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Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons
Citation:
Valdivia, P., M. Martin, W. Lefew, D. Hall, J. Ross, K. Houck, AND Tim Shafer. Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons. Presented at Society of Toxicology Meeting, Phoenix, AZ, March 23 - 27, 2014.
Impact/Purpose:
Abstract will be presented at the Society of Toxicology Meeting, March 23-27, 2014, Phoenix, AZ
Description:
Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons P Valdivia1, M Martin2, WR LeFew3, D Hall3, J Ross1, K Houck2 and TJ Shafer3 1Axion Biosystems, Atlanta GA and 2NCCT, 3ISTD, NHEERL, ORD, US EPA, RTP, NC Assessment of spontaneous activity in neuronal cultures using multi-well microelectrode arrays (MEA) systems is a rapid, efficient and sensitive method to detect neuroactivity of drugs, chemicals, and particles. Effects of 68 ToxCast compounds (biased for neuroactive compounds) on neuronal activity using 48 well MEA plates were examined previously. In this experiment, effects of 20 additional ToxCast compounds, with a bias towards those inactive in ToxCast ion channel assays, were examined. Five additional compounds, known to be without effect on neuronal function in MEAs (negatives) were included. Further, these experiments refined data analysis approaches by considering recording stability post-hoc and establishing criteria for data inclusion. On day in vitro 14, 1 hr of baseline activity was recorded prior to exposing the cortical networks to 40 µM of each compound for 1 hr; the percent change in channel mean firing rate (MFR) was determined in the absence and presence of each chemical. Post-hoc analysis determined that the first 20 min of baseline recording was a period of activity stabilization and thus were omitted from analysis. A hit detection threshold of a 50% change in weighted (wMFR) was determined based on 1.5 standard deviations beyond the mean response to DMSO treatment; none of the 5 known negatives altered wMFR beyond this threshold. However, of the 20 ToxCast chemicals, 11 altered wMFR beyond the hit threshold. Hits included tetramethrin and fenthion, 3/5 conazoles, piperonyl butoxide, vinclozolin, lactofen, prochloraz, butyl benzyl phthalate and genistein. None of the 25 chemicals were cytotoxic. Concentration-response assessments were concordant with the single point screen result for 7/8 chemicals. These results indicate that spontaneous activity of cortical neurons measured with MEAs may be sensitive to chemicals with actions on endpoints other than ion channels. (This abstract was supported by CRADA #644-11 with Axion Biosystems and does not reflect EPA Policy)