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

Published on Jan 1, 2005in Journal of Biochemical and Molecular Toxicology3.606
· DOI :10.1002/JBT.20043
James V. Rogers16
Estimated H-index: 16
(Battelle Memorial Institute),
Young W. Choi13
Estimated H-index: 13
(Battelle Memorial Institute)
+ 4 AuthorsCarol L. K. Sabourin24
Estimated H-index: 24
(Battelle Memorial Institute)
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 ≥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. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:289–299, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20043
📖 Papers frequently viewed together
29 Citations
22 Citations
76 Citations
#1Carol L. K. Sabourin (Battelle Memorial Institute)H-Index: 24
#2James V. Rogers (Battelle Memorial Institute)H-Index: 16
Last. Robert P. Casillas (Battelle Memorial Institute)H-Index: 20
view all 9 authors...
Sulfur mustard [bis(2‐chloroethyl)sulfide, SM] is a chemical warfare agent that penetrates the skin rapidly and causes extensive blistering. Using the mouse ear vesicant model (MEVM), we evaluated the effect of topically applied anti‐inflammatory agents (octyl homovanillamide and heptyl isovanillamide) on ear edema formation and gene expression following SM exposure. Relative ear weight and real‐time reverse transcriptase polymerase chain reaction of GM‐CSF, IL‐1β, and IL‐6 were used to evaluate...
9 CitationsSource
#1Carol L. K. Sabourin (Battelle Memorial Institute)H-Index: 24
#2Michele M. Danne (Battelle Memorial Institute)H-Index: 2
Last. Robert P. Casillas (United States Army Medical Research Institute of Chemical Defense)H-Index: 20
view all 8 authors...
Cutaneous exposure to sulfur mustard [bis(2-chloroethyl) sulfide (SM)] produces a delayed inflammatory skin response that is followed by severe dermal injury. Assessment of anti-inflammatory therapies against SM-induced skin injury has mainly relied on qualitative histopathological evaluation. The goal of this study was to identify proinflammatory biomarkers in the hairless mouse vesicant model that could be used as additional indicators of SM-induced skin injury for evaluating anti-inflammatory...
23 CitationsSource
#1James V. Rogers (FFO: Wright-Patterson Air Force Base)H-Index: 4
#2Carol M. Garrett (Wright State University)H-Index: 3
Last. James N. McDougal (Wright State University)H-Index: 13
view all 3 authors...
Occupational skin disease is the second most significant cause of occupational disease, after accidents. Irritation from occupational chemicals such as solvents, hydrocarbons, and surfactants are one cause of this disease. Gene expression studies provide useful information about normal processes in the skin and responses of the skin to exogenous chemicals. We exposed rats, cutaneously, to sodium lauryl sulfate (SLS, 1% and 10% aqueous solution), m-xylene (pure liquid), and d-limonene (pure liqui...
26 CitationsSource
Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that s...
27 CitationsSource
#1Simone Di Giovanni (Children's National Medical Center)H-Index: 31
#2Susan M. Knoblach (GUMC: Georgetown University Medical Center)H-Index: 23
Last. Alan I. Faden (GUMC: Georgetown University Medical Center)H-Index: 114
view all 6 authors...
Spinal cord injury causes secondary biochemical changes leading to neuronal cell death. To clarify the molecular basis of this delayed injury, we subjected rats to spinal cord injury and identified gene expression patterns by high-density oligonucleotide arrays (8,800 genes studied) at 30 minutes, 4 hours, 24 hours, or 7 days after injury (total of 26 U34A profiles). Detailed analyses were limited to 4,300 genes consistently expressed above background. Temporal clustering showed rapid expression...
238 CitationsSource
#1Takao Ohtsuka (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 37
#2Hoon Ryu (UMMS: University of Massachusetts Medical School)H-Index: 55
Last. Sam W. Lee (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 69
view all 5 authors...
Cyclin G is a transcriptional target gene of tumor suppressor p53. Recent studies present evidence that cyclin G may play a central role in the p53-Mdm2 autoregulated module, but the precise function of cyclin G remains elusive. Here, we show a negative effect of cyclin G on the stability of p53 and p73. Cyclin G expression resulted in a dramatic decrease of p53 protein levels in response to DNA damage and abrogated irradiation-mediated G1 arrest along with an increase of S phase in MCF7 cells c...
