Pathogenesis of 2,2′-dichlorodiethyl sulfide in hairless guinea pigs

Published on Nov 12, 1993in Toxicology4.099
· DOI :10.1016/0300-483X(93)90116-A
Jeffrey J. Yourick5
Estimated H-index: 5
,
Jeffrey S. Dawson3
Estimated H-index: 3
+ 2 AuthorsLarry W. Mitcheltree12
Estimated H-index: 12
Sources
Abstract
Abstract Developing skin lesions on hairless guinea pigs due to 2,2′-dichlorodiethyl sulfide (sulfur mustard, HD) exposure were examined to determine the time course for the appearance of histopathologic markers in relationship to skin NAD + and NADP + content after HD exposure. Hairless guinea pig skin was exposed to HD for 8 min by means of a vapor cup. Skin punches were taken at 1, 2, 4, 8, 12, 16, 20 and 24 h after HD exposure. Intracellular edema (IE) appeared at 2 h and increased steadily over 24 h. Epidermal necrosis (EN) and pustular epidermatitis (PE) developed at 8 h and reached a maximum at 16 h. Follicular necrosis (FN) appeared at 8 h and increased up to 24 h. Microvesicles (MV) developed between 12–16 h reaching a maximum at 24 h. Niacinamide (750 mg/kg, ip) pretreatment (30-min) reduced the incidence of MV (40%) and FN (45%) at 24 h, but did not reduce IE, EN, or PE. In all animals, skin NAD + content decreased to a minimum (20% of control) at 16 h, but NAD + decreases did not precede microvesicle formation. Skin NADP + content increased (260%) between 1–2 h and returned to control at 4 h. Skin cell NADP + increases may be indicative of an early phase of cellular oxidative stress that may contribute to HD-induced dermal pathogenesis. Since NAD + reductions did not precede microvesication and NAM-induced increases in NAD + content did not delay or reduce early cellular alterations, the contributory role of NAD + to microvesicle formation may be limited and other biochemical changes should be investigated.
📖 Papers frequently viewed together
267 Citations
69 Citations
86 Citations
References17
Newest
#1T.J. Oberly (Eli Lilly and Company)H-Index: 9
#2K. C. Michaelis (Eli Lilly and Company)H-Index: 2
Last. M.L. Garriott (Eli Lilly and Company)H-Index: 13
view all 5 authors...
The mouse lymphoma assay (MLA) and Chinese hamster ovary (CHO) cell assay are sensitive indicators of mutagenicity. The CHO assay has been modified technically to permit treatment in suspension and soft agar cloning comparable to the MLA. This methodology eliminates the risk of metabolic cooperation and the trauma of trypsinization. In addition, a larger population of cells can be treated and cloned for mutant selection. In order to compare the effectiveness of the test systems, 10 chemicals wer...
29 CitationsSource
#1Clark L. GrossH-Index: 11
#2Joy K. InnaceH-Index: 1
Last. William J. SmithH-Index: 20
view all 5 authors...
Glutathione (GSH) is the major nonprotein thiol that can protect cells from damage due to electrophilic alkylating agents by forming conjugates with the agent. Sulfur mustard (HD) is an electrophilic alkylating agent that has potent mutagenic, carcinogenic, cytotoxic, and vesicant properties. Compounds that elevate or reduce intracellular levels of GSH may produce changes in cytotoxicity induced by sulfur mustard. Pretreatment of human peripheral blood lymphocytes (PBL) for 72 hr with 1 mM buthi...
98 CitationsSource
Abstract It has been postulated that sulfur mustard (HD) damage may activate poly(ADP-ribose) polymerase (PADPRP), resulting in depletion of cellular NAD + . This biochemical alteration is postulated to result in blister (vesicle) formation. It has been previously demonstrated that niacinamide (NAM), an inhibitor of PADPRP and a precursor for NAD + synthesis, may be useful as a pretreatment compound to reduce HD-induced microvesication. The present study was undertaken to determine whether niaci...
23 CitationsSource
#1E. GentilhommeH-Index: 2
#2Y. NeveuxH-Index: 1
Last. Jean Thivolet (French Institute of Health and Medical Research)H-Index: 49
view all 6 authors...
Abstract Human keratinocyte cultures were treated with bis(betachloroethyl)sulphide (BCES), an alkylating and vesicant agent. At concentrations of 5 × 10−4 to 5 × 10−3 m , spontaneous detachment of the epithelium from the culture plate was observed, reproducing in vitro the cutaneous vesication observed in vivo. Progressive cellular alterations were shown with increasing concentrations of BCES (5 × 10−5 to 5 × 10−3 m ). At low concentrations (5 × 10−5 m ), lesions of the nucleus, a significant t...
