The aryl hydrocarbon receptor system

International audienceThe aryl hydrocarbon receptor (AhR) recognizes a large number of xenobiotics, such as polyaromatic hydrocarbons (PAHs) and dioxins, and it activates several metabolic and detoxification pathways. Recent evidence suggests that this receptor also has important endogenous functions subsequent to activation by natural dietary compounds and/or endogenous metabolites. This receptor, thus, has physiological functions that extend beyond specific instances of detoxification. Understanding the roles played by this receptor might be enhanced by a systems biology approach. Indeed, the AhR "ligandome" is very complex and the different classes of ligands involved could induce widely diverse effects. The protein "interactome" of the AhR comprises several tens of proteins and it is altered by the binding of ligands to the receptor. Furthermore, large-scale studies have shown cell and tissue-specific patterns of regulated gene expression which may depend upon the type of ligand, although these aspects need further substantiation. Finally, the AhR biological effects are extensive and include detoxification, cellular proliferation and migration, immune regulation and neuronal effects. A holistic approach should provide a better understanding of the biology of this receptor in addition to providing new avenues for the identification of specific toxicity mechanisms

Effets de mélanges de xénobiotiques agissant par des voies de signalisation différentes (conséquences moléculaires dans des modèles hépatiques humains)

PARIS-BIUP (751062107) / SudocSudocFranceF

A head and neck cancer tumor response-specific gene signature for cisplatin, 5-fluorouracil induction chemotherapy fails with added taxanes.

BACKGROUND: It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). CONCLUSIONS/SIGNIFICANCE: Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic options. Although highly specific for tumor responses to PF induction, the gene signature is unsuccessful when taxanes are added. The results illustrate the subtlety in developing "personalized medicine"

The association between environmental exposures to chlordanes, adiposity and diabetes-related features: a systematic review and meta-analysis

International audienceChlordane compounds (CHLs) are components of technical chlordane listed in the Stockholm convention on persistent organic pollutants identified as endocrine disrupting chemicals (EDCs) and may interfere with hormone biosynthesis, metabolism or action resulting in an unbalanced hormonal function. There is increasing scientific evidence showing EDCs as risk factors in the pathogenesis and development of obesity and obesity-related metabolic syndromes such as type 2 diabetes, but there is no systematized information on the effect of CHLs in humans. Our aim is to identify the epidemiological data on the association between CHLs with adiposity and diabetes using a systematic approach to identify the available data and summarizing the results through meta-analysis. We searched PubMed and Web of Science from inception up to 15 February 2021, to retrieve original data on the association between chlordanes, and adiposity or diabetes. For adiposity, regression coefficients and Pearson or Spearman correlation coefficients were extracted and converted into standardized regression coefficients. Data were combined using fixed effects meta-analyses to compute summary regression coefficients and corresponding 95% confidence intervals (95% CI). For the association between chlordanes and diabetes, Odds ratios (ORs) were extracted and the DerSimonian and Laird method was used to compute summary estimates and respective 95% CI. For both, adjusted estimates were preferred, whenever available. Among 31 eligible studies, mostly using a cross-sectional approach, the meta-analysis for adiposity was possible only for oxychlordane and transchlordane, none of them were significantly associated with adiposity [(β = 0.04, 95% CI 0.00; 0.07, I2 = 89.7%)] and (β = 0.02, 95% CI − 0.01; 0.06), respectively. For diabetes, the estimates were positive for all compounds but statistically significant for oxychlordane [OR = 1.96 (95% CI 1.19; 3.23)]; for trans-nonachlor [OR = 2.43 (95% CI 1.64; 3.62)] and for heptachlor epoxide [OR = 1.88 (95% CI 1.42; 2.49)]. Our results support that among adults, the odds of having diabetes significantly increase with increasing levels of chlordanes. The data did not allow to reach a clear conclusion regarding the association with adiposity

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2

International audienceTCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is an environmental pollutant which binds the aryl hydrocarbon receptor (AhR), a transcription factor that triggers variousbiological responses. In this study, we show that TCDD treatment counteracts the p53 activation elicited by a genotoxic compound, etoposide, in the human hepatocarcinoma cell line HepG2 and we delineated the mechanisms of this interaction. Using siRNA knock-down experiments, we found that the newly described metastasis marker, anterior gradient-2 (AGR2), is involved in this effect. Both AGR2 mRNA and protein levels were increased (6-and 4-fold, respectively) by TCDD treatment and this effect was mediated by the AhR receptor. The half-life of AGR2 mRNA was unchanged by TCDD treatment. Analysis of the promoter of the AGR2 gene revealed 3 putative xenobiotic responsive elements (XRE) in the proximal 3.5 kb promoter. Transient transfection of HepG2 cells by the Gaussia luciferase reporter gene driven by various deleted and mutated fragments of the promoter indicated that only the most proximal XRE was active. These results suggest that AhR ligands such as TCDD may contribute to tumour progression by inhibiting p53 regulation by genotoxicants via the increased expression of the metastasis marker AGR2

INDUCTION OF THE RAS ACTIVATOR SON OF SEVENLESS 1 BY ENVIRONMENTAL POLLUTANTS MEDIATES THEIR EFFECTS ON CELLULAR PROLIFERATION

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