Document Detail

2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.
MedLine Citation:
PMID:  23152189     Owner:  NLM     Status:  MEDLINE    
Chloracne is commonly observed in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood. Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses. TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis. Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids. TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate. NADH and Krebs cycle intermediates were decreased, whereas NAD(+) was increased. Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide. Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR. Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation. Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation.
Lawrence H Kennedy; Carrie Hayes Sutter; Sandra Leon Carrion; Quynh T Tran; Sridevi Bodreddigari; Elizabeth Kensicki; Robert P Mohney; Thomas R Sutter
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-14
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  132     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-08-29     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  235-49     Citation Subset:  IM    
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MeSH Terms
Cell Differentiation / drug effects*
Cells, Cultured
Chromatography, High Pressure Liquid
Gene Expression / drug effects
Glycolysis / drug effects
Keratinocytes / cytology,  drug effects*,  metabolism
Mitochondria / drug effects
Oligonucleotide Array Sequence Analysis
Reactive Oxygen Species / metabolism*
Real-Time Polymerase Chain Reaction
Tetrachlorodibenzodioxin / toxicity*
Grant Support
Reg. No./Substance:
0/Reactive Oxygen Species; DO80M48B6O/Tetrachlorodibenzodioxin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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