ABSTRACT: Transcriptional Profiles Induced by the Aryl Hydrocarbon Receptor Agonists 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 2,3,7,8-Tetrachlorodibenzofuran and 2,3,4,7,8-Pentachlorodibenzofuran in Primary Rat Hepatocytes
Project description:Aryl hydrocarbon receptor ChIP-Seq performed in livers of female mice gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 2hrs
Project description:Aryl hydrocarbon receptor ChIP-Seq performed in livers of male mice gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 2hrs
Project description:The aryl hydrocarbon receptor (AHR) mediates the toxic effects of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Frogs are very insensitive to the toxic effects of TCDD.
Project description:We report mRNA sequencing from decidual stromal cells after 24 hours and 6 days treatment with Aryl Hydrocarbon Receptor (AHR) activators 100 µM L-kynurenine or 10 nM TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin)
Project description:The aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters differentiation of B cells and suppresses antibody production. The objectives of this study was to use a combination of whole genome, microarray-based chromatin immunoprecipitation (ChIP-on-chip) and time course gene expression microarray analysis on the mouse B-cell line CH12.LX following exposure to lipopolysaccharide (LPS) or LPS and TCDD to identify the primary and downstream transcriptional elements of B-cell differentiation that are altered by the AHR.
Project description:The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxic effects of the environmental contaminant, dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a diverse range of toxic responses, including hepatic damage and lethal wasting syndrome; however, the mechanisms of dioxin-induced toxicity are still unknown. Here we show that the loss of TCDD-inducible poly(ADP-ribose) polymerase (TIPARP; ARTD14), an ADP-ribosyltransferase and AHR repressor, increases sensitivity to dioxin-induced toxicity and lethality. Tiparp-/- mice treated with a single injection of 100 mg/kg dioxin display an accelerated lethal wasting syndrome with no Tiparp-/- mice surviving beyond day 5; all Tiparp+/+ mice survived up to 30 days post treatment. Tiparp-/- mice displayed dramatic increases in liver steatosis and hepatotoxicity. At the molecular level, TIPARP selectively ADP-ribosylates AHR, but not AHR nuclear translocator (ARNT) and the Tiparp-dependent repression of AHR is reversed by the ADP-ribosylase and macrodomain containing protein MacroD1, but not MacroD2. These results describe previously unidentified roles for Tiparp, MacroD1, and ADP-ribosylation in AHR signaling, dioxin toxicity and lethality. 12 samples were analyzed. There were 4 treatment groups and each treatment group was done in triplicate. Gene expression changes were determine in hepatic RNA isolated from (1) corn oil treated C57BL/6;129Sv mice; (2) 30 ug/kg/bw 2,3,7,8-Tetrachlorodibenzo-p-dioxin C57BL/6;129Sv mice; (3) corn oil treated C57BL/6;129Sv Tiparp-/- mice; and (4) 30 ug/kg/bw 2,3,7,8-Tetrachlorodibenzo-p-dioxin C57BL/6;129Sv Tiparp-/- mice
Project description:The aryl hydrocarbon receptor (AHR) mediates the toxic effects of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Frogs are very insensitive to the toxic effects of TCDD. Experiment Overall Design: XLK-WG cells (ATCC) were grown to ~90% confluence in RPMI-1640 media supplemented with 20% FBS at 29 degrees and 5% CO2. Cells were subsequently exposed to 100 nM TCDD, FICZ, or DMSO vehicle (0.25%) for 3 hr prior to extraction of total RNA. Experiment Overall Design: Study included three complete biological replicates of each treatment.
Project description:Comparison of expression profiles detected inundifferemtitated HepaRG cells exposed to DMSO, TCDD for 24h. The aryl hydrocarbon receptor (AhR) activation has been shown to stimulate proliferation, promote apoptosis or alter differentiation of adult rat liver progenitors. We investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation on a human model of bipotent liver progenitors, undifferentiated HepaRG cells. We used both intact undifferentiated HepaRG cells, and HepaRG cells with silenced Hippo pathway effectors, YAP1 and TAZ, which play key role(s) in tissue specific progenitor cell self-renewal and expansion, including liver, cardiac or respiratory progenitors.
Project description:An in vitro model of human hematopoietic stem cell differentiation is found to allow development of multiple immune lineages through use of single-cell methods. Using this model, we demonstrate that activation of aryl hydrocarbon receptor (AHR) signaling drives human hematopoietic stem and progenitor cells (HSPCs) to differentiate towards myeloid lineages at the expense of lymphoid lineages. Gene perturbations in progenitor cells and lineage-specified immune cells by AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are identified.
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.
