Document Detail


Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.
MedLine Citation:
PMID:  19075041     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05-2 mg) and time- (3-168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.
Authors:
Neera Tewari-Singh; Sumeet Rana; Mallikarjuna Gu; Arttatrana Pal; David J Orlicky; Carl W White; Rajesh Agarwal
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-12-15
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  108     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-02-19     Completed Date:  2009-08-10     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  194-206     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Administration, Topical
Analysis of Variance
Animals
Apoptosis / drug effects
Biomarkers, Pharmacological / metabolism*
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Epidermis / drug effects,  metabolism
Female
Inflammation / chemically induced*,  metabolism
Mast Cells / metabolism
Mice
Mice, Hairless
Mustard Gas / administration & dosage,  analogs & derivatives*,  toxicity
Neutrophil Infiltration / drug effects
Peroxidase / metabolism
Proliferating Cell Nuclear Antigen / metabolism
Random Allocation
Skin / cytology,  injuries,  pathology*
Grant Support
ID/Acronym/Agency:
U54 ES015678/ES/NIEHS NIH HHS; U54 ES015678/ES/NIEHS NIH HHS; U54 ES015678-030003/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Biomarkers, Pharmacological; 0/Proliferating Cell Nuclear Antigen; 693-07-2/2-chloroethyl ethyl sulfide; EC 1.11.1.7/Peroxidase; T8KEC9FH9P/Mustard Gas
Comments/Corrections

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