A Mouse Model of Acute and Delayed Complications of Sulfur Mustard Analogue, 2-Chloroethyl Ethyl Sulfide

Ghazanfari, Tooba; Kaboudanian Ardestani, Sussan; Varmazyar, Mohsen; Eghtedar Doost, Marzieh; Heidari, Fatemeh; Kianmehr, Zahra; Gharebaghi, Reza; Sedaghat, Reza; Ghasemi, Hasan; Naghizadeh, Mohammad Mehdi; Heshmati, Marjan; Vaez-Mahdavi, Mohammad Reza; Faghihzadeh, Soghrat

doi:10.32598/Immunoregulation.1.3.127

A Mouse Model of Acute and Delayed Complications of Sulfur Mustard Analogue, 2-Chloroethyl Ethyl Sulfide

Document Type : Original Article

Authors

¹ Immunoregulation Research Center , Shahed University< Tehran, Iran

² Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

³ Immunoregulation Research Center, Shahed University, Tehran, Iran.

⁴ Department of Biology, Faculty of Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran

⁵ Department of Anatomy Tissue and Pathology, School of Medicine, Shahed University, Tehran, Iran.

⁶ Department of Ophthalmology, Shahed University, Tehran, Iran.

⁷ Department of Social Medicine, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.

⁸ Department of Physiology, School of Medicine, Shahed University, Tehran, Iran

⁹ Department of Biostatistics and Epidemiology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.

10.32598/Immunoregulation.1.3.127

Abstract

Background: Numerous studies have been conducted on humans, animals, and cell cultures exposed to Sulfur Mustard (SM). However, the precise mechanism and cause or long-term pattern of SM injuries are not well defined. There is no protocol available for treating people with severe eye, lung, and skin ailments. The current study aimed to develop an animal model of the acute and delayed complications of SM exposure.
Materials and Methods: Two strains of mice (BALB/c and C57BL/6), 6-8 weeks old at the onset of the study, were exposed to 2-Chloroethyl Ethyl Sulfide (CEES) (1-200 mg/kg) and solvents (Tyrode’s solution, Polyethylene Glycol 300, herbal oil) for a duration of 12 hours to 7 months. The administration route was Intraperitoneal (IP) injection. The mortality rate, signs, and apparent side effects were explored. At the end of the study, the mice’s lung, liver, and spleen tissues were extracted and fixed for future histopathological assessments.
Results: Tyrode’s solution and Polyethylene Glycol 300 solvents were not appropriate for the present research. Pathological features observed in BALB/c mice were better than the C57BL/6 mice. Overall, 10 mg/kg CEES was the most suitable dose, because it had the least mortality rate and demonstrated the most pathological findings, such as the infiltration of inflammatory cells and proliferation of fibroblasts and fibrotic tissue in the lung. Five months after the CEES administration, the delayed phase complications were studied.
Conclusion: The IP injection of 10 mg/kg CEES to BALB/c mice imitates short- and long-term complications of SM exposure in humans. This model is useful for preventing and treating SM exposure.

Keywords

References

Khateri S, Ghanei M, Keshavarz S, Soroush M, Haines D. Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime exposure to mustard agent. Journal of Occupational and Environmental Medicine. 2003; 45(11):1136-43. [DOI:10.1097/01.jom.0000094993.20914.d1]
Gould NS, White CW, Day BJ. A role for mitochondrial oxidative stress in Sulfur Mustard analog 2-Chloroethyl Ethyl Sulfide-induced lung cell injury and antioxidant protection. The Journal of Pharmacology and Experimental Therapeutics. 2009; 328(3):732-9. [DOI: 10.1124/jpet.108.145037] [PMID] [PMCID]
Hassan ZM, Ebtekar M. Modeling for immunosuppression by Sulfur Mustard. International Immunopharmacology. 2001; 1(3):605-10. [DOI:10.1016/S1567-5769(00)00036-9]
Malaviya R, Sunil VR, Cervelli J, Anderson DR, Holmes WW, Conti ML, et al. Inflammatory effects of inhaled Sulfur Mustard in rat lung. Toxicology and Applied Pharmacology. 2010; 248(2):89-99. [DOI:10.1016/j.taap.2010.07.018] [PMID] [PMCID]
Mishra NC, Rir sima ah J, Grotendorst GR, Langley RJ, Singh SP, Gundavarapu S, et al. Inhalation of Sulfur Mustard causes long-term T cell-dependent inflammation: Possible role of Th17 cells in chronic lung pathology. International Immunopharmacology. 2012; 13(1):101-8. [DOI:10.1016/j.intimp.2012.03.010] [PMID] [PMCID]
Joseph LB, Gerecke DR, Heck DE, Black AT, Sinko PJ, Cervelli JA, et al. Structural changes in the skin of hairless mice following exposure to Sulfur Mustard correlate with inflammation and DNA damage. Experimental and Molecular Pathology. 2011; 91(2):515-27. [DOI:10.1016/j.yexmp.2011.05.010] [PMID] [PMCID]
McNutt P, Hamilton T, Nelson M, Adkins A, Swartz A, Lawrence R, et al. Pathogenesis of acute and delayed corneal lesions after ocular exposure to Sulfur Mustard vapor. Cornea. 2012; 31(3):280-90. [DOI:10.1097/ICO.0B013E31823D02CD] [PMID]
O’Neill HC, White CW, Veress LA, Hendry Hofer TB, Loader JE, Min E, et al. Treatment with the catalytic metalloporphyrin AEOL 10150 reduces inflammation and oxidative stress due to inhalation of Sulfur Mustard analog 2-Chloroethyl Ethyl Sulfide (CEES). Free Radical Biology & Medicine. 2010; 48(9):1188-96. [DOI: 10.1016/j.freeradbiomed.2010.01.039] [PMID] [PMCID]
Ahmadi KA, Mohammad Hosseini Akbari H. [Effect of Sulfur Mustard on the rat lung (Persian)]. Journal of Military Medicine. 2005; 7(3):219-23.
Poursaleh Z, Harandi AA, Vahedi E, Ghanei M. Treatment for Sulfur Mustard lung injuries: New therapeutic approaches from acute to chronic phase. DARU Journal of Pharmaceutical Sciences. 2012; 20(1):27. [DOI:10.1186/2008-2231-20-27] [PMID] [PMCID]
The Comprehensive R Archive Network. R Network Software. London: The Comprehensive R Archive Network; 2018.
Yang YC, Ward JR, Luteran T. Hydrolysis of mustard derivatives in aqueous acetone-water and ethanol-water mixtures. The Journal of Organic Chemistry. 1986; 51(14):2756-9. [DOI:10.1021/jo00364a025]
Wiley-VCH. Polyethylene Glycol [MAK Value Documentation, 1998]. In: Wiley-VCH, editor. The Mak-Collection for Occupational Health and Safety. Weinheim: Wiley-VCH; 2002.
Gautam A, Vijayaraghavan R, Sharma M, Ganesan K. Comparative toxicity studies of Sulfur Mustard (2, 2′-dichloro diethyl sulfide) and monofunctional Sulfur Mustard (2-Chloroethyl Ethyl Sulfide), administered through various routes in mice. Journal of Medical Chemical, Biological and Radiological Defense. 2006; 4:1-21.
Vijayaraghavan R, Kulkarni A, Pant SC, Kumar P, Rao PV, Gupta N, et al. Differential toxicity of Sulfur Mustard administered through percutaneous, subcutaneous,