Developmental Neurotoxicity Zebrafish Assay and Data Collection - task order 1

发育神经毒性斑马鱼测定和数据收集 - 任务顺序 1

基本信息

批准号：
10475421
负责人：
ARANTZA MURIANA
金额：
$ 16.94万
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：
2021-07-06 至 2022-07-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475421
关键词：
3-Dimensional Address Adult Adverse effects Animal Model Animals Apoptosis Attention deficit hyperactivity disorder Biological Assay Bladder Botanicals Cell physiology Chemical Exposure Chemicals Consensus Contractor Control Groups Data Data Collection Development Dimethyl Sulfoxide Dose Edema Embryo Endocrine Disruptors Environmental Exposure Equilibrium Etiology Evaluation Event Exposure to Fertilization Flame Retardants Growth Head Hour Human In Vitro Incidence Incubated Intellectual functioning disability Larva Learning Disabilities Methods Mission Modeling Morphology Movement National Toxicology Program Necrosis Nervous system structure Netherlands Neurodevelopmental Disorder Neurotoxins Parents Phase Population Positioning Attribute Process Public Health Readiness Research Resources Series Swimming System Technology Testing Thallium Time Toxic Environmental Substances Toxic effect Zebrafish analog autism spectrum disorder base bisphenol A developmental neurotoxicity developmental toxicity environmental agent environmental chemical exposed human population flexibility good laboratory practice hazard in vitro Assay in vivo evaluation innovation migration mortality neural network neurobehavior neurodevelopment novel postnatal prenatal 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.

全球范围内人们普遍担心神经发育障碍（例如自闭症谱系障碍、注意力缺陷多动障碍 (ADHD)、智力障碍和其他学习障碍）在全球范围内的人口数量不断增加，而环境暴露可能是影响因素。由于神经发育及其多个关键过程的复杂性，其中一个或多个可能受到环境因素的干扰，目前评估具有未知发育神经毒性潜力的环境化合物的方法在很大程度上仍然无效。结合新颖和创新方法的发育神经毒性综合测试策略可以更好地为公共卫生决策提供有关发育神经毒性危害及其如何影响神经发育障碍病因的决策。发育中的神经系统比成人神经系统更容易受到化学物质的影响。发育中的神经系统的脆弱性是由关键神经发育细胞过程（即增殖、迁移、分化、凋亡、突触发生、网络成熟）在时间上限定的、严格调控的产前和产后发育阶段的出现造成的。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利影响。为了解决这一问题，全球一致认为需要开发一个新的框架来更有效地识别具有发育神经毒性潜力的化合物。国家毒理学计划在推进发育神经毒性领域具有独特的地位，因为其使命是及时推进公共卫生，并拥有资源、研究灵活性、专业知识以及与利益相关者的持续接触。国家毒理学计划设想开发和实施用于体外和体内测试的新工具和技术，以便能够识别、优先考虑和预测具有发育神经毒性潜力的化合物。重要的是，这些数据将可以免费公开访问。在此，我们建议为国家毒理学计划创建一系列涵盖增殖、迁移、凋亡和神经网络成熟等关键神经发育细胞过程的检测方法，以快速有效地测试具有发育神经毒性潜力的化合物类别。该电池包括高度准备的 2D 或 3D 体外测定和补充动物模型，并将涵盖几个关键的神经发育过程，这些过程是确定优先级、机制理解和进一步测试潜力的关键步骤。该电池将面临测试超过 100 种化学物质的挑战，这些化学物质是已知的神经毒物，已知对人类具有发育神经毒性但对动物未知，或者具有未知但怀疑的人类广泛接触的发育神经毒性潜力（阻燃剂、BPA 类似物、全氟烷基和多氟烷基物质、铊、嗜球果伞素）。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、全氟烷基和多氟烷基物质 (PFAS)、铊、甲氧基丙烯酸酯、植物药。