title: Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.
abstract: 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.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.forename: Sumeet
authors.initials: S
authors.lastname: Rana
authors.forename: Mallikarjuna
authors.initials: M
authors.lastname: Gu
authors.forename: Arttatrana
authors.initials: A
authors.lastname: Pal
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000287:Administration, Topical; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D020556:Neutrophil Infiltration / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011897:Random Allocation; D012867:Skin / Q000166:cytology / Q000293:injuries / Q000473:pathology*
chemical_list: D054316:Biomarkers, Pharmacological; D018809:Proliferating Cell Nuclear Antigen; C031278:2-chloroethyl ethyl sulfide; D009195:Peroxidase; D009151:Mustard Gas