Teratogenic Effects of Sulfur Mustard on Mice Fetuses

Document Type: Original Article


1 Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Basic Sciences, Mashhad Azad University, Mashhad, Iran


Sulfur Mustard (SM) has been used as a chemical warfare agent, in the World War I and more recently during Iraq-Iran war in early 1980s’. Its biological poisoning effect could be local or systemic and its effect depends on environmental conditions, exposed organs, and the extent and duration of exposure. It is considered as a strong alkylating agent with known mutagenic, carcinogenic effects; although a few studies have been performed on its teratogenicity so far.
Materials and Methods
Mice were administered with SM intraperitoneally with a dose of 0.75 and 1.5 mg/kg in different periods of their gestation (gestational age of 11, 13 and 14 weeks). Control mice groups were included. Between 5 and 9 mice were used in each group. Dams underwent cesarean section on day 19 of their gestation. External examination was performed on the animals investigating craniofacial and septal defects and limb malformations such as adactyly and syndactyly. All data were analyzed by Chi-Square test and Fisher's exact test. The P- value less than 0.05 was considered significant.
Craniofacial and septal defects as well as the limb malformations were the most common types of birth defects, displaying an extremely complex biomedical problem.
This study confirms a significant correlation between SM exposure and its teratogenic effect. We postulated that the malformations could be caused by an uncontrolled migration of neural crest cells, causing developmental disorders. In addition to environmental factors, modifying genes could play an important role in the pathogenesis of the defects.


1. Wheeler GP. Studies related to the mechanism of action of cytotoxic alkylating agents. Cancer Res 1962; 22:65 1-88.

2. Balali M, Hefazi M. The clinical toxicology of sulfur mustard. Arch Iran Med  2005; 8 :162-179.

3. Balali M, Balali B. Sulphur mustard poisoning and its complications in Iranian veterans. IJM  2009; 34:155-171.

4. Compton JF. Chemical and toxicological properties. In: Military Chemical and Biological Agents,? Caldwell; 1997. p. 5-17.

5. Abbas AY Taher. Cleft lip and palate in Tehran. Cleft Palate Craniofac J 1992; 29:1.

6. WHO. Health aspect of biological and chemical weapons. Geneva: WHO, 1970.

7. Lakshmana Rao PV, Vijayaraghavan R, Bhaskar ASB. Sulphur mustard induced DNA damage in mice after dermal and inhalation exposure. Toxicology 1999; 139:39-51.

8. Ludlum DB, Papirmeister B. DNA modification by sulfur mustards and nitrosoureas and repair of these lesions. Basic Life Sci 1986; 38:119-125.

9. Rall DP, Pechura CM. Effects on health of mustard gas. Nature 1993; 366:398-399.

10. Freitag L, Firusian N, Stamatis G, Greschuchna D. The role of bronchoscopy in pulmonary complications due to mustard gas inhalation. Chest  1991; 1436-1441.

11. Monica W, Bey T. Mustard gas or sulfur mustard: an old chemical agent as a new terrorist threat. Pre  Dis Med?  2009; 24:19-29.

12. Aasted A, Darre E, Wulf HC. Mustard gas: clinical toxicological and mutagenuc aspects based on modern experience. Ann Plast Surg  1987; 19:330-333.

13.  Easton DF, Peto J, Doll R. Cancers of the respiratory tract in mustard gas workers. Br J Ind Med  1988; 45:652-659.

14.  Somani SM, Babu SR. Toxicodynamics of sulfur mustard. Int J Clin Pharmacol Ther Toxicol 1989; 27:419-435.

15. Ribiro PL, Mitra RS, Bernstein IA. Assessment of the role of DNA damage and repair in the survival of primary cultures of rat cutaneous keratinocytes exposed to bis (2-chloroethyl) sulfide. Toxicol Appl Pharmacol 1991; 111:342-351.

16. Wormser U, Izrael M, Van der Zee EA, Brodsky B, Yanai J A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity, Neurotoxicolo.Teratolo 2005;  27:65-71.

17. Young DL, Schneider RA, Hu D, Helms JA. Genetic and teratogenic approaches to craniofacial development. Crit Rev Oral Biol Med 2000; 11:304-317.

18.  Murray JC. Gene/environment causes of cleft lip/palate. Clin Genet 2002; 61:248-256.

19. Strauss RP. The organization and delivery of craniofacial health services: the state of the art. Cleft Palate Craniofac J 1999; 36:189-195.

20. Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J 1987; 24:216-225.

21.  OginoT. Congenital anomalies of the hand:asian perspective. Clin Orthop 1996; 323:12-21.

22.  Ogino T, Kato H. Clinical and experimental studies on teratogenic mechanisms of congenital absence of digits in longitudinal deficiencies. Cong Anom 1993; 33:187-196.

23.  Donovan J, Kordylewska A, Jan YN, Utset MF.

 tetralogy of fallot and other congenital heart defects in Hey2 mutant