73 CitationsSource
#1Robert K. KanH-Index: 12
#2Christina M. PlevaH-Index: 3
Last. John P. PetraliH-Index: 3
view all 5 authors...
The present study was aimed to examine whether apoptosis is involved in the pathogenesis of sulfur mustard (SM)-induced basal cell death. Skin sites of the hairless guinea pig exposed to SM vapor for 8 minutes were harvested at 3, 6, 12, 24, and 48 hours postexposure. Immunohistochemical detection of basal cell apoptosis was performed using the ApopTag in situ apoptosis labeling kit. Only occasional apoptotic basal cells (BC) were observed in nonexposed and perilesional control sites. At lesiona...
44 CitationsSource
#1Carol L. K. Sabourin (Battelle Memorial Institute)H-Index: 24
#2Michele M. Danne (Battelle Memorial Institute)H-Index: 2
Last. Robert P. Casillas (Battelle Memorial Institute)H-Index: 20
view all 5 authors...
Cutaneous exposure to sulfur mustard [bis(2-chloroethyl) sulfide; SM] produces a delayed inflammatory skin response and severe tissue injury. Pig skin has organ similarities to human skin that is characterized by the content and types of epidermal lipids, the density of hair follicles and presence of sweat glands, which together afford penetration of topically applied compounds, complex inflammatory responses, and subsequent wound healing. The goal of this study was to identify in vivo proinflam...
92 CitationsSource
#1M. ToyodaH-Index: 3
#2M. NakamuraH-Index: 5
Last. M. MorohashiH-Index: 4
view all 6 authors...
SummaryBackground Neurogenic components, such as neurotrophic factors and neuropeptides, are probably involved in the pathogenesis of atopic dermatitis (AD) via the neuroimmunocutaneous system. Numerous in vitro and in vivo studies have shown that nerve growth factor (NGF), the best-characterized member of the neurotrophin family, modulates the synthesis of the neuropeptide substance P (SP), both of which may be associated with the pathogenesis of human allergic diseases. Objectives To evaluate ...
274 CitationsSource
Nerve growth factor (NGF) regulates the survival and development of specific populations of neurones and is involved in wound healing. A further area of study relating to the role of neurotrophins in the mature animal has concerned the possibility that NGF may be a pivotal mediator of inflammation and pain. It has previously been shown that injection of intradermal NGF can result in a neutrophil-dependent hyperalgesia in the rat. The purpose of the present study was to examine the pathological c...
18 CitationsSource
Cited By32
#1Robin Lüling (LMU: Ludwig Maximilian University of Munich)H-Index: 3
#2Harald John (LMU: Ludwig Maximilian University of Munich)H-Index: 20
Last. Dirk Steinritz (LMU: Ludwig Maximilian University of Munich)H-Index: 22
view all 7 authors...
The chemosensory transient receptor potential ankyrin 1 (TRPA1) ion channel perceives different sensory stimuli. It also interacts with reactive exogenous compounds including the chemical warfare agent sulfur mustard (SM). Activation of TRPA1 by SM results in elevation of intracellular calcium levels but the cellular consequences are not understood so far. In the present study we analyzed SM-induced and TRPA1-mediated effects in human TRPA1-overexpressing HEK cells (HEKA1) and human lung epithel...
7 CitationsSource
#1Albert L RuffH-Index: 4
#2Sarah Lynn BeachH-Index: 1
Last. James F. DillmanH-Index: 16
view all 5 authors...
Sulfur mustard [SM, bis-(2-chloroethyl) sulfide] is a highly reactive bifunctional alkylating agent that has been used as a vesicating agent in warfare scenarios to induce severe lung, skin, and eye injury. SM cutaneous lesions are characterized by both vesication and severe inflammation, but the molecular mechanisms that lead to these signs and symptoms are not well understood. There is a pressing need for effective therapeutics to treat this injury. An understanding of the molecular mechanisms...
#1Hossein AyatollahiH-Index: 13
#2Mohammad Rafiee (MUMS: Mashhad University of Medical Sciences)H-Index: 6
Last. Azam Moradi ZarmehriH-Index: 3
view all 9 authors...
