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GSE99199
Mus musculus
40 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The Keap1/Nrf2 signaling pathway is a tractable target for the pharmacological prevention of tumorigenesis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two classes of Nrf2-activating chemopreventive agents. Natural dithiolethiones have been widely used in clinical trials for cancer chemoprevention. Synthetic triterpenoids, however, have been shown to be significantly more potent Nrf2 activators and are under clinical evaluation for the treatment of chronic kidney disease. This study seeks to characterize the structure-activity relationship between D3T and CDDO-Im in mouse liver tissue. To this end we treated Wt and Nrf2-null mice with 300 umol/kg bw D3T and 3, 10, and 30 umol/kg bw CDDO-Im every other day for 5 days and evaulated global gene expression changes as a product of both treamtent and genotype using Affymetrix microarray.
Publication Title
Pharmacogenomics of Chemically Distinct Classes of Keap1-Nrf2 Activators Identify Common and Unique Gene, Protein, and Pathway Responses In Vivo.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Saccharomyces cerevisiae
- 16 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Yeast transcription factor Yap1 mediates adaptive response against H2O2 and the cystein thiol reactive Michael acceptor, N-ethylmaleimid (NEM) and acrolein. The response against H2O2 was found to be distinct from that against NEM and acrolein.
Publication Title
Yap1 activation by H2O2 or thiol-reactive chemicals elicits distinct adaptive gene responses.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Combining genome-wide microarray and functional analyses, we found that EGFR activation abrogates barrier function, increasing transepidermal water loss (TEWL) and transepithelial permeability of water-soluble ions and higher molecular weight dextrans, in part by disrupting the expression of tight junction proteins. EGF decreases certain lipid matrix free fatty acids and ceramides by its actions to repress the expression of specific biosynthetic enzymes.
Publication Title
EGFR regulation of epidermal barrier function.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
TCDD increased expression of numerous differentiation specific genes and decreased expression of numerous genes involved in mitochondrial health and redox homeostasis
Publication Title
2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Rattus norvegicus
- 16 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a)
Description
The activities of the dithiolethione analogs, D3T, OLT, and TBD are pharmacologically well-understood. These compounds act as chemopreventive agents whose ability is to block or diminish early stages of carcinogenesis. In addition, the three compounds are classified as monofunctional Phase II enzyme inducers and activate the same pathway, namely the Keap1-Nrf2 signal pathway. The three dithiolethiones were showed to ameliorate the AFB1-induced toxicity through increasing phase II enzymes including glutathione S-transferase (GST). The parent D3T was observed to be the most potent chemoprotective agent. Oltipraz, a clinically approved drug, has been shown to exhibit less efficacy than its analogs for inhibition of aflatoxin-induced hepatic foci.TBD was suggested to be better than OLT as a chemopreventive agent because of its reduced toxicity profile.
Publication Title
Chemical genomics of cancer chemopreventive dithiolethiones.
Sample Metadata Fields
No sample metadata fields
View Samples- Saccharomyces cerevisiae
- 12 Downloadable Samples
Illumina HiSeq 2500
Description
S-adenosylmethionine (SAM) is the methyl donor for biological methylation modifications that regulate protein and nucleic acid functions. Here we show that methylation of a phospholipid, phosphatidylethanolamine (PE), is the major consumer of SAM in budding yeast. The induction of phospholipid biosynthetic genes is accompanied by induction of the enzyme that hydrolyzes S-adenosylhomocysteine (SAH), a product and inhibitor of methyltransferases. Beyond its function for the synthesis of phosphatidylcholine (PC), the methylation of PE facilitates the turnover of SAM for the synthesis of cysteine and glutathione. Strikingly, cells that lack PE methylation accumulate SAM, which leads to hypermethylation of histones and the major phosphatase PP2A, dependency on cysteine, and sensitivity to oxidative stress. Without PE methylation, particular sites on histones then become methyl sinks to enable the turnover of SAM. These findings reveal an unforeseen metabolic function for phospholipid and histone methylation intrinsic to the life of a cell. Overall design: Two biological replicates of wild type and cho2? cells in YPL media, in SL media after 1 hour and in SL media after 3 hour were collected for sequencing.
Publication Title
A Metabolic Function for Phospholipid and Histone Methylation.
