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      Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydrocarbon receptor knock down

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          Abstract

          Background

          2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a potent activator of the aryl hydrocarbon receptor (AhR) and causes chloracne in humans. The pathogenesis and role of AhR in chloracne remains incompletely understood.

          Objective

          To elucidate the mechanisms contributing to the development of the chloracne-like phenotype in a human epidermal equivalent model and identify potential biomarkers.

          Methods

          Using primary normal human epidermal keratinocytes (NHEK), we studied AhR activation by XRE-luciferase, AhR degradation and CYP1A1 induction. We treated epidermal equivalents with high affinity TCDD or two non-chloracnegens: β-naphthoflavone (β-NF) and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Using Western blotting and immunochemistry for filaggrin (FLG), involucrin (INV) and transglutaminase-1 (TGM-1), we compared the effects of the ligands on keratinocyte differentiation and development of the chloracne-like phenotype by H&E.

          Results

          In NHEKs, activation of an XRE-luciferase and CYP1A1 protein induction correlated with ligand binding affinity: TCDD > β-NF > ITE. AhR degradation was induced by all ligands. In epidermal equivalents, TCDD induced a chloracne-like phenotype, whereas β-NF or ITE did not. All three ligands induced involucrin and TGM-1 protein expression in epidermal equivalents whereas FLG protein expression decreased following treatment with TCDD and β-NF. Inhibition of AhR by α-NF blocked TCDD-induced AhR activation in NHEKs and blocked phenotypic changes in epidermal equivalents; however, AhR knock down did not reproduce the phenotype.

          Conclusion

          Ligand-induced CYP1A1 and AhR degradation did not correlate with their chloracnegenic potential, indicating that neither CYP1A1 nor AhR are suitable biomarkers. Mechanistic studies showed that the TCDD-induced chloracne-like phenotype depends on AhR activation whereas AhR knock down did not appear sufficient to induce the phenotype.

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          Most cited references66

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          In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.

          A retroviral vector system based on the human immunodeficiency virus (HIV) was developed that, in contrast to a murine leukemia virus-based counterpart, transduced heterologous sequences into HeLa cells and rat fibroblasts blocked in the cell cycle, as well as into human primary macrophages. Additionally, the HIV vector could mediate stable in vivo gene transfer into terminally differentiated neurons. The ability of HIV-based viral vectors to deliver genes in vivo into nondividing cells could increase the applicability of retroviral vectors in human gene therapy.
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            Identification of a novel mechanism of regulation of Ah (dioxin) receptor function.

            Ah receptor (AhR) is a ligand-activated transcription factor that mediates pleiotropic effects of environmental pollutants such as 2,3, 7,8-tetrachlorodibenzo-p-dioxin on host animals. In addition to induction of drug-metabolizing enzymes, the liganded AhR complex was found to activate gene expression of a factor designated AhR repressor (AhRR), which inhibits AhR function by competing with AhR for dimerizing with Arnt and binding to the XRE sequence. Thus, AhR and AhRR form a regulatory circuit in the xenobiotic signal transduction pathway and provide a novel mechanism of regulation of AhR function that may determine tissue-specific sensitivity to environmental pollutants.
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              Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.

              UVB radiation-induced signaling in mammalian cells involves two major pathways: one that is initiated through the generation of DNA photoproducts in the nucleus and a second one that occurs independently of DNA damage and is characterized by cell surface receptor activation. The chromophore for the latter one has been unknown. Here, we report that the UVB response involves tryptophan as a chromophore. We show that through the intracellular generation of photoproducts, such as the arylhydrocarbon receptor (AhR) ligand 6-formylindolo[3,2-b]carbazole, signaling events are initiated, which are transferred to the nucleus and the cell membrane via activation of the cytoplasmatic AhR. Specifically, AhR activation by UVB leads to (i) transcriptional induction of cytochrome P450 1A1 and (ii) EGF receptor internalization with activation of the EGF receptor downstream target ERK1/2 and subsequent induction of cyclooxygenase-2. The role of the AhR in the UVB stress response was confirmed in vivo by studies employing AhR KO mice.
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                Author and article information

                Journal
                J Dermatol Sci
                J. Dermatol. Sci
                Journal of Dermatological Science
                Elsevier
                0923-1811
                1873-569X
                1 January 2014
                January 2014
                : 73
                : 1
                : 10-22
                Affiliations
                [a ]Dermatological Sciences, 2nd Floor Leech Building, Medical Science, Institute of Cellular Medicine, Newcastle University, NE2 4HH, United Kingdom
                [b ]Toxicology, Institute of Cellular Medicine, Newcastle University, NE1 7RU, United Kingdom
                [c ]Global Safety Assessment, Alderley Park, AstraZeneca, Cheshire, United Kingdom
                Author notes
                [* ]Corresponding author. Tel.: +44 0191 222 5840. nick.reynolds@ 123456ncl.ac.uk
                [1]

                Tel.: +44 0191 222 7188.

                [2]

                Tel.: +44 0191 222 7188.

                [3]

                Tel.: +44 0191 222 7188.

                [4]

                Tel.: +44 0191 222 7255.

                Article
                S0923-1811(13)00306-X
                10.1016/j.jdermsci.2013.09.001
                3885976
                24161567
                e8b57540-4a9c-4c5d-9f1b-f022cb78157b
                © 2014 Elsevier Ireland Ltd.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 28 December 2012
                : 22 July 2013
                : 2 September 2013
                Categories
                Article

                Dermatology
                ahrr, aryl hydrocarbon repressor protein,cyp1a1, cytochrome p450 1a1,ite, 2-(1′h-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester,tcdd, 2,3,7,8-tetrachlorodibenzo-p-dioxin,tgm-1, transglutaminase-1,xre, xenobiotic response element,aryl hydrocarbon receptor,β-naphthoflavone,ite,epidermal equivalent,ahr, aryl hydrocarbon receptor,α-nf, α-naphthoflavone,β-nf, β-naphthoflavone,tcdd,keratinocyte

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