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Integrated -OMIC Analysis Following Chemical-Induced Alterations of Neural Network Formation in Vitro
Citation:
Marable, C., B. Chorley, W. Henderson, S. Hester, AND T. Shafer. Integrated -OMIC Analysis Following Chemical-Induced Alterations of Neural Network Formation in Vitro. International Neurotoxicology Meeting, Dusseldorf, GERMANY, September 29 - October 03, 2019.
Impact/Purpose:
Presentation to the International Neurotoxicology Association INA-17 meeting September 2019. This work provides associations between genomic and transcriptomic changes in developing cortical networks and in vivo human neurodevelopmental diseases.
Description:
Early-life environmental exposures to developmental neurotoxicants carries a risk for children’s health. Studies have shown associations between neurotoxicant exposure and increased risk of neurodevelopmental disorders (NDD), such as autism spectrum and attention-deficit disorders. Further, these NDDs have been linked with altered neuronal gene expression and metabolism. The current study sought to determine which nervous systems signaling pathways and upstream physiological regulators may contribute to chemically-induced neural network dysfunction as measured using microelectrode arrays (MEAs). Rat primary cortical neural networks grown on MEAs were exposed (0.1 -10 uM) for 12 days to known in vivo neurotoxicants cytosine arabinoside (CA), 5 fluorouracil (5FU), domoic acid (DA), cypermethrin (CM), deltamethrin (DM), and haloperidol. These exposures targeted specific concentrations that exhibited altered network activity in the absence of acute cytotoxicity. RNA-seq from cells and LC-MS/MS of media provided gene expression and metabolite identification, respectively. The integration of differentially expressed genes and metabolites for each neurotoxicant were analyzed using Ingenuity Pathway Analysis (IPA). Integrated transcriptomic and metabolomic signatures for DNA synthesis inhibitors, CA and 5FU, were most correlated with MEA network activity loss as well as IPA’s database of genes, pathways, and metabolites associated with NDD of interest. Key markers of the axonal guidance signaling, ephrin receptor signaling and GDNF family ligand-receptor interactions, neuroinflammation signaling, neuregulin signaling, and NGF signaling pathways. Upstream regulator prediction in IPA identified CREB1, beta-estradiol, BDNF, TGFB1, SOX2, Levodopa, NTRK2, dopamine, quinolinic acid, TSC2, and PRODH as significantly associated with altered neurophysiological function; these regulators are also associated with NDD in vivo. These findings suggest that observed pathway-level effects in vitro are informative of in vivo responses. Further research is needed to determine the complex mechanistic interactions underlying the MEA detected neurotoxicants, identified transcriptomic and metabolic signatures, and neural developmental disorders. This abstract does not necessarily reflect EPA policy.