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Screening the ToxCast Phase II library for acute neurotoxicity using cortical neurons grown on multi-well microelectrode array (mwMEA) plates
Citation:
Strickland, J., M. Martin, K. Houck, J. Ross, AND Tim Shafer. Screening the ToxCast Phase II library for acute neurotoxicity using cortical neurons grown on multi-well microelectrode array (mwMEA) plates. 2017 International Neurotoxicology Association Meeting, Florianopolis, BRAZIL, May 20 - 24, 2017.
Impact/Purpose:
This abstract describes screening of ToxCast compounds for acute neurotoxicity using neural networks grown on microelectrode arrays.
Description:
We have used primary cortical neurons grown in multi-well microelectrode array (mwMEA) plates to screen the ToxCast Phase II library of 1055 unique compounds for the ability to cause acute neurotoxicity. Each compound was screened at a single high concentration of 40 µM in triplicate. Following normalization of mean firing rate (nMFR), hit calls were made based on exceeding 2x the standard deviation of DMSO-treated control wells. Overall, 325 compounds exceeded the nMFR threshold. Of these, 308 compounds reduced nMFR past the hit threshold, while 17 compounds increased it beyond the threshold. Compounds classified as pesticides, pharmaceuticals, fungicides, chemical intermediates and herbicides accounted for ~78% of the hits. Changes in nMFR occurred largely in the absence of cytotoxicity, as only 8 compounds decreased viability following exposure. Further, based on hits in the single point screen, 384 compounds were identified for concentration-response evaluation. While complete analyses of these data are still ongoing, preliminary analysis indicates that pyrethroid insecticides cause both concentration and time-dependent changes in network function that aligns with the presence or absence of an α-cyano group. This is consistent with known structure-activity relationships for interactions of these compounds with voltage-gated sodium channels as well as acute neurotoxicity of these compounds. Overall, these results demonstrate that neural networks grown on MEAs can be a useful approach to screen compounds for the potential to cause acute neurotoxicity (This abstract was supported by a Cooperative Research and Development Agreement between the US EPA and Axion Biosystems (EPA CRADA #644-11). This abstract does not reflect EPA policy).