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GSE61037
Mus musculus
65 Downloadable Samples
Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that produces myriad toxicities in most mammals. In rodents alone, there is a huge divergence in the toxicological response across species, as well as among different strains within a species. But there are also significant differences between males and females animals of a single strain. These differences are inconsistent across model systems: the severity of toxicity is greater in female rats than males, while male mice and guinea pigs are more sensitive than females. Because the specific events that underlie this difference remain unclear, we characterized the hepatic transcriptional response of adult male and female C57BL/6 mice to 500g/kg TCDD at multiple time-points. The transcriptional profile diverged significantly between the sexes. Female mice demonstrated a large number of altered transcripts as early as 6h following treatment, suggesting a large primary response. Conversely, male animals showed the greatest TCDD-mediated response 144h following exposure, potentially implicating significant secondary responses. Nr1i3 was statistically significantly induced at all time-points in the sensitive male animals. This mRNA encodes the constitutive androstane receptor (CAR), a transcription factor involved in the regulation of xenobiotic metabolism, lipid metabolism, cell cycle and apoptosis. Surprisingly though, changes at the protein level (aside from the positive control, CYP1A1) were modest, with only FMO3 showing clear induction, and no genes with sex-differences. Thus, while male and female mice show transcriptional differences in their response to TCDD, their association with TCDD-induced toxicities remains unclear.
Publication Title
Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 40 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
2,3,7,8tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 g/kg) in adult male and female C57BL/6Kuo mice.
Publication Title
Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Sample Metadata Fields
Sex, Specimen part
View Samples- Rattus norvegicus
- 44 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600 g/kg for H/W rats is higher than for any other wild-type mammal known. We have previously shown that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 g/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. . A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome.
Publication Title
Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity.
Sample Metadata Fields
Sex
View Samples- Rattus norvegicus
- 15 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
In many mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as lethal weight loss as a result of severe and persistent hypophagia. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR) a transcription factor. Because TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, we hypothesized that wasting syndrome is due to TCDD-induced dysregulation of genes involved in regulation of food-intake. We therefore focused on the hypothalamus, as it is the regulatory center of food-intake and energy balance in the central nervous system. We profiled mRNA abundance in hypothalamic tissue from two rat strains with widely differing sensitivities to wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23 hours after exposure to TCDD (100 g/kg) or corn oil vehicle. We found that TCDD exposure caused minimal transcriptional dysregulation effects in the hypothalamus, with only 6 genes changed in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.
Publication Title
Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.
Sample Metadata Fields
Sex
View Samples- Rattus norvegicus
- 27 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Rodents exposed to the environmental contaminant, TCDD, suffer from a number of acute and chronic toxicities, including lethality and a wasting syndrome. Hypothesizing that the wasting syndrome may be caused by changes in adipose tissue -- either in its hormonal regulation or in homeostatic effects -- we profiled the transcriptional response of rat white adipose to TCDD. We employed two separate rat strains: the Long-Evans strain is sensitive to TCDD toxicities while the Han/Wistar strain is over four orders of magnitude more resistant. One day after TCDD exposure few genes were altered in either strain, but after four days a modest number of transcriptional alterations were observed. Strikingly, TCDD had far fewer effects than did a feed-restriction protocol intended to mimic the wasting syndrome itself. Notably several classic TCDD-responsive genes were modulated at all time-points, including Cyp1a1, Cyp1b1, and Nqo1. We therefore concluded that rat adipose tissue is unlikely to be the primary driver of the wasting syndrome, and that another tissue is likely involved.
Publication Title
Transcriptional profiling of rat white adipose tissue response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.
Sample Metadata Fields
Sex
View Samples- Rattus norvegicus
- 56 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
We profiled hepatic transcriptional responses of 6 strains of rats with varying sensitivity to a dioxin, TCDD, at 19 hours following exposure. The resistant rats exhibited significantly reduced transcriptional responses in comparison to the sensitive strains. We hypothesize that genes which show differential changes between the resistant and sensitive rats may potentially explain sensitivity.
Publication Title
Inter-strain heterogeneity in rat hepatic transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Homo sapiens
- 27 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for LN. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered mRNA abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that the levels of gene expression in renal remission were similar to active patients without LN. In secondary analyses, gene expression correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As expression levels of the individual genes correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of steroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.
Publication Title
Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 22 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The NAT enzymes are polymorphic xenobiotic metabolizing enzymes that catalyze the transfer of an acetyl moiety from acetyl coenzyme A (acetyl-CoA) to the nitrogen or oxygen atom of primary arylamines, hydrazines, and their N-hydroxylated metabolites. NATs therefore play an important role in the detoxification and/or activation of arylamine drugs and carcinogens. The involvement of acetyl-CoA in energy metabolism suggests that there may be relationships between NAT activity and energy metabolism. Previous studies have suggested a role for NAT2 in insulin sensitivity that is exacerbated on high fat diet, using Nat1 knockout mice. To study mice with no NAT activity at all, we used a Nat1/Nat2 double-KO model, with animals fed either a regular chow or high fat/high sugar diet for 12 weeks. Analysis of basal parameters suggested a decrease in fatty-acid oxidation and hepatic gluconeogenesis. To further evaluate the cause of this, RNA was isolated and processed using Affymetrix Mouse Gene 2.0 microarrays.
Publication Title
A readout of metabolic efficiency in arylamine N-acetyltransferase-deficient mice reveals minor energy metabolism changes.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Topical corticosteroids and calcineurin inhibitors are well known treatments of atopic dermatitis (AD), but differ in their efficacy and side effects. A study in AD patients has demonstrated that betamethasone valerate (BM) though clinically more efficient impaired skin barrier repair in contrast to pimecrolimus. Objective: The present study elucidates the mode of action of topical BM and pimecrolimus cream in AD.
Publication Title
Gene expression is differently affected by pimecrolimus and betamethasone in lesional skin of atopic dermatitis.
Sample Metadata Fields
Specimen part
View Samples- Danio rerio
- 7 Downloadable Samples
Illumina HiSeq 2000
Description
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer. Overall design: WT (4 replicates) and homozygous rabl3-TR41 mutant (3 replicates) larval zebrafish at 21 days of age.
Publication Title
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples