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Title: Integration of metabolic activation with a predictive toxicogenomics signature to classify genotoxic versus nongenotoxic chemicals in human TK6 cells [BaP 8hr]      
dateReleased:
04-15-2015
description:
The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the molecular pathways involved in the response, is becoming more common. In a companion paper, a genomic biomarker was developed in human TK6 cells to classify chemicals as genotoxic or non-genotoxic. Because TK6 cells are not metabolically competent, we set out to broaden the utility of the biomarker for use with chemicals requiring metabolic activation. Specifically, chemical exposures were conducted in the presence of rat liver S9. The ability of the biomarker to classify genotoxic (benzo[a]pyrene, BaP; aflatoxin B1, AFB1) and non-genotoxic (dexamethasone, DEX; phenobarbital, PB) agents correctly was evaluated. Cells were exposed to increasing chemical concentrations for 4h and collected 0h, 4h and 20h post-exposure. Relative survival, apoptosis, and micronucleus frequency were measured at 24h. Transcriptome profiles were measured with Agilent microarrays. Statistical modeling and bioinformatics tools were applied to classify each chemical using the genomic biomarker. BaP and AFB1 were correctly classified as genotoxic at the mid- and high concentrations at all three time points, whereas DEX was correctly classified as non-genotoxic at all concentrations and time points. The high concentration of PB was misclassified at 24h, suggesting that cytotoxicity at later time points may cause misclassification. The data suggest that the use of S9 does not impair the ability of the biomarker to classify genotoxicity in TK6 cells. Finally, we demonstrate that the biomarker is also able to accurately classify genotoxicity using a publicly available dataset derived from human HepaRG cells. This experiment examined the whole genome transcriptional response of TK6 cells exposed to BaP for 4 hours followed by a 4h in fresh media (8h time point) at 3 different concentrations, including a low (0.45 μg/ml), a medium (1.4 μg/ml), and a high (10 μg/ml) concentration, in addition to negative controls (±S9), vehicle controls (±S9) and a direct-acting positive control, cisplatin (-S9) at 24 μg/ml (PC-24). Each concentration and time point had 3 biological replicates. There were a total 12 samples (24 arrays) included in the final analysis using a two-colour dye swap design. Please note that each sample data table contains normalized data combined from two replicates and the sample-dye assignment information for each of the raw data files is included in the 'readme.txt' (available as Series supplementary file).
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-51173
refinement:
raw
alternateIdentifiers:
51173
keywords:
functional genomics
dateModified:
04-17-2015
availability:
available
types:
gene expression
name:
Homo sapiens
ID:
A-GEOD-14550
name:
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Probe Name Version)
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-51173/E-GEOD-51173.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-51173/E-GEOD-51173.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51173
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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