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Developmental Neurotoxicity Neural Crest Cell Migration Assay Data Collection - task order 1

发育神经毒性神经嵴细胞迁移测定数据收集 - 任务顺序 1

基本信息

批准号：
10475428
负责人：
MARCEL LEIST
金额：
$ 5.23万
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：
2021-07-12 至 2022-07-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475428
关键词：
3-Dimensional Address Adult Adverse effects Animal Model Animals Apoptosis Area Attention deficit hyperactivity disorder Biological Assay Botanicals Cell physiology Cells Chemical Exposure Chemicals Consensus Contractor Data Data Collection Development Dimethyl Sulfoxide Dose EGF gene Endocrine Disruptors Environmental Exposure Etiology Event Exposure to FGF2 gene Flame Retardants Growth Hour Human Image In Vitro Intellectual functioning disability Label Learning Disabilities Methods Migration Assay Mission Morphology National Toxicology Program Nervous system structure Neural Crest Cell Neurodevelopmental Disorder Neurotoxins Population Positioning Attribute Process Public Health Readiness Research Resources Series Stains TFAP2A gene Technology Testing Thallium Time analog autism spectrum disorder bisphenol A calcein AM cell motility developmental neurotoxicity differentiation protocol environmental agent environmental chemical exposed human population flexibility hazard immunocytochemistry in vitro Assay in vivo evaluation innovation interest migration nestin protein neural network neurodevelopment neurodevelopmental effect novel postnatal prenatal synaptogenesis tool transcriptional coactivator p75

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.

神经发育障碍（如自闭症谱系障碍、注意缺陷多动障碍（ADHD）、智力残疾和其他学习障碍）在全球人口中呈上升趋势，这是全球关注的问题，而环境暴露可能是促成因素。由于神经发育及其多个关键过程的复杂性，其中一个或多个过程可能受到环境因子的干扰，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。一种包含新颖和创新方法的发育性神经毒性综合检测策略可以更好地告知有关发育性神经毒性危害的公共卫生决策，以及它们如何可能导致神经发育障碍的病因。发育中的神经系统比成人的神经系统更容易受到化学物质的伤害。发育中的神经系统的脆弱性是由于关键的神经发育细胞过程（即增殖、迁移、分化、凋亡、突触发生、网络成熟）在时间上确定的和严格调节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生过程中，暴露于环境化学物质可能以剂量和/或时间依赖的方式引起不良反应。