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Screening for Developmental Neurotoxicants using In Vitro "Brain on a Chip" Cultures
Citation:
Brown, J., K. Wallace, D. Hall, W. Mundy, AND Tim Shafer. Screening for Developmental Neurotoxicants using In Vitro "Brain on a Chip" Cultures. Society of Toxicology, San Diego, CA, March 22 - 27, 2015.
Impact/Purpose:
To be presented at the annual Society of Toxicology Meeting in San Diego, CA. March 22-26, 2015
Description:
Currently there are thousands of chemicals in the environment that have not been screened for their potential to cause developmental neurotoxicity (DNT). The use of microelectrode array (MEA) technology allows for simultaneous extracellular measurement of action potential (spike) rates and patterns from multiple locations in neural networks. Further, repeated measurements over successive days from these "brain on a chip" cultures allows the development of spontaneous activity to be monitored and the effect of chemical exposures on network development to be characterized. This experiment examined the ontogeny of spontaneous network activity in primary rat neural cells dosed with a “training set” of 5 chemicals (Bis 1, mevastatin, Na3VO4, acetaminophen, and loperamide) previously assessed in neurite outgrowth and synapse formation assays. Cells were grown on 48 well MEA plates and treated with chemical (0.01-30 uM) 2 hours after plating. Their activity was recorded for a period of 15 minutes on days in vitro (DIV) 2, 5, 7, 9, and 12. Cell viability was assessed on DIV 12. When mean firing rate (MFR) and number of active electrodes (#AE) were examined on DIV 12, networks treated with acetaminophen showed no effect on MFR, #AE or viability. Compared to controls, networks treated with Bis 1 and loperamide showed a decrease in MFR at concentrations below those that caused cell death. MFR for cells treated with Bis 1 decreased at 1uM, and those treated with loperamide decreased at 0.1 uM. Mevastatin and Na3VO4 had effects on MFR and #AE only at concentrations that were also cytotoxic. Mevastatin caused cytotoxicity at its lowest concentration (0.01 uM). Na3VO4 became cytotoxic at 1 uM. These results demonstrate that neural networks grown on MEA plates ("brain on a chip" cultures) may provide a physiological, high throughput, high content method to screen chemicals for their potential to cause developmental neurotoxicity. (This abstract does not reflect USEPA Policy)