title: 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 (3.2mg) 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 24h (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.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Dinesh G
authors.initials: DG
authors.lastname: Goswami
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kant
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Rancourt
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Deepanshi
authors.initials: D
authors.lastname: Dhar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Rajesh.Agarwal@UCDenver.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D006413:Hematopoietic System / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity*; D008812:Mice, Hairless; D009929:Organ Size / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000293:injuries; D013154:Spleen / Q000187:drug effects* / Q000473:pathology; D016019:Survival Analysis
chemical_list: D002619:Chemical Warfare Agents; D008466:Mechlorethamine
keywords: Leucocytes; Nitrogen mustard; SKH-1 hairless mice; Skin topical exposure; Systemic toxicity