NDLI: 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.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Forrester, Alison R. Elias, Martina S. Woodward, Emma L. Graham, Mark Williams, Faith M. Reynolds, Nick J.
Description	Author Affiliation: Forrester AR ( Dermatological Sciences, 2nd Floor Leech Building, Medical Science, Institute of Cellular Medicine, Newcastle University, NE2 4HH, United Kingdom. Electronic address: a.forrester@tigem.it.); Elias MS ( Dermatological Sciences, 2nd Floor Leech Building, Medical Science, Institute of Cellular Medicine, Newcastle University, NE2 4HH, United Kingdom. Electronic address: m.s.elias@newcastle.ac.uk.); Woodward EL ( Dermatological Sciences, 2nd Floor Leech Building, Medical Science, Institute of Cellular Medicine, Newcastle University, NE2 4HH, United Kingdom. Electronic address: e.l.woodward@ncl.ac.uk.); Graham M ( Global Safety Assessment, Alderley Park, AstraZeneca, Cheshire, United Kingdom. Electronic address: mark.j.graham@me.com.); Williams FM ( Toxicology, Institute of Cellular Medicine, Newcastle University, NE1 7RU, United Kingdom. Electronic address: faith.williams@ncl.ac.uk.); Reynolds NJ ( Dermatological Sciences, 2nd Floor Leech Building, Medical Science, Institute of Cellular Medicine, Newcastle University, NE2 4HH, United Kingdom. Electronic address: nick.reynolds@ncl.ac.uk.)
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: ß-naphthoflavone (ß-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>ß-NF>ITE. AhR degradation was induced by all ligands. In epidermal equivalents, TCDD induced a chloracne-like phenotype, whereas ß-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 ß-NF. Inhibition of AhR by -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.
File Format	HTM / HTML
ISSN	09231811
e-ISSN	1873569X
DOI	10.1016/j.jdermsci.2013.09.001
Journal	Journal of Dermatological Science
Issue Number	1
Volume Number	73
Language	English
Publisher	Elsevier
Publisher Date	2014-01-01
Publisher Place	Netherlands
Access Restriction	Open
Subject Keyword	Discipline Dermatology Basic Helix-loop-helix Transcription Factors Agonists Chloracne Etiology Epidermis Drug Effects Gene Knockdown Techniques Keratinocytes Toxicity Receptors, Aryl Hydrocarbon Genetics Metabolism Cell Differentiation Cells, Cultured Pathology Cytochrome P-450 Cyp1a1 Biosynthesis Dose-response Relationship, Drug Enzyme Induction Indoles Intermediate Filament Proteins Ligands Phenotype Protein Precursors Rna Interference Thiazoles Transfection Transglutaminases Beta-naphthoflavone Comparative Study Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Biochemistry Molecular Biology Dermatology

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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.