Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

Kan, Robert K.; Pleva, Christina M.; Hamilton, Tracey A.; Anderson, Dana R.; Petrali, John P.

doi:10.1080/01926230390183661

Cited by 19 publications

(4 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies supporting the induction of apoptosis following SM exposure to cultured cells and whole skin have identified characteristic apoptotic features, including increases in p53, reduction in Bcl-2 levels, nucleosomal DNA fragmentation, PARP cleavage, and caspase activation [24,25,27,45,46]. In the present study, microarray analysis has identified gene transcripts at all six SM doses that are associated with apoptosis, including retinoic acid receptor beta (RAR␤), TNF receptor superfamily ligands, and cyclin G. The role of both retinoic acid receptors and TNF receptor ligands in apoptosis has been studied extensively [47][48][49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of gene expression in murine skin exposed to sulfur mustard

Rogers

Choi

Kiser

et al. 2005

J. Biochem. Mol. Toxicol.

View full text Add to dashboard Cite

The chemical warfare agent sulfur mustard [bis-(2-chloroethyl)-sulfide; SM] produces a delayed inflammatory response followed by blister formation in skin of exposed individuals. Studies are underway evaluating the efficacy of pharmacological compounds to protect against SM skin injury. Microarray analysis provides the opportunity to identify multiple transcriptional biomarkers associated with SM exposure. This study examined SM-induced changes in gene expression in skin from mice cutaneously exposed to SM using cDNA microarrays. Ear skin from five mice, paired as SM-exposed right ear and dichloromethane vehicle-exposed left ear at six dose levels (0.005, 0.01, 0.02, 0.04, 0.08, and 0.16 mg; 6 mM to 195 mM range), was harvested at 24 h post-exposure. SM-induced gene expression was analyzed using cDNA microarrays that included 1,176 genes. Genes were selected on the basis of all mice (N=5) in the same dose group demonstrating a > or =2-fold increase or decrease in gene expression for the SM-exposed tissue compared to the dichloromethane vehicle control ear tissue at all six SM doses. When skin exposed to all six concentrations of SM was compared to controls, a total of 19 genes within apoptosis, transcription factors, cell cycle, inflammation, and oncogenes and tumor suppressors categories were found to be upregulated; no genes were observed to be downregulated. Differences in the number and category of genes that were up- or down-regulated in skin exposed to low (0.005-0.01 mg) and high (0.08-0.16 mg) doses of SM were also observed. The results of this study provide a further understanding of the molecular responses to cutaneous SM exposure, and enable the identification of potential diagnostic markers and therapeutic targets for treating SM injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Microarray analysis of gene expression in murine skin exposed to sulfur mustard

Rogers

Choi

Kiser

et al. 2005

J. Biochem. Mol. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Cellular shrinkage, cytoplasmic budding, nuclear fragmentation, and apoptotic bodies are pathognomonic of apoptosis. Confirmation by transmission electron microscopy of cytoplasmic budding bearing nuclear fragments is essential in the differential diagnosis of cellular apoptosis (Kan et al, 2003). Apoptosis contributes to the mechanisms of removal of unwanted cells in normal physiological processes (e.g., during organ development, sloughing of the endometrium in early menstruation period, immune response, etc.).…”

Section: Introductionmentioning

confidence: 99%

A Convenient Fluorometric Method to Study Sulfur Mustard–Induced Apoptosis in Human Epidermal Keratinocytes Monolayer Microplate Culture

Ray¹,

Hauck

Kramer

et al. 2005

Drug and Chemical Toxicology

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information sister cultures so that the apoptotic mechanisms and the effects of test compounds can be compared statistically. SM affects diverse cellular mechanisms, including endoplasmic reticulum (ER) Ca 2 ' homeostasis, mitochondrial functions, energy metabolism, and death receptors, each of which can independently trigger apoptosis. However, the biochemical pathway in any of these apoptotic mechanisms is characterized by a pathway-specific sequence of caspases, among which caspase-3 is a key member. Therefore, we exposed 80-90% confluent HEK cultures to SM and monitored apoptosis by measuring the fluorescence generated due to hydrolysis of a fluorogenic caspase-3 substrate (acetyl-or benzyl oxycarbonyl-Asp-Glu-Val-Aspfluorochrome, also designated as AC-or Z-DEVD-fluorochrome) added to the assay medium. Fluorescence was measured using a plate reader. We used two types of substrates, one (Sigma-Aldrich, CASP-3-F) required cell disruption and the other (Beckman-Coulter CellProbe HT Caspase-3/7 Whole Cell Assay Kit) was cell permeable. The latter substrate was useful in experiments such as determining the time-course of apoptosis immediately following SM exposure without disruption (e.g., due to cell processing). In SM-exposed HEK, fluorescence generated from the fluorogenic caspase-3 substrate hydrolysis increased in a time (0-24 h) and concentration (0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mM) dependent manner. SM caused maximum fluorescence at about 0.5 mM. However, at 2 mM SM, fluorescence decreased compared with 0.5 mM, which remains to be explained. Following 0.3 mM SM exposure, which is considered to be the in vitro equivalent of a vesicating dose in vivo (Smith, W. J., Sanders, K. M., Ruddle, S. E., Gross, C. L. (1993). Cytometric analysis of DNA changes induced by sulfur mustard. J. Toxicol.-Cut. Ocular Toxicol. 12(4):337-347.), a small fluorescence increase was observed at 6 to 8 h, which was markedly higher at 12 h. At 24 h, all SM concentrations increased fluorescence. Fluorescence increase due to SM was prevented 100% by a caspase-3-specific peptide inhibitor AC-DEVD-CHO (acetyl-Asp-Glu-Val-Asp-aldehyde, 0.1 mM), but less effectively by a general caspase inhibitor Z-VAD-FMK (benzyl oxycarbonyl-Val-AlaAsp-fluoromethylketone, 0.01 mM), indicating that the fluorescence increase was due to caspase-3-mediated apoptosis. These results suggest potential applications of this method to study apoptosis mechanisms involving caspase-3 substrates and possibly those involving other caspase substrates.

