Developmental Neurotoxicity Zebrafish Bioavailability Assay - task order 3

发育神经毒性斑马鱼生物利用度测定 - 任务顺序 3

基本信息

批准号：
10475424
负责人：
ARANTZA MURIANA
金额：
$ 16.39万
依托单位：
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2022-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475424
关键词：
3-Dimensional Address Adult Adverse effects Animal Model Animals Apoptosis Attention deficit hyperactivity disorder Biological Assay Biological Availability Botanicals Cell physiology Chemical Exposure Chemicals Consensus Contracts Data Development Dose Embryo Endocrine Disruptors Environmental Exposure Etiology Evaluation Event Exposure to Flame Retardants Gas Chromatography Growth Human In Vitro Inductively Coupled Plasma Mass Spectrometry Intellectual functioning disability Learning Disabilities Mass Fragmentography Mass Spectrum Analysis Methods Mission National Toxicology Program Nervous system structure Neurodevelopmental Disorder Neurotoxins Population Positioning Attribute Process Public Health Readiness Research Resources Technology Testing Thallium Time Zebrafish analog autism spectrum disorder bisphenol A developmental neurotoxicity environmental agent environmental chemical experimental study exposed human population flexibility hazard in vitro Assay in vivo evaluation innovation liquid chromatography mass spectrometry migration neural network neurodevelopment novel postnatal prenatal purge synaptogenesis tool

项目摘要

There is global concern that neurodevelopmental disorders (e.g., autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), intellectual disability, and other learning disabilities) are rising in populations worldwide, and that environmental exposures may be contributing factors. Current methods to evaluate environmental compounds with unknown developmental neurotoxicity potential remain largely ineffective due to the complexity of neurodevelopment with its multiple key processes, one or more of which might be perturbed by an environmental agent. An integrated testing strategy for developmental neurotoxicity that incorporates novel and innovative methods could better inform public health decisions on developmental neurotoxicity hazards and how they might contribute to the etiology of neurodevelopmental disorders. The developing nervous system is more vulnerable to chemical exposure than the adult nervous system. Vulnerability of the developing nervous systems results from the emergence of key neurodevelopmental cellular processes (i.e., proliferation, migration, differentiation, apoptosis, synaptogenesis, network maturation) during temporally defined, and tightly regulated prenatal and postnatal developmental stages. Exposure to environmental chemicals during the ontogeny of these key neurodevelopmental events may cause adverse effects in a dose and/or time-dependent manner. To address this concern, there is global consensus on the need for the development of a new framework to identify compounds with developmental neurotoxicity potential more effectively. The National Toxicology Program is uniquely positioned to advance the field of developmental neurotoxicity due to its mission of timely advancement of public health, combined with having resources, research flexibility, expertise, and continual engagement with stakeholders. The National Toxicology Program envisions developing and implementing new tools and technologies for both in vitro, and in vivo testing to be able to identify, prioritize, and predict compounds with potential for developmental neurotoxicity. Importantly, this data will be freely and publicly accessible. Herein, we propose to create a battery of assays that cover key neurodevelopmental cellular processes of proliferation, migration, apoptosis, and neural network maturation for the National Toxicology Program to test classes of compounds with developmental neurotoxicity potential rapidly and efficiently. The battery includes high readiness 2D or 3D in vitro assays and complementary animal models and will cover several key neurodevelopmental processes that serve as a critical step for prioritization, mechanistic understanding, and potential for further testing. The battery will be challenged by testing >100 chemicals that are known neurotoxicants, have known developmental neurotoxicity in humans but unknown in animals, or have unknown but suspected developmental neurotoxicity potential with widespread human exposure (flame retardants, BPA analogs, perfluoroalkyl and polyfluoroalkyl substances, thallium, strobilurins). Key words: public health, developmental neurotoxicity, neurodevelopmental disorders, environmental exposures, cellular processes, endocrine disruptors, flame retardants, bisphenol-A (BPA) analogs, perfluoroalkyl and polyfluoroalkyl substances (PFAS), thallium, strobilurins, botanicals.

全球关注的是，全球人口中的神经发育障碍（例如自闭症谱系障碍，注意力缺陷多动症（ADHD），智力残疾和其他学习障碍）正在增加，并且环境暴露可能是促成因素。当前评估具有未知发育神经毒性潜力的环境化合物的方法，由于神经发育与其多个关键过程的复杂性，其多个关键过程的复杂性，其中一个或多个可能受到环境药物的扰动。结合新颖和创新方法的发育神经毒性的综合测试策略可以更好地告知关于发育神经毒性危害的公共卫生决策，以及它们如何对神经发育障碍的病因贡献。与成人神经系统相比，发育中的神经系统更容易受到化学暴露。发育中神经系统的脆弱性是由于关键神经发育过程的出现（即，在时间定义的过程中，增殖，迁移，分化，凋亡，突触发生，网络成熟，网络成熟）的出现以及严格调节的产前和产后发育阶段。在这些关键神经发育事件的个体发育过程中，暴露于环境化学物质可能会以剂量和/或时间依赖性方式引起不良反应。为了解决这一问题，关于开发新框架以更有效地识别具有发育神经毒性潜力的化合物的新框架的必要性达成了全球共识。国家毒理学计划的独特位置可以推进发展性神经毒性领域，因为它及时提高了公共卫生的任务，并具有资源，研究灵活性，专业知识以及与利益相关者的持续参与。国家毒理学计划设想为体外开发和实施新的工具和技术，并在体内测试能够识别，优先级和预测具有发育神经毒性潜力的化合物。重要的是，这些数据将是可以自由公开访问的。本文中，我们建议创建一系列测定法，以涵盖国家毒理学计划的增殖，迁移，凋亡和神经网络成熟的关键神经发育过程，以快速有效地测试具有发育神经毒性潜力的化合物类别。电池包括高昂准备2D或3D体外测定和互补的动物模型，将涵盖几个关键的神经发育过程，这是优先次序，机械理解和进一步测试潜力的关键步骤。 The battery will be challenged by testing >100 chemicals that are known neurotoxicants, have known developmental neurotoxicity in humans but unknown in animals, or have unknown but suspected developmental neurotoxicity potential with widespread human exposure (flame retardants, BPA analogs, perfluoroalkyl and polyfluoroalkyl substances, thallium, strobilurins). 关键词：公共卫生，发育神经毒性，神经发育障碍，环境暴露，细胞过程，内分泌干扰物，阻燃剂，双酚-A（BPA）类似物，荧光素烷基和聚氟烷基物质（PFAS），thallium，thallium，thallium，protobilurinicals，botobilitics，botanical，bototanics。