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Novel quantitative methods for characterization of chemical induced functional alteration in developing neuronal cultures
Citation:
Hall, D., E. Cortterill, K. Wallace, J. Brown, S. Eglen, W. Mundy, AND Tim Shafer. Novel quantitative methods for characterization of chemical induced functional alteration in developing neuronal cultures. Society of Toxicology, San Diego, CA, March 22 - 27, 2015.
Impact/Purpose:
To be presented at the annual SOT meeting in San Diego, CA
Description:
ABSTRACT BODY: Thousands of chemicals lack adequate testing for adverse effects on nervous system development, stimulating research into alternative methods to screen chemicals for potential developmental neurotoxicity. Microelectrode arrays (MEA) collect action potential spiking and bursting patterns from in vitro cultures of rat cortex, offering a high-content method to assess chemical-induced alterations in development of functional neural networks. However, appropriate methods are needed to analyze information-rich MEA recordings to determine the endpoints that best distinguish developmentally neurotoxic chemicals from controls. The present study evaluated a 2 step analytic approach for its ability to identify and describe alterations in developing neural networks treated with a training set of 5 compounds (acetaminophen, bis-1, domoic acid, loperamide, mevastatin and NaVO4). On days in vitro (DIV) 2, 5, 7, 9 and 12 data were collected and analyzed for 17 different bursting parameters (burst rate, duration, etc). In controls, all of these parameters showed a clear developmental trajectory. First, random forest and support vector machine classification techniques rank the effect of a given chemical on these parameters, providing a subset endpoints most affected by each chemical. Following this, linear regression analysis across DIV was conducted for each concentration and utilized to determine concentration–dependent developmental effects. For acetaminophen, a negative control, no endpoints had significant concentration-related trends. For the remaining 4 compounds, significant concentration-related trends were observed for various endpoints, with mean firing rate, #bursts/min, and correlation of activity altered for 4, 3 and 2 chemicals, respectively. This analysis approach allows greater utilization of the high content data from MEAs for characterizing chemicals for potential developmental neurotoxicity. (This abstract does not reflect Agency Policy)