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Series GSE174722 Query DataSets for GSE174722
Status Public on Apr 19, 2022
Title Integrated Omic Analyses Identify Pathways and Regulators Associated with Chemical Alterations of in vitro Neural Network Formation
Organism Rattus norvegicus
Experiment type Expression profiling by high throughput sequencing
Summary Development of in vitro new approach methodologies (NAMs) has been driven by the need for developmental neurotoxicity (DNT) hazard data on thousands of chemicals. The network formation assay (NFA) characterizes DNT hazard based on changes in network formation but provides no mechanistic information. This study investigated nervous system signaling pathways and upstream physiological regulators underlying chemically-induced neural network dysfunction. Rat primary cortical neural networks grown on microelectrode arrays were exposed (0.1 -10 µM) for 12 days in vitro (DIV) to cytosine arabinoside (CA), 5 fluorouracil (5FU), domoic acid (DA), cypermethrin (CM), deltamethrin (DM), and haloperidol; these exposures targeted specific concentrations that altered network activity in previous studies. RNA-seq from cells and GC/MS of media extracts collected on DIV 12 provided gene expression and metabolomic identification, respectively. The integration of differentially expressed genes and metabolites for each neurotoxicant were analyzed using Ingenuity Pathway Analysis (IPA). All six compounds altered gene expression that linked to developmental disorders and neurological diseases. Other enriched canonical pathways overlapped among compounds of the same class; for example, genes altered by both CA and 5FU exposures are enriched in axonal guidance pathways. Analysis of upstream regulators was heterogeneous across compounds, but identified regulators included CREB1, BDNF, TGFβ1, NTRK2, and PRODH. These results demonstrate that transcriptomic and metabolomic changes following chemical exposure can be determined in the NFA and that different classes of compounds produce differing responses. This approach can enhance information obtained from NAMs and contribute to the identification and development of AOPs associated with DNT.
 
Overall design This study investigated nervous system signaling pathways and upstream physiological regulators underlying chemically-induced neural network dysfunction. Rat primary cortical neural networks grown on microelectrode arrays were exposed (0.1 -10 µM) for 12 days in vitro (DIV) to cytosine arabinoside (CA), 5 fluorouracil (5FU), domoic acid (DA), cypermethrin (CM), deltamethrin (DM), and haloperidol; these exposures targeted specific concentrations that altered network activity in previous studies. RNA-seq from cells and GC/MS of media extracts collected on DIV 12 provided gene expression and metabolomic identification, respectively. The integration of differentially expressed genes and metabolites for each neurotoxicant were analyzed using Ingenuity Pathway Analysis (IPA). All six compounds altered gene expression that linked to developmental disorders and neurological diseases.
 
Contributor(s) Marabel CA, Frank CL, Seim RF, Hester S, Henderson WM, Chorley B, Shafer TJ
Citation(s) 34927697
Submission date May 19, 2021
Last update date Apr 19, 2022
Contact name Susan Hester
E-mail(s) hester.susan@epa.gov
Phone 919-541-1320
Organization name US EPA
Street address 109 TW Alexander Dr
City RTP
State/province NC
ZIP/Postal code 27711
Country USA
 
Platforms (1)
GPL20084 Illumina NextSeq 500 (Rattus norvegicus)
Samples (71)
GSM5324709 rat cortical neurons_GRC321-ONT1_S6_Haloperidol_0
GSM5324710 rat cortical neurons_GRC321-ONT2_S12_Haloperidol_0.3
GSM5324711 rat cortical neurons_GRC321-ONT3_S2_Haloperidol_1
Relations
BioProject PRJNA731184
SRA SRP320557

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Supplementary file Size Download File type/resource
GSE174722_Partek_GRC321_327_Full_Project_1_Gene_counts.xlsx 9.2 Mb (ftp)(http) XLSX
GSE174722_Partek_GRC321_327_Full_Project_1_Normalized_counts.xlsx 12.5 Mb (ftp)(http) XLSX
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