Dose-dependent emergence of acute and recurrent corneal lesions in sulfur mustard-exposed rabbit eyes

•Toxic effects of 300−1,500 mg min/m3 sulfur mustard (SM) vapor were characterized in rabbit corneas.•Recurrent edematous lesions (RELs) emerged in a stereotyped fashion over a 20 wk period.•Likelihood of REL emergence was strongly correlated to SM vapor dose.•However, REL pathophysiologies were sim...

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Bibliographic Details
Published in:	Toxicology letters Vol. 341; pp. 33 - 42
Main Authors:	McNutt, Patrick M., Kelly, Kyle E.M., Altvater, Amber C., Nelson, Marian R., Lyman, Megan E., O’Brien, Sean, Conroy, Matthieu T., Ondeck, Celinia A., Bodt, Skylar M.L., Wolfe, Sarah E., Schulz, Susan M., Kniffin, Denise M., Hall, Nicole B., Hamilton, Tracey A.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-05-2021
Subjects:	Alkylating agents Animals Chemical Warfare Agents - toxicity Cornea Cornea - drug effects Cornea - pathology Corneal Injuries - chemically induced Dose-Response Relationship, Drug Drug Administration Schedule Female Mustard Gas - administration & dosage Mustard Gas - toxicity Mustard gas keratopathy Rabbits Sulfur mustard CEC MGK Mustard gas keratopathy OCT Cornea TECD Alkylating agents Sulfur mustard REL SM
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Summary:	•Toxic effects of 300−1,500 mg min/m3 sulfur mustard (SM) vapor were characterized in rabbit corneas.•Recurrent edematous lesions (RELs) emerged in a stereotyped fashion over a 20 wk period.•Likelihood of REL emergence was strongly correlated to SM vapor dose.•However, REL pathophysiologies were similar regardless of SM vapor dose.•These data illustrate optimal SM vapor doses for future therapeutic and mechanistic studies. Sulfur mustard (SM) is a lipid soluble alkylating agent that causes genotoxic injury. The eye is highly sensitive to SM toxicity and exposures exceeding 400 mg min/m3 can elicit irreversible corneal pathophysiologies. Development of medical countermeasures for ocular SM exposure has been hindered by a limited understanding of dose-dependent effects of SM on corneal injury. Here, clinical, histological and ultrastructural analyses were used to characterize the effects of SM dose on corneal injury progression. Corneas were evaluated for up to 20 wk following exposure to saturated SM vapor for 30−150 s, which corresponds to 300−1,500 mg min/m3. In acute studies, a ceiling effect on corneal edema developed at doses associated with full-thickness corneal lesions, implicating endothelial toxicity in corneal swelling. Recurrent edematous lesions (RELs) transiently emerged after 2 wk in a dose-dependent fashion, followed by the development of secondary corneal pathophysiologies such as neovascularization, stromal scarring and endothelial abnormalities. RELs appeared in 96 % of corneas exposed for ≥ 90 s, 52 % of corneas exposed for 60 s and 0 % of corneas exposed for 30 s. While REL latency was variable in corneas exposed for 60 s, REL emergence was synchronized at exposures ≥ 90 s. Corneas did not exhibit more than one REL, suggesting RELs are part of a programmed pathophysiological response to severe alkylating lesions. In post-mortem studies at 12 wk, corneal edema was positively correlated to severity of endothelial pathologies, consistent with previous findings that endothelial toxicity influences long-term outcomes. These results provide novel insight into long-term corneal pathophysiological responses to acute toxicity and identify exposure conditions suitable for therapeutic testing.
ISSN:	0378-4274 1879-3169
DOI:	10.1016/j.toxlet.2021.01.016