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Comparison of a high-density microelectrode array (MEA) assay for neurotoxicity screening using a 3D human iPSC-derived brain organoid model versus a 2D rat cortical cell model
Citation:
Carstens, K., E. Gronskaya, D. Jaeckel, T. Shafer, M. Zurich, AND D. Pamies. Comparison of a high-density microelectrode array (MEA) assay for neurotoxicity screening using a 3D human iPSC-derived brain organoid model versus a 2D rat cortical cell model. International Conference on Developmental Neurotoxicity Testing (DNT5), Konstanz, GERMANY, April 07 - 10, 2024. https://doi.org/10.23645/epacomptox.25742760
Impact/Purpose:
This poster presentation will be presented at the DNT5 conference in Konstanz, Germany in an effort to share research and network with an international group of researchers and stakeholders. This research falls under EPA's Chemical Safety for Sustainability research program, addressed the need to develop and evaluate new approach methods (NAMs) to assess neurotoxicity potential in a human-relevant model.
Description:
The relationship between environmental chemical exposure and a spectrum of neurological diseases is well-established. However, unraveling the underlying mechanism between human exposure and toxic outcomes presents significant challenges. Evaluation of neurotoxicity potential using animal testing is resource intensive (financial, labor, and animal use) and faces uncertainties regarding biological relevance to human health outcomes. Therefore, there is a need to develop efficient and human-relevant in vitro new approach methodologies (NAMs) to screen chemicals for neurotoxicity potential. Recording of neural network activity using the microelectrode array (MEA) technology has been identified as a reliable and reproducible method to evaluate neurotoxicity. Much of this research has been performed in 2D rat primary cortical cell model and studies evaluating human-relevant models are limited. The BrainSpheres model is a promising functional human induced pluripotent stem cell (iPSC)-derived 3D brain model comprising neurons, astrocytes, and oligodendrocytes. In this study, we demonstrate reproducible spontaneous neural firing and network bursting parameters from 8-week-old BrainSpheres using a high-density MEA technology. The performance of this model was evaluated as a human-relevant NAM by conducting a multi-concentration, 12-day exposure study of a set of ten chemicals, including two assay positive controls (Loperamide, Domoic Acid), one assay negative control (acetaminophen), and seven evaluation chemicals. Concentration-response modeling was performed on parameters measuring features of neuronal activity, such as mean firing rate and network connectivity, and compared to screening data from a similar MEA model using a 2D-rat model. Similar to the 2D-rat model, Loperamide and Domoic Acid demonstrated bioactivity at non-cytotoxic concentrations in the BrainSphere model, while Acetaminophen was inactive. For the seven chemicals that demonstrated bioactivity in both models, minimum potencies estimated by each model fell within 0.5 log10-µM for three chemicals and were more potent in the rat model by more than 0.5 log10-µM for four chemicals, suggesting that the 2D-rat model may be more sensitive for detecting changes in neural activity. Only Loperamide demonstrated cytotoxicity in the BrainSpheres, while four chemicals, including Loperamide, were cytotoxicity in the 2D-rat model. These results indicate that differences in experimental design and biological relevance between models should be considered in the fit-for-purpose implementation of NAMs for human neurotoxicity assessment. (This abstract does not reflect the policy of the US Environmental Protection Agency).
URLs/Downloads:
DOI: Comparison of a high-density microelectrode array (MEA) assay for neurotoxicity screening using a 3D human iPSC-derived brain organoid model versus a 2D rat cortical cell model
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