show abstract

“…Maruziyet sonrası derideki tipik belirtilerdeneritem ve blister oluşumunun neden olduğu gerginlik rahatsızlık verici düzeydedir. Bül oluşumu dermis ile epidermis tabakalarını bir arada tutan protein bağların harabiyetisonrasında ortaya çıkar ve maruziyetten bir gün sonra belirgin hale gelir (34,35). Bununla birlikte ortaya çıkan şiddetli kaşıntı, derideki yanmaya bağlı olarak oluşan büller sonrası azalır.…”

Section: Nitrojen Mustard (Terapötik Kullanım);unclassified

Mustard group chemical warfare agents and clinical effects

Kalkan¹,

Aykutluğ²,

Topal³

2017

Health Care Acad J

View full text Add to dashboard Cite

ÖZETMustard gazı geçtiğimiz yüzyıl içerisinde en çok kullanılan, yüz binlerce insanın ölümüne ve yaralanmasına yol açan vezikan ajanlar olarak sınıflandırılan kimyasal silah grubudur. Sülfür mustard (SM) ve analoğu olan Nitrojen mustard (NM)bu gruba dahil iki kimyasal ajandır. İçinde bulunduğumuz orta doğu ve yakın coğrafyadaki İran, Irak, Libya, Suriye gibi ülkelerin elinde tonlarca sülfür mustard gazı bulunduğu ve bunun bölge ülkeleri için çok ciddi bir tehdit olduğu artık herkes tarafından bilinen bir gerçektir. Ortaya çıkardığı devasa etkiler nedeniyle mustard gazı "savaş gazlarının kralı"ünvanınıalmıştır. Tarih sürecinde ilk defa 1.Dünya Savaşı'nda kullanılmış olan mustard gazı, takip eden yıllar içerisinde defalarca silahlı mücadelelerde kullanılmış asker ve sivillerin kitlesel ölümüne ve yaralanmasına neden olmuştur. Elde edilmesi, depolanması ve kullanımı konusundaki kolaylık mustard gazının tercih edilmesinin en önemli nedenleridir. Mortaliteden çok mobiditeye neden olmasımustard gazının bir savaş ajanı olarak tercih edilmesinin diğer nedenidir. Bu nedenle devletler yıllarca yaralıların bakımıyla uğraşmış ve bu durum maddi ve manevi bir yıkıma neden olmuştur. Oldukça yüksek toksisiteye sahip olması maruz kalınan doz ile doğru orantılı olarak ani ölümleri de beraberinde getirmektedir. Başlıca etkilerini göz, akciğer ve deri üzerinde gösteren mustard gazı kanser oluşumu da dahil olmak üzere vücutta birçok hasara yol açmaktadır. Nitrojen mustard kimyasal yapısı ve oluşturmuş olduğu toksisite bakımından SM ile büyük ölçüde benzerlik göstermektedir. Oluşturmuş olduğu etkiler nedeniyle kullanımı yasaklanmıştır. Kullanımı sonrasında yaralanan kişiler üzerinde yapılan çalışmalar kemoterapötik bir ajan olarak kullanılabileceği sonucunu doğurmuştur. Antidotu bulunmayan tek kimyasal ajan olması nedeniyle yaklaşık yarım yüzyıldır üzerinde yürütülen antidot geliştirme çabaları belli bir düzeye kadar gelmiştir ancak bu konuda halen alınması gereken önemli mesafeler bulunmaktadır. ABSTRACTMustard gas is the most used chemical weapon group in the past century, which is classified as a vesicant agent that leads to the death and injury of hundreds of thousands of people. Sulfur mustard (SM) and its analogue Nitrogen mustard (NM) are the two chemical agents involved in this group. This is a fact known by everyone that Iran, Iraq, Libya, Syria like countries in the middle east and close geography have tons of sulfur mustard gas in the hands which is a serious threat to the countries of the region.Due to the enormous effects that it has caused, mustard gas has taken the title of "king of the battle gasses". Mustard gas, which was used in World War I for the first time in history, has caused massive deaths and injuries of soldiers and civilians, which have been used repeatedly in armed struggles over the following years. The convenience of obtaining, storing and using is the most important reason why mustard gas is preferred as a waragent. More morbidity than mortality is the another reason why it is preferred as a war agent...

show abstract

Sulfur Mustard-Induced Apoptosis in Hairless Guinea Pig Skin

Cited by 19 publications

References 29 publications

Microarray analysis of gene expression in murine skin exposed to sulfur mustard

Microarray analysis of gene expression in murine skin exposed to sulfur mustard

A Convenient Fluorometric Method to Study Sulfur Mustard–Induced Apoptosis in Human Epidermal Keratinocytes Monolayer Microplate Culture

Mustard group chemical warfare agents and clinical effects

Contact Info

Product

Resources

About