱动其DNT的程度。我们的工作将确定单一和联合化学DNT中线粒体功能障碍的贡献，告知不良结果途径和干预工作的发展。