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

• 批准号: 10475424
• 负责人: ARANTZA MURIANA
• 金额: $ 16.39万
• 依托单位国家: 美国
• 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

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）、智力残疾和其他学习障碍）在全世界人口中正在上升，环境暴露可能是促成因素。由于神经发育的复杂性及其多个关键过程，其中一个或多个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。采用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关于发育神经毒性危害的公共卫生决策提供信息，以及它们如何有助于神经发育障碍的病因学。发育中的神经系统比成人神经系统更容易受到化学品的影响。发育中的神经系统的脆弱性是由关键神经发育细胞过程的出现引起的（即，增殖、迁移、分化、凋亡、突触发生、网络成熟）。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品可能会以剂量和/或时间依赖性方式引起不良反应。 为了解决这一问题，全球一致认为需要制定一个新的框架，以更有效地识别具有发育神经毒性潜力的化合物。国家毒理学计划是独特的定位，以推进发育神经毒性领域，由于其及时推进公共卫生的使命，结合资源，研究的灵活性，专业知识，并与利益相关者的持续参与。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，这些数据将可以自由且公开地访问。 在此，我们建议创建一组试验，涵盖关键的神经发育细胞增殖，迁移，凋亡和神经网络成熟的国家毒理学计划，以快速有效地测试类化合物与发育神经毒性潜力。 该系列包括高准备度2D或3D体外试验和补充动物模型，并将涵盖几个关键的神经发育过程，这些过程是确定优先顺序、理解机制和进一步测试潜力的关键步骤。将通过测试超过100种已知的神经毒物、已知对人类具有发育神经毒性但对动物具有未知毒性或对人类广泛接触具有未知但疑似发育神经毒性的化学物质（阻燃剂、BPA类似物、全氟烷基和多氟烷基物质、铊、嗜球果伞素）来挑战该组合。 关键词：公共卫生、发育神经毒性、神经发育障碍、环境接触、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、嗜球果伞素、植物药。