(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.
Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes.
Sex, Age, Specimen partView Samples
Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared to white adipose tissue (WAT), PVAT and BAT from C57BL/6 mice fed a high fat diet for 13 weeks had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80, CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b+/CD11c+ macrophages in BAT (1.0%) in comparison to WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from thermal and inflammatory stress.
Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation.
Specimen part, TreatmentView Samples
Tissue samples were collected from patients diagnosed with HNSCC (oropharynx, hypopharynx, larynx). Samples were taken from the tumor site (tumor samples) and from a site distant to the tumor (normal samples) prior to therapy.
Prognostic biomarkers for HNSCC using quantitative real-time PCR and microarray analysis: β-tubulin isotypes and the p53 interactome.
Age, Specimen part, SubjectView Samples
Loss of Rb family in HSCs results in a severe phenotype, such as enhanced proliferation and increase in stem cell number. In addition, HSCs were higly mobilized but failed to transplant. Rb family deficient mice rapidly exhibit a myeloproliferative disease with eosinophilic characteristics. Meanwhile, the lymphoid compartment was severely decreased, due to high apoptotic activity in this lineage.
Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family.
No sample metadata fieldsView Samples
We used microarrays to identify genes differentially expressed in EBV-infected human B cells supporting lytic replication vs. those refractory to EBV lytic replication.
Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes.
Specimen partView Samples
Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a key causal role in tumorigenesis. According to an alternative view, chromosomal instabilities are mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that deregulation of some key pathways, such as MAPK, p53, cell cycle regulation and Polycomb group factors, in addition to activation of several genes like Myc, AML, B-Catenin and the ETS family transcription factors, are key steps in cancer development driven by 20q amplification. Finally we identified 13 cancer initiating genes, located on 20q13, which were significantly overexpressed in many tumors, with expression levels correlated with tumor grade and outcome; these probably play key roles in inducing malignancy via20q amplification.
Amplification of the 20q chromosomal arm occurs early in tumorigenic transformation and may initiate cancer.
Specimen partView Samples
Expression profiles of Drosophila melanogaster in response to ionizing radiation, formaldehyde, toluene, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Overall design: RNA-seq analysis on 25,415 transcripts to measure the change in gene expression in males and females separately. An analysis of the genes unique to each treatment yielded a list of genes as a gene expression signature. In the case of radiation exposure, both sexes exhibited a reproducible increase in their expression of the transcription factors sugarbabe and tramtrack.
Mining gene expression data for pollutants (dioxin, toluene, formaldehyde) and low dose of gamma-irradiation.
Age, Cell line, Treatment, SubjectView Samples
We wanted to examine the effect of vitamin D3 and endogenous mutant p53 expressed in SKBR3 cells on gene expression paterns.
Modulation of the vitamin D3 response by cancer-associated mutant p53.
Specimen part, Cell line, TreatmentView Samples
This SuperSeries is composed of the SubSeries listed below.
An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance.
Specimen part, TreatmentView Samples