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Concentration-Response Evaluation of ToxCast Compounds for Multivariate Activity Patterns of Neural Network Function (INA 17)
Citation:
Kosnick, M., J. Strickland, S. Marvel, D. Wallis, K. Wallace, A. Richard, D. Reif, AND T. Shafer. Concentration-Response Evaluation of ToxCast Compounds for Multivariate Activity Patterns of Neural Network Function (INA 17). International Neurotoxicology Association INA-17, Dusseldorf, N/A, GERMANY, September 29 - October 03, 2019. https://doi.org/10.23645/epacomptox.24530218
Impact/Purpose:
Poster presented to the International Neurotoxicology Association INA-17 meeting September 2019. Screening chemicals for acute effects on neural network function will be valuable to OPPTS under the Lautenberg Chemical Safety Act.
Description:
The US Environmental Protection Agency’s ToxCast program has generated toxicity data for thousands of chemicals. However, it is recognized that the current panel of assays does not adequately assess the potential for chemical neurotoxicity. Networks of neurons grown on microelectrode arrays (MEAs) offer a promising approach to screen compounds efficiently for effects on neural firing, bursting, and connectivity patterns. Previously, MEAs were employed in a single-concentration screen of a portion of the ToxCast Phase II library for effects on mean firing rate (MFR) of networks of primary cortical cells. Here, we expand on this approach by retesting 384 compounds from EPA’s ToxCast Phase II library in concentration response across 43 network activity parameters (MFR, burst rate, burst duration, etc) to evaluate neural network function. This set of 384 compounds included 222 that were active in the previous single concentration screen. To identify the parameters most crucial in characterizing neuroactivity, we applied hierarchical clustering and machine learning methods to the full suite of chemical-parameter response data. Our approach identified 15 network parameters crucial in characterizing activity of 237 compounds that were response actives (“hits”). Potencies in this network function assay were compared to other ToxCast assays, and recognized neurotoxic compounds were among the most potent chemicals in this assay compared to other ToxCast assays. Of the MEA chemical-parameter responses, we identified three k-means clusters of chemical-parameter activity (i.e. multivariate MEA response patterns). Next, we evaluated the MEA clusters for enrichment of chemical features using a subset of ToxPrint chemotypes, revealing chemical structural features that distinguished the MEA clusters. Finally, we assessed the distributions of known neurotoxicants within the clusters and found that the MEA clusters discriminated specific bioactivity mechanisms. Taken together, these results demonstrate that multivariate MEA activity patterns can efficiently screen for diverse chemical activities relevant to neurotoxicity, and that response patterns may have predictive value related to chemical structural features. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: Concentration-Response Evaluation of ToxCast Compounds for Multivariate Activity Patterns of Neural Network Function (INA 17)
KOSNIK_INA_POSTER.PDF (PDF, NA pp, 822.786 KB, about PDF)