Transcription profiking of rat and human primary hepatocytes response to aryl hydrocarbon receptor agonists
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Erik Carlson
PROVIDER: E-GEOD-14555 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project 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. Experiment Overall Design: Primary hepatocyte cultures, separated into 2 pools of 3 female Sprague Dawley rats each, were treated with vehicle (0.5% DMSO), TCDD (-14 to -6.5 log10 M) , or PCB 126 (-12 to -5 log10 M) for 48h. Total RNA was extracted and screened with RG-U34A microarrays for dose response.
2009-09-17 | E-GEOD-14554 | biostudies-arrayexpress
Project 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. Experiment Overall Design: Primary hepatocyte cultures derived from 3 human donors were treated with vehicle (0.5% DMSO), TCDD (-14 to -6.5 log10 M) , or PCB 126 (-12 to -5 log10 M) for 48h. Total RNA was extracted and screened with HG-U133A microarrays for dose response.
2009-09-05 | E-GEOD-14553 | biostudies-arrayexpress
Project description:Toxicogenomic Comparison of TCDD and PCB 126 Responsiveness in Primary Rat Hepatocytes
| PRJNA114395 | ENA
Project description:Toxicogenomic Comparison of TCDD and PCB 126 Responsiveness in Primary Human Hepatocytes
| PRJNA114393 | ENA
Project 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.
2009-08-19 | GSE14553 | GEO
Project 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.
2009-08-19 | GSE14554 | GEO
Project description:The ability to predict metastatic potential is of clinical and biological importance. Numerous metastasis/relapse predictors exist for breast cancer patients; however, what is less well established is whether predicting metastasis to specific organs sites is feasible. In this study we sought to determine: 1) the degree to which gene signatures vary across tumors and their metastases, 2) if genomic intrinsic subtypes associate with particular organs of relapse, and 3) if other genomic signatures can predict spread to specific organs. Using a gene expression microarray data set of >1000 breast tumors and metastases, we observed that >90% of 298 gene signatures were similarly expressed between matched pairs of breast tumors and metastases; those most altered were reflective of cell types including fibroblasts and immune cells. Significant associations were identified between tumor subtypes and organ of first relapse. Among these, HER2-enriched tumors were significantly associated with liver, and Basal-like and Claudin-low tumors with brain and lung. Correspondingly, previously published brain and lung metastasis signatures, along with embryonic stem cell and tumor initiating cell signatures, were also associated with Basal-like and Claudin-low subtypes. These signatures strongly correlated with low Differentiation Scores (DS) and, to a lesser extent, high proliferation. Interestingly, within Basal-like and Claudin-low tumors, low DS further predicted for brain and lung metastases. In total, intrinsic subtype and DS provide clinically useful information that identifies the distant organ sites that should be most closely monitored for signs of disease recurrence. 414 samples profiled on Agilent microarrays.