Sample Metadata Fields
Cell line, Subject, Time
View Samples- Homo sapiens, Rattus norvegicus
- 61 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a), Affymetrix Human Genome U133A Array (hgu133a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 40 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a), Affymetrix Human Genome U133A Array (hgu133a)
Description
(Abstract) Toxicogenomics has great potential for enhancing our understanding of environmental chemical toxicity, hopefully leading to better-informed human health risk assessments. This study employed toxicogenomic technology to reveal species differences in response to two prototypical aryl hydrocarbon receptor (AHR) agonists, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the polychlorinated biphenyl (PCB) congener PCB 126. Dose responses of primary cultures of rat and human hepatocytes were determined using species-specific microarrays sharing over 4,000 gene orthologs. Forty-seven human and 79 rat genes satisfied dose response criteria for both chemicals and were subjected to further analysis including the calculation of EC50 and the relative potency (REP) of PCB 126 for each gene. Only 5 responsive orthologous genes were shared between the two species, yet the geometric mean of the REPs for all rat and human modeled responsive genes were 0.06 (95% Confidence Interval (CI); 0.03-0.1) and 0.002 (95% CI; 0.001-0.005), respectively, suggesting broad species differences in the initial events that follow AHR activation but precede toxicity. This indicates that there are species differences in both the specific genes that responded and the agonist potency and relative potency for those genes. This observed insensitivity of human cells to PCB 126 is consistent with more traditional measurements of AHR activation (i.e., CYP1A1 enzyme activity) and suggests that the species difference in PCB 126 sensitivity is likely due to certain aspects of AHR function. That a species divergence also exists in this expanded AHR-regulated gene repertoire is a novel finding and should help when extrapolating animal data to humans.
Publication Title
Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Rattus norvegicus
- 12 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a)
Description
Chronic exposure of Sprague-Dawley (SD) rats to either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or Aroclor 1254 results in female-selective induction of hepatic tumors. The relative potency of dioxins and PCB mixtures, such as Aroclor 1254, is often estimated using the internationally endorsed toxic equivalency (TEQ) approach. Comparing the genome wide changes in gene expression in both genders following exposure to toxic equivalent doses of these chemicals should identify critical sets of early response genes while further defining the concept of the TEQ of halogenated aromatic hydrocarbons. Aroclor 1254 at 0.6, 6.0 and 60 mg/kg body weight and TEQ doses of TCDD (0.3 and 3.0 g/kg), calculated to match the top two Aroclor 1254 doses, were orally administered to SD rats for three consecutive days. Day 4 gene expression in hepatic tissue was determined using microarrays. A linear mixed-effects statistical model was developed to analyze the data in relation to treatment, gender, and gender*treatment (G*T) interactions. The genes most changed included 54 genes with and 51 genes without a significant model G*T term. The known aryl hydrocarbon receptor (AHR) battery genes (Cyp1a1, Cyp1a2, Cyp1b1, Aldh3a1), and novel genes, responded in a TEQ dose-dependent manner in both genders. However, an important observation was the apparent disruption of sexually dimorphic basal gene expression, particularly for female rats. Since many of these genes are involved in steroid metabolism, exposure to either TCDD or Aroclor 1254 could disrupt proliferative signals more in female rats as a possible consequence of altered estrogen metabolism. This study extends the findings of previous rodent bioassays by identifying groups of genes, other than the well-characterized AHR response genes, whose disruption may be important in the tumorigenic mechanism in this rat strain.
Publication Title
Toxicogenomic analysis of gender, chemical, and dose effects in livers of TCDD- or aroclor 1254-exposed rats using a multifactor linear model.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To identify distinct transcriptional patterns between the major subcortical dopamine targets commonly studied in addiction we studied differences in gene expression between the bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAc), and dorsal striatum (dStr) using microarray analysis. We first tested for differences in expression of genes encoding transcripts for common neurotransmitter systems as well as calcium binding proteins routinely used in neuroanatomical delineation of brain regions. This a priori method revealed differential expression of corticotropin releasing hormone (Crh), the GABA transporter (Slc6a1), and prodynorphin (Pdyn) mRNAs as well as several others. Using a gene ontology tool, functional scoring analysis, and Ingenuity Pathway Analysis, we further identified several physiological pathways that were distinct among these brain regions. These two different analyses both identified calcium signaling, G15 coupled protein receptor signaling, and adenylate cyclase-related signaling as significantly different among the BNST, NAc, and dStr. These types of signaling pathways play important roles in, amongst other things, synaptic plasticity. Investigation of differential gene expression revealed several instances that may provide insight into reported differences in synaptic plasticity between these brain regions. The results support other studies suggesting that crucial pathways involved in neurotransmission are distinct among the BNST, NAc, and dStr, and provide insight into the potential use of pharmacological agents that may target region-specific signaling pathways. Further, these studies provide a framework for future mouse-mouse comparisons of transcriptional profiles after behavioral/pharmacological manipulation.
Publication Title
Microarray analysis reveals distinctive signaling between the bed nucleus of the stria terminalis, nucleus accumbens, and dorsal striatum.
Sample Metadata Fields
No sample metadata fields
View Samples