Sulfur mustard (SM) was used by the Iraqi army against the Iranian troops in the Iran-Iraq war from 1983-1988. This chemical gas affects different organs including the skin, lungs and the hematopoietic system. Any exposure to SM increases the risk of chromosomal breaking, hyperdiploidy and hypodiploidy. Studies have shown that the risk for acute myeloblastic and lymphoblastic leukemia increases in veterans exposed to SM. FLT3 mutations including ITD and TKD mutations had been observed in some ca...
2 CitationsSource
Abstract Sulphur mustard (SM) is a highly toxic chemical agent and poses a current threat to both civilians and military personnel in the event of a deliberate malicious release. Acute SM toxicity develops over the course of several hours and mainly affects the skin and mucosal surfaces of the eyes and respiratory system. In cases of acute severe exposure, significant lung injury can result in respiratory failure and death. Systemic levels of SM can also be fatal, frequently due to immunodepleti...
7 CitationsSource
#1Ali Najafi (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 17
#2Ali Masoudi-NejadH-Index: 28
Last. M R Nourani (BMSU: Baqiyatallah University of Medical Sciences)H-Index: 5
view all 5 authors...
AbstractThere is much data about the acute effects of sulfur mustard gas on humans, animals and cells. But less is known regarding the molecular basics of chronic complications in humans. Basically, mustard gas, as an alkylating agent, causes several chronic problems in the eyes, skin and more importantly in the pulmonary system which is the main cause of death. Although recent proteomic research has been carried out on bronchoalveolar lavage (BAL) and serum, but high-throughput transcriptomics ...
18 CitationsSource
#1Ali Najafi (UT: University of Tehran)H-Index: 17
#2Ali Masoudi-Nejad (UT: University of Tehran)H-Index: 28
Last. Ali Moeini (UT: University of Tehran)H-Index: 17
view all 5 authors...
Airway remodeling is a pathophysiologic process at the clinical, cellular, and molecular level relating to chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD), asthma and mustard lung. These diseases are associated with the dysregulation of multiple molecular pathways in the airway cells. Little progress has so far been made in discovering the molecular causes of complex disease in a holistic systems manner. Therefore, pathway and network reconstruction is an...
10 CitationsSource
BACKGROUND: To date, sulphur mustard (SM) cutaneous toxicity has been commonly assessed on account of several animal models such as pigs and weanling pigs. Few experiments however, have been carried out on mice so far. In this study, we aimed at quantifying spontaneous wound healing processes after SM exposure on a SKH-1 mouse model through non-invasive methods over an extended period of time. METHODS: Animals were exposed to 10 μL net SM in a vapor cup system. Measurements of barrier function (...
11 CitationsSource
#1Charlotte Amy HallH-Index: 1
There is potential for haemorrhaging injuries that become contaminated with toxic chemicals e.g. sulphur mustard (SM). There are no specific medical countermeasures for such injuries at present. It is proposed that haemostats could simultaneously stop bleeding and decontaminate wounds. Products must be able to clot SM-contaminated blood and reduce SM percutaneous absorption to be considered suitable. Sulphur mustard did not significantly affect coagulation in vitro or in vivo. Overall SM did not...
2 Citations
#1Jennifer A. Price (Battelle Memorial Institute)H-Index: 8
#2James V. Rogers (Battelle Memorial Institute)H-Index: 16
Last. John S. GrahamH-Index: 18
view all 7 authors...
Chlorine is an industrial chemical that can cause cutaneous burns. Understanding the molecular mechanisms of tissue damage and wound healing is important for the selection and development of an effective post-exposure treatment. This study investigated the effect of cutaneous chlorine vapor exposure using a weanling swine burn model and microarray analysis. Ventral abdominal sites were exposed to a mean calculated chlorine vapor concentration of 2.9 g/L for 30 min. Skin samples were harvested at...
1 CitationsSource
#1Virginie ValletH-Index: 1
#2T. Poyot (AG: Analysis Group)H-Index: 1
Last. Isabelle BoudryH-Index: 9
view all 7 authors...
Sulfur mustard (HD) ranks among the alkylating chemical warfare agents. Skin contact with HD produces an inflammatory response that evolves into separation at the epidermal–dermal junction conducting to blistering and epidermis necrosis. Up to now, current treatment strategies of HD burns have solely consisted in symptomatic management of skin damage. Therapeutic efficacy studies are still being conducted; classically using appropriate animal skin toxicity models. In order to substantiate the us...
13 CitationsSource