2011-06-20 | E-GEOD-26338 | biostudies-arrayexpress
Project description:Although the tumor promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs) and related compounds in liver tissue are primarily attributed to activation of the aryl hydrocarbon receptor (AhR), the underlying molecular mechanisms are still unclear. Liver progenitor (oval) cells have been suggested to constitute a potential target for hepatocarcinogenic chemicals. To better understand AhR-driven pathways we analyzed the transcriptional program in response to coplanar PCB 126 in rat liver progenitor WB-F344 cells using high density microarrays. After 6h treatment, we identified 145 significantly deregulated genes considered to be direct AhR-dependent target genes. The number of differentially regulated genes increased to 658 and 968 genes after 24h and 72h, respectively. Gene ontology analysis revealed that these genes were primarily involved in drug and lipid metabolism, cell cycle and growth control, cancer developmental processes, cell-cell communication and adhesion. Interestingly, the Wnt and TGF-beta signaling pathways, both being involved in developmental and tumorigenic processes, belonged to the most affected pathways. AhR and ARNT-dependent regulation of selected target genes of interest was then confirmed using TCDD as a model AhR agonist, together with pharmacological inhibition of the AhR and by RNA-interference techniques. We demonstrated AhR-dependent regulation of emerging and novel AhR target genes, such as Fst, Areg, Hbegf, Ctgf, Btg2, and Foxq1. Among them, the transcription factor Foxq1, recently suggested to contribute to tumor promotion and/or progression, was found to be regulated at both mRNA and protein levels by AhR/ARNT activation. 18 Total samples were analyzed (3 independent repeats for each treatment and time point). We generated the following pairwise comparisons: Control vs. PCB 126 at 6 h; Control vs. PCB 126 at 24 h; Control vs. PCB 126 at 72 h;
2013-05-01 | E-GEOD-41902 | biostudies-arrayexpress
Project description:In this study, we exposed Caenorhabditis elegans wild types N2 to the model indirect-acting toxicants aflatoxin B1 (AFB1), benzo(a)pyrene (B(a)P), the PCB mixture Aroclor 1254 (PCB1254), and 2,3,7,8-tetrachlorodibenzodioxin (TCDD). In microarray experiments, we studied one concentration of AFB1 (30 μM), one concentration of B(a)P (30 μM), two concentrations of PCB1254 (1 μM and 30 μM), and two concentrations of TCDD (1 μM and 10 μM). As a control M9 medium with 0.5% DMSO was used. Age synchronized worms at developmental L4 larval stage were exposed to treatment for 24 hours. After flash freezing the samples, RNA was isolated, labeled and hybridized on oligo microarray (Agilent) slides.
2022-04-25 | E-MTAB-11143 | biostudies-arrayexpress
Project description:Lymphomas are classified according to the World Health Organization (WHO) classification which defines subtypes on the basis of clinical, morphological, immunophenotypic, molecular and cytogenetic criteria. Using this model, 8 of 9 of the validation samples were classified successfully. This pilot study demonstrates that such a microarray tool may be a promising diagnostic approach for small B-cell non-Hodgkin’s lymphoma. Keywords: Small B-Cell non-Hodgkin’s Lymphoma, Low Density DNA Microarray, Diagnosis Fresh-frozen tumor biopsies performed before treatment and clinical data were obtained retrospectively from 68 patients in five different institutions after lab investigations involving cytology, immunohistochemistry, cytogenetics (conventional cytogenetics and fluorescent in situ hybridization [FISH]), and/or molecular analysis. The samples were then classified unanimously by a panel of five pathologists as one of the 4 subtypes: 17 B-CLL, 14 MZL, 23 FL and 14 MCL. The immunohistochemical criteria used for identifying the 4 subtypes of SBCL were: CD20+/-, CD5+, CD23+ for B-CLL; CD20+, CD5+, CD23-, Cyclin D1+ for MCL; CD20+, CD10+, Bcl2+ for FL; CD20+, CD5-, CD10- for S-MZL. 28 samples were rejected for technical issues with RNA. The remaining 40 samples include the 4 different subtypes with this following distribution: Follicular Lymphoma/FL (n=15), Mantle Cell Lymphoma/MCL (n=7), B-Chronic Lymphocytic Leukemia/B-CLL (n=6) and Splenic Marginal Zone Lymphoma/S-MZL (n=12). The expression profile of 107 genes was evaluated in these 40 samples defined as a training set. Replicates were performed for samples of sufficient quantity, and a total of 79 gene expression profiles, comprised of 12 samples in triplicate, 15 samples in duplicate and 13 samples evaluated singly, were then analyzed. A second group of 13 patients was defined as test set and used to validate the gene signatures highlighted from the training set analysis. These patients were selected by a pathologist independent from the first analysis and include 4 FL, 3 B-CLL, 5 MCL and 1 S-MZL. Four samples were rejected for technical issues with RNA. The remaining 9 samples include the 4 different subtypes: 2 FL, 3 B-CLL, 3 MCL and 1 S-MZL. A total of 13 gene expression profiles were analyzed (4 samples evaluated in duplicate and 5 samples investigated singly).
2009-03-24 | E-GEOD-11635 | biostudies-arrayexpress