Compounds with direct immunotoxic properties, including metals, mycotoxins, agricultural pesticides and industrial chemicals, form potential human health risks due to exposure through food, drinking water, and the environment. Insights into the mechanisms of action are currently lacking for the majority of these direct immunotoxicants. Therefore, the present work aimed to gain insights into the molecular mechanisms underlying direct immunotoxicity. To this end, we assessed in vitro the effects of 31 test compounds on the transcriptome of the human Jurkat T cell line. These compounds included direct immunotoxicants, immunosuppressive drugs with different mode of actions, and non-immunotoxic control chemicals. Pathway analysis of the microarray data allowed us to identify canonical pathways and Gene Ontology processes that were transcriptionally regulated in common by immunotoxicants (i) with structural similarities, such as the tributyltins TBTC and TBTO that activated the retinoic acid / X receptor (RAR / RXR) signaling pathway, and (ii) without structural similarities, such as As2O3, DBTC, diazinon, MeHg, ochratoxin A, S9 treated ochratoxin A, S9 treated cyclophosphamide, and S9 treated benzo[a]pyrene, that activated unfolded protein response, and FTY720, lindane, and propanil, that activated the cholesterol biosynthesis pathway. In addition, processes uniquely affected by individual immunotoxicants were identified, such as the induction of Notch receptor signaling and the down regulation of acute phase response genes by ochratoxin A. These findings were validated by quantitative Real-Time PCR (Q-RT-PCR) analysis of genes involved in these processes. Our study indicated that diverse modes of action are involved in direct immunotoxicity and that a set of pathways or genes, rather than one single gene can be used to screen compounds for direct immunotoxicity.
Toxicogenomics-based identification of mechanisms for direct immunotoxicity.
Specimen part, Cell line
View SamplesThe transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR.
Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
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Sex, Specimen part, Disease
View SamplesIgE antibodies are key mediators of food allergy, and the production of IgE is tightly regulated at the moleculaer and cellular level in the germinal center of lymph glands where specific sets of genes are up-regulated.
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Sex, Specimen part, Disease
View SamplesThe accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes stress and induces the unfolded protein response (UPR) which is characterised in part by the transcriptional induction of genes involved in assisting protein folding. Translational responses to ER stress have been less well described and here we report on a genome-wide analysis of translational regulation in the response to the ER stress-inducing agent dithiothreitol (DTT) in Saccharomyces cerevisiae. Although the observed polysome profiles were similar under control and ER stress conditions microarray analysis identified transcipt-specific translational regulation. Genes with functions in ribosomal biogenesis and assembly were translationally repressed under ER stress. In contrast mRNAs for known UPR genes, including the UPR transcription factor HAC1, the ER-oxidoreductase ERO1 and the ER-associated protein degradation (ERAD) gene DER1 were enriched in polysomal fractions under ER stress conditions. In addition, we show that splicing of HAC1 mRNA is required for efficient ribosomal loading and that Gcn2p is required for normal HAC1 splicing, so shedding light on the role of this protein kinase in the UPR pathway.
Transcript-specific translational regulation in the unfolded protein response of Saccharomyces cerevisiae.
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View SamplesFunctional genomic analysis using different types of baker's yeast.
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View SamplesThe evaluation of mycotoxicity of type B trichothecenes using a yeast gene expression comparison analysis. The yeast BY4743 derivative PDR5 mutant was used for this study. The yeast cells were treated with trichothecene mycotoxins, and incubated at 25 degree for two hours, respectively. Total RNA was isolated with commercial kit (FastRNA Pro Red kit, Q-Biogene), and amplified RNA (aRNA) was synthesized with 3'IVT Express kit (Affymetrix). All samples were hybridized with Gene Chip (Yeast Genome 2.0 Array, Affymetrix), then each array chip was scanned by GeneChip Sanner 3000 (Affymetrix).
Comprehensive gene expression analysis of type B trichothecenes.
Treatment
View SamplesGenes whose expression correlated to the degree of thermotolerance in S. cerevisiae were identified by DNA microarray analysis.
Identification of a gene, FMP21, whose expression levels are involved in thermotolerance in Saccharomyces cerevisiae.
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View SamplesThe assessment of toxicity about patulin using yeast gene expression comparison analysis. Yeast BY4743 derivative SOD1 mutant was used for this study. Ascorbic acid was used to evaluate the anti-toxic effect to patulin.
Gene expression profiles of yeast Saccharomyces cerevisiae sod1 caused by patulin toxicity and evaluation of recovery potential of ascorbic acid.
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View SamplesThe assessment of toxicity about deoxynivalenol (DON) using yeast gene expression comparison analysis. Two yeast strains, parental BY4743 and PTC1 mutant, were used for this study. SDS was used to raise the penetration of the yeast cell membrane.
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