Developmental Neurotoxicity Zebrafish Assay and Data Analysis and Reporting - task order 2

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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.