35 CitationsSource
#1Nabil M. ElsayedH-Index: 15
#2Stanley T. OmayeH-Index: 26
Last. Don W. KorteH-Index: 5
view all 4 authors...
Vesicant-induced pathogenesis is initiated by rapid alkylation and cross-linking of DNA purine bases causing strand breaks leading subsequently to NAD depletion and cell death. We postulated that vesicants may also be associated with free radical-mediated oxidative stress distal to the site of exposure. To test this postulate in the lung, we injected 3 groups (n = 8) of 5-month-old, male, athymic, nude mice, weighing 30–35 g with a single subcutaneous (s.c.) injection (5 μl/mouse) of butyl 2-chl...
65 CitationsSource
#1Jeffrey J. Yourick (United States Army Medical Research Institute of Chemical Defense)H-Index: 1
#2Connie R. Clark (United States Army Medical Research Institute of Chemical Defense)H-Index: 1
Last. Larry W. Mitcheltree (United States Army Medical Research Institute of Chemical Defense)H-Index: 4
view all 3 authors...
It has been proposed that sulfur mustard (HD) may indirectly activate poly(ADP-ribose) polymerase (PADPRP) by alkylating cellular DNA (Papirmeister et al., 1985). Activation of PADPRP results in the depletion of cellular NAD+, which initiates a series of biochemical processes that have been proposed to culminate in blister formation. Preventing PADPRP activation and NAD+ depletion should inhibit blister formation. Niacinamide is both an inhibitor of PADPRP and a precursor for NAD+ synthesis. The...
69 CitationsSource
Abstract Blister formation due to sulfur mustard (HD) exposure was studied in an ex vivo human skin model. Pieces of fresh human skin were exposed to HD vapor and subsequently incubated in medium for 48 hr. During this culture period cellular NAD + levels and uptake of glucose from the medium decreased relative to the duration of the exposure to HD. In light microscopic sections of skin that were exposed to HD for 6 min, clefts of variable size could be clearly observed between the epidermis and...
49 CitationsSource
#1Millard M. MershonH-Index: 6
Last. John V. WadeH-Index: 4
view all 5 authors...
Abstract Sulfur mustard (HD; 1,1′-thiobis[2-chloroethane]) induces fluid-filled blisters in man but not in conventional laboratory animals. An animal model is needed to emulate both cytotoxic (vesicant) and vascular (irritant) responses of human skin to HD exposures. An acceptable model must permit reproducible comparisons of uniformly graded and dose-related HD control responses with reduced responses that may follow antivesicant treatments. Hairless guinea pigs were evaluated by exposing six o...
86 CitationsSource
#1William J. SmithH-Index: 20
#2Clark L. GrossH-Index: 11
Last. Henry Louis Meier (DA: United States Department of the Army)H-Index: 11
view all 4 authors...
Human epidermal keratinocytes in culture were studied to evaluate their usefulness in demonstrating toxic events following exposure to sulfur mustard. Exposure of keratinocytes to sulfur mustard over a concentration range of 1–1000 μM HD, reduced NAD+ levels from 96% to 32% of control levels. When keratinocytes were exposed to a concentration of 300 μM HD, NAD+ levels began to fall at 1 hour and reached a plateau of 47% of control levels at 4 hours. Niacinamide, an inhibitor of the enzyme poly(A...
69 CitationsSource
In cultured human epidermal cells exposure to the vesicant sulfur mustard (HD) causes a decrease of the NAD+ content, which depends on the dose and the time period between exposure to HD and NAD+ measurement. Presumably, this NAD+ loss is due to activation of the enzyme NAD:protein ADP-ribosyltransferase (ADPRT) and may lead to glycolysis inhibition, disturbance of energy metabolism, and eventually cell death. Since prevention of this NAD+ depletion could lead to cell survival, HD-exposed cultur...
68 CitationsSource
Cited By23
Newest
#1Joanna A. Ruszkiewicz (University of Konstanz)H-Index: 2
#2Alexander Bürkle (University of Konstanz)H-Index: 4
Last. Aswin Mangerich (University of Konstanz)H-Index: 18
view all 3 authors...
Abstract Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the...
1 CitationsSource
#1Simone RothmillerH-Index: 6
#2Sarah SchröderH-Index: 1
Last. Annette Schmidt (Bundeswehr University Munich)
view all 10 authors...
Abstract Background Sulfur mustard (SM) is a potent blistering chemical warfare agent, which was first used in 1917. Despite the Chemical Weapons Convention, a use was recently reported in Syria in 2015. This emphasizes the importance to develop countermeasures against chemical warfare agents. Despite intensive research, there is still no antidote or prophylaxis available against SM. Methods The newly developed SM-resistant keratinocyte cell line HaCaT/SM was used to identify new target structur...
