Topical nitrogen mustard exposure causes systemic toxic effects in mice

Abstract

Vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) are reported to be easily absorbed by skin upon exposure causing severe cutaneous injury and blistering. Our studies show that topical exposure of NM (3.2 mg) onto SKH-1 hairless mouse skin, not only caused skin injury, but also led to significant body weight loss and 40–80 % mortality (120 h post-exposure), suggesting its systemic effects. Accordingly, further studies herein show that NM exposure initiated an increase in circulating white blood cells by 24 h (neutrophils, eosinophils and basophils) and thereafter a decrease (neutrophils, lymphocytes and monocytes). NM exposure also reduced both white and red pulp areas of the spleen. In the small intestine, NM exposure caused loss of membrane integrity of the surface epithelium, abnormal structure of glands and degeneration of villi. NM exposure also resulted in the dilation of glomerular capillaries of kidneys, and an increase in blood urea nitrogen/creatinine ratio. Our results here with NM are consistent with earlier reports that exposure to higher SM levels can cause damage to the hematopoietic system, and kidney, spleen and gastrointestinal tract toxicity. These outcomes will add to our understanding of the toxic effects of topical vesicant exposure, which might be helpful towards developing effective countermeasures against injuries from acute topical exposures.

Comparative Pulmonary Protective Efficacy of Amifostine and it’s Analogue S-2(2-aminoethylamino)ethyl Phenyl Sulfide (DRDE-07) against Sulphur Mustard Induced Oxidative Stress and Inflammation in Female Mice

“…28,29 The previously published report has shown that cutaneous exposure of SM and its analogue not only limited to local injury but also caused a systemic effect. 30,31 The systemic effect occurs mainly due to the overexpression of inflammatory cytokines, which leads to organ dysfunction resulting in severe body weight loss 31,32 In the present study also, a severe decrease in body weight and morphological change were observed which suggest this could be results of intestinal epithelial damage which leads to insufficiency of dietary nutrients. Previously, Batal et al reported comparative internal organs toxicity after cutaneous exposure of SM and found that lung was the second most affected organ following cutaneous exposure of SM.…”

Defining the timing of 25(OH)D rescue following nitrogen mustard exposure

“…Without treatment, the lesion deepened and progressively worsened by day 10 post-exposure. The systemic toxic effects of NM reaches beyond local injury to cause cytopenia in blood, loss of intestinal barrier function, dilation of capillaries in the kidney, and bone marrow suppression 9,15 . Thus, the model is consistent with work previously reported by us and others that NM and SM induced skin vesication progressively deteriorates into a full thickness wound if continued inflammation is not suppressed by intervention with an anti-inflammatory drug 9,16 .…”

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

“…NM is particularly toxic to the skin, and able to cause systemic toxicity from topical absorption[22]. However unlike SM, NM has never been used in combat and fell out of favor for military use due to difficulties with its storage[23].…”

“…NM may have a similar mechanism of action as SM due to its high reactivity, ability to alkylate DNA, and cause oxidative stress. NM mechanism of action produces DNA alkylation that is mediated with an immonium ion instead of a sulphonium ion[22]. NM is believed to directly cause oxidative stress in affected tissues, which then mediates activation of signaling pathways leading to cell microvesication and death[24].…”