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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide.

Authors: Black, Adrienne T; Hayden, Patrick J; Casillas, Robert P; Heck, Diane E; Gerecke, Donald R; Sinko, Patrick J; Laskin, Debra L; Laskin, Jeffrey D

Published In Toxicol Appl Pharmacol, (2010 Dec 01)

Abstract: Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100-1000 μM) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300-1000 μM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE₂ synthases, leukotriene (LT) A₄ hydrolase and LTC₄ synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1-2 (GSTA1-2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.

PubMed ID: 20840853 Exiting the NIEHS site

MeSH Terms: Biomarkers/metabolism; Blotting, Western; Cell Proliferation/drug effects; Dose-Response Relationship, Drug; Eicosanoids/biosynthesis; Histones/biosynthesis; Humans; Irritants/toxicity*; Keratinocytes/cytology; Keratinocytes/drug effects; Mustard Gas/analogs & derivatives*; Mustard Gas/toxicity; Poly Adenosine Diphosphate Ribose/biosynthesis; Proliferating Cell Nuclear Antigen/biosynthesis; RNA, Messenger/biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Skin/cytology; Skin/drug effects*; Time Factors

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