6 CitationsSource
#1Aswin Mangerich (University of Konstanz)H-Index: 18
#2Malgorzata Debiak (University of Konstanz)H-Index: 7
Last. Alexander Bürkle (University of Konstanz)H-Index: 66
view all 14 authors...
Abstract Mustard agents are potent DNA alkylating agents with mutagenic, cytotoxic and vesicant properties. They include bi-functional agents, such as sulfur mustard (SM) or nitrogen mustard (mustine, HN2), as well as mono-functional agents, such as “half mustard” (CEES). Whereas SM has been used as a chemical warfare agent, several nitrogen mustard derivatives, such as chlorambucil and cyclophosphamide, are being used as established chemotherapeutics. Upon induction of specific forms of genotox...
22 CitationsSource
#1Malgorzata Debiak (University of Konstanz)H-Index: 7
#2Kirsten Lex (University of Konstanz)H-Index: 3
Last. Alexander Bürkle (University of Konstanz)H-Index: 4
view all 9 authors...
Abstract Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard-induced pathologies, supported ...
4 CitationsSource
#4Robert P. Casillas (Battelle Memorial Institute)H-Index: 20
This chapter describes the dermal toxicity events of the alkylating agent, sulfur mustard [bis(2-chloroethyl) sulfide], which ultimately causes detachment of the epidermis from the dermis. Skin exposure to sulfur mustard (SM) starts a series of dermal toxicity events with severity determined in part by mediators of injury that regulate inflammation, immune responses, apoptosis, necrosis, and a number of signaling pathways. This complex series of events involves a host of normal skin responses to...
4 CitationsSource
#1Laurie B. Joseph (RU: Rutgers University)H-Index: 12
#2Diane E. Heck (NYMC: New York Medical College)H-Index: 38
Last. Jeffrey D. Laskin (RU: Rutgers University)H-Index: 69
view all 10 authors...
Abstract Sulfur mustard (SM) is a bifunctional alkylating agent causing skin inflammation, edema and blistering. A hallmark of SM-induced toxicity is follicular and interfollicular epithelial damage. In the present studies we determined if SM-induced structural alterations in hair follicles and sebaceous glands were correlated with cell damage, inflammation and wound healing. The dorsal skin of hairless mice was treated with saturated SM vapor. One to seven days later, epithelial cell karyolysis...
10 CitationsSource
#1James B. Kirkland (U of G: University of Guelph)H-Index: 23
Abstract Through its involvement in over 400 NAD(P)-dependent reactions, niacin status has the potential to influence every area of metabolism. Niacin deficiency has been linked to genomic instability largely through impaired function of the poly ADP-ribose polymerase (PARP) family of enzymes. In various models, niacin deficiency has been found to cause impaired cell cycle arrest and apoptosis, delayed DNA excision repair, accumulation of single and double strand breaks, chromosomal breakage, te...
45 CitationsSource
#1Janet M. Benson (LRRI: Lovelace Respiratory Research Institute)H-Index: 30
#2Brad M. Tibbetts (LRRI: Lovelace Respiratory Research Institute)H-Index: 5
Last. Gary R. Grotendorst (LRRI: Lovelace Respiratory Research Institute)H-Index: 32
view all 4 authors...
Sulfur mustard (SM), a vessicating agent, has been used in chemical warfare since 1918. The purpose of this study was to quantitate SM vapor deposition, tissue distribution, and excretion following intratracheal inhalation in rats and cutaneous exposure in guinea pigs. 14C-SM vapors for inhalation studies were generated by metering liquid 14C-SM into a heated J tube. Vapors were transported via carrier air supplemented with oxygen and isoflurane to an exposure plenum. Anesthetized rats with tran...
9 CitationsSource
#1Kamyar Ghabili (Tabriz University of Medical Sciences)H-Index: 21
#2Paul S. AgutterH-Index: 15
Last. Mohammadali Mohajel Shoja (IU: Indiana University)H-Index: 39
view all 6 authors...
Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents...
130 CitationsSource
#1Janet M. Benson (LRRI: Lovelace Respiratory Research Institute)H-Index: 30
#2JeanClare Seagrave (LRRI: Lovelace Respiratory Research Institute)H-Index: 31
Last. Thomas H. March (LRRI: Lovelace Respiratory Research Institute)H-Index: 22
view all 7 authors...
The objective of these studies was to provide detailed analyses of the time course of sulfur mustard (SM) vapor-induced clinical, histological, and biochemical changes following cutaneous exposure in hairless guinea-pigs. Three 6 cm2 sites on the backs of each guinea-pig were exposed to SM vapor (314 mg3) for 6 minutes (low dose) or 12 minutes (high dose). Animals were killed at 6, 24, and 48 hours, or 2 weeks postexposure. Erythema, edema, histopathology, and analysis of matrix metalloproteinas...
22 CitationsSource