Direct binding of sulfur mustard and chloroethyl ethyl sulphide to human cell membrane-associated proteins; implications for sulfur mustard pathology

Sayer, Natalie M.; Whiting, Rachel; Green, A.C.; Anderson, Kevin; Jenner, John; Lindsay, Christopher D.

doi:10.1016/j.jchromb.2009.11.030

Cited by 19 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trichrome staining of CEES-treated full-thickness skin equivalents also revealed alterations in keratin organization in the stratum corneum. These results are in agreement with earlier studies demonstrating that vesicants induce keratin aggregation and abnormal filament assembly and can directly modify cytoskeletal proteins including cytokeratins 5, 6, 9, 14 and 16, actin and annexin A2 (Dillman et al , 2003; Hess and FitzGerald, 2007; Mol et al , 2008; Sayer et al , 2009). Single amino acid mutations in keratin 5 and keratin 14 can perturb filament assembly, resulting in skin blistering diseases (Uitto et al , 2007).…”

Section: Discussionsupporting

confidence: 93%

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Black

Hayden

Casillas

et al. 2010

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT™, a commercially available full-thickness human skin equivalent. CEES (100–1000 μM) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300–1000 μM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE2 synthases, leukotriene (LT) A4 hydrolase and LTC4 synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1–2 (GSTA1–2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.

show abstract

Section: Discussionsupporting

confidence: 93%

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Black

Hayden

Casillas

et al. 2010

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…While PARP inhibition induced a shift from necrosis to apoptosis in SM treated cells (Kehe et al, 2008), our current analysis did not reveal such a shift for CEES treated cells. Furthermore, a proteomics approach studying membrane associated target pro teins of SM and CEES identified differential subsets of proteins that were modified by SM and CEES, underscoring the different cellular mechanisms by which these two compounds exert their toxic effects (Sayer et al, 2010). Taken together, this implies that caution is indicated when using CEES as the only surrogate to study SM related molecular mechanisms, since CEES and SM may trigger considerably different molecular responses in the cell.…”

Section: (I) Cees and Hn2 As Sm Surrogatesmentioning

confidence: 97%

“…The mono functional alkylating agent CEES is widely used as such a substitute, because it represents the mono functional analogue to SM [ Fig. 1, Jain et al, 2011;Jowsey et al, 2009;Sayer et al, 2010;Wang et al, 2012)]. In addition, the bi functional nitrogen mustard is used as a surrogate agent, because it takes into account the bi functional reaction mechanism of SM [ Fig.…”

Section: (I) Cees and Hn2 As Sm Surrogatesmentioning

confidence: 99%

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

et al. 2016

View full text Add to dashboard Cite

Letters ; 244 (2016). -S. 56-71 https://dx.doi.org/10.1016/j.toxlet.2015In particular, we recorded substance specific as well as dose and time dependent PARylation responses using independent bioanalytical methods based on single cell immuno fluorescence microscopy and quantitative isotope dilution mass spectrometry. Furthermore, we analyzed if and how PARylation contributes to mustard induced toxicity by treating HaCaT cells with CEES, SM, and HN2 in combination with the clinically relevant PARP inhibitor ABT888. As evaluated by a novel immunofluorescence based protocol for the detection of N7 ETE guanine DNA adducts, the excision rate of CEES induced DNA adducts was not affected by PARP inhibition. Furthermore, while CEES induced moderate changes in cellular NAD + levels, annexin V/PI flow cytometry analysis revealed that these changes did not affect CEES induced short term cytotoxicity 24 h after treatment. In contrast, PARP inhibition impaired cell proliferation and clonogenic survival, and potentiated micronuclei formation of HaCaT cells upon CEES treatment. Similarly, PARP inhibition affected clonogenic survival of cells treated with bi functional mustards such as SM and HN2.In conclusion, we demonstrate that PARylation plays a functional role in mustard induced cellular stress response with substance specific differences. Since PARP inhibitors exhibit therapeutic potential to treat SM related pathologies and to sensitize cancer cells for mustard based chemotherapy, potential long term effects of PARP inhibition on genomic stability and carcinogenesis should be carefully considered when pursuing such a strategy.

show abstract

“…Sulphur Mustard binding to specific proteins could contribute to the complex pathology seen after SM exposure (19). An Iranian study revealed that Smad3 and 4 may be involved in the airway remodeling process in SMinduced patients by activation of TGF-b (20).…”

Section: Attempts For Understanding the Underlying Mechanismsmentioning

confidence: 99%

Effects of Mustard Gas on Veterans: A Review

Jahromy

Mohsenian

Rezagholizamenjany

et al. 2017

Ann Mil Health Sci Res

View full text Add to dashboard Cite

Context: Sulfur Mustard has been an important subject of research for Iranian scientists since 1983, when the Iraq army used this chemical weapon against Iranians, causing injury for more than 30000 people, still suffering from its late effects.Evidence Acquisition: This review was based on previous studies, found from online databases. Results: Sulfur mustard is synthesized by different methods, and its exposure could cause severe, irreversible damage to the skin, respiratory tract, and eyes. In the eyes, it has a wide spectrum of complications. These complications begin with an asymptomatic period, following irritation and redness, and ends with damage to the corneal structure with photophobia, temporary blindness, and blepharospasm.Conclusions: Based on this, this review discusses some of the attempts made to define aspects of sulfur mustard and its mechanisms.

show abstract

Direct binding of sulfur mustard and chloroethyl ethyl sulphide to human cell membrane-associated proteins; implications for sulfur mustard pathology

Cited by 19 publications

References 23 publications

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences

Effects of Mustard Gas on Veterans: A Review

Contact Info

Product

Resources

About