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Human Brain Organoid Model to Study Developmental Neurotoxicity
Citation:
Conley, J., E. Hunter, AND T. Shafer. Human Brain Organoid Model to Study Developmental Neurotoxicity. North Carolina Society of Toxicology (NCSOT) Annual Meeting, RTP, NC, September 14, 2023. https://doi.org/10.23645/epacomptox.24157887
Impact/Purpose:
Presentation to the North Carolina Society of Toxicology (NCSOT) Annual Meeting September 2023
Description:
Human in vitro models of the developing brain are important for studying neurodevelopment and the potential developmental neurotoxicity (DNT) of environmental and pharmacological compounds. Exposure to these compounds during neurodevelopment can potentially cause adverse effects such as morphological alterations and/or function changes in the developing brain. Over the past 15 years, in vitro two-dimensional models have been developed as assays to characterized chemicals for potential DNT hazard. Organoids are a three-dimensional (3D) cell culture system that mimic the complex structure and development of the human brain better than their two-dimensional counterparts. In this study, we establish and characterize an induced pluripotent stem cell (iPSC)-derived brain organoid model containing mature neurons and glial cells originally developed at Johns Hopkins University. Immunocytochemistry and high-content imaging of the organoids show a decrease in proliferation and neural progenitor markers and an increase in neuronal, astrocyte, and oligodendrocyte markers during differentiation (weeks 0-10), indicating that during this time the organoids are progressing along a neurodevelopmental ontogeny. Neural organoids were plated on a high-density microelectrode array (hdMEA) to measure the spontaneous electric field potentials produced. Treatment with Picrotoxin (PTX), Tetrodotoxin (TTX) and Nicotine (NIC) resulted in the expected changes in spontaneous electrical activity following an acute one-hour exposure; PTX increased network activity while TTX and NIC decreased network activity. This work demonstrates the importance of 3D organotypic models for neurotoxicological studies, especially as rat primary cortical cultures do not have robust responses to nicotine. Future studies will develop an exposure protocol relevant to neurodevelopment and assess effects of additional compounds, including neonicotinoid insecticides and per- and polyfluoroalkyl substances (PFAS). This abstract does not represent US EPA policy.
URLs/Downloads:
DOI: Human Brain Organoid Model to Study Developmental Neurotoxicity
JCONLEY_NCSOT_9.14.23_FINAL.PDF (PDF, NA pp, 1083.131 KB, about PDF)