Citation:

McConnell, E., M. McClain, J. Ross, W. Lefew, AND Tim Shafer. Evaluation of Multi-Well Microelectrode Arrays for Neurotoxicity Screening Using a Chemical Training Set. NEUROTOXICOLOGY. Intox Press, Inc, Little Rock, AR, 33(5):1048-57, (2012).

Impact/Purpose:

This is an advance for the field in that it demonstrated the ability of MEA approaches to detect chemical toxicity and moved this platform to a higher throughput. For the Agency, these results provide a plausible method for testing for neurotoxicity and developmental neurotoxicity and increase the confidence that effects of previously uncharacterized compounds can be predicted using this approach.

Description:

Microelectrode array (MEA) approaches have been proposed as a tool for detecting functional changes in electrically-excitable cells, including neurons, exposed to drugs, chemical or particles. However, conventional single well-MEA systems lack the throughput necessary for screening large numbers of uncharacterized compounds. Recently, multi-well MEA (mwMEA) formats have become available to address the need for increased throughput. The current experiments examined the effects of a training set of 30 chemicals on spontaneous activity in networks of cortical neurons grown on mwMEA plates. Each plate contained 12 wells with 64 microelectrodes/well, for a total of 768 channels. Of the 30 chemicals evaluated, 23 were known to alter neuronal function in vivo ("positives"), including 6 GABAergic and 3 glutamatergic antagonists/agonists, 4 pyrethroids, 3 metals, 2 cholinesterase inhibitors, 2 nicotinic acetylcholine receport agonists, valproic acid, verapamil, and fluoxetine. Seven compounds expected to have no effect on neuronal function were tested as "negatives" (glyphosate, acetaminophen, dimethly phthalate, paraquate, saccharin, d-sorbitol, amoxicillin). Following collection of 33 minutes of baseline activity, chemical effects (50um or highest soluble concentration) were recorded for 33 minutes. Twenty of the positives altered the mean network spike rate by more than the 14% threshold (two standard deviations from the mean for DMSO control). The three positives without effect were bifenthrin, nicotine and imidacloprid. None of the negative compounds caused a change in activity beyond the threshold. Based on these results, the mwMEA assay has both high sensitivity (87% identification of positive compounds) and specificity (100% of identification of negative compounds). These experiments demonstrate the capacity of mwMEAs to screen compounds for neurotoxic effects mediated by a broad variety of mechanisms.

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