The ToxiFin Platform: Advancing High-Throughput Screening and Mechanistic Insights For Developmental Neurotoxicants Using the Zebrafish Model

SUMMARY With increasing rates of neurodevelopmental disorders in children, there is an urgent need to assess the impact of household, agricultural, and industrial chemicals on neurological development. Conventional rodent testing is costly and time-consuming, hindering widespread adoption. This study aims to develop a high-throughput and sensitive screening platform for developmental neurotoxicity (DNT) testing, making it accessible to manufacturers, agricultural users, waste generators, and local governments. The results of expanded DNT testing could inform governmental policies, improve environmental clean-up efforts, and guide the development of safer alternatives to neurotoxic chemicals. Current methods rely on treating rat mothers during pregnancy and lactation, limiting testing to a fraction of the thousands of chemicals present in the environment. Moreover, these methods may not detect subtle effects on synapse formation and circuitry performance. To address these limitations, this study proposes the ToxiFin platform, utilizing the zebrafish model for cost-effective and high-fidelity DNT screening. This platform incorporates automated screening and analysis methods to efficiently provide endpoints relevant to circuit formation, circuit function, and brain organization. Aim 1 focuses on developing a high-throughput screen for neural circuit formation by engineering a transgenic zebrafish line with bioluminescent signals when synapses are formed. Aim 2 aims to develop an efficient and scalable screen for assessing developmental neurotoxic effects on neural circuit function and central nervous system organization. This will be achieved through screening behaviors associated with neurodevelopmental health, from embryo to adult stages. The proposed platform has the potential to assess a broader range of chemicals for DNT, diversify endpoints for detection, and enable effective risk assessment, regulation, and intervention strategies. By utilizing the zebrafish model, this study offers a cost-effective and efficient alternative to conventional rodent testing methods, with implications for public health and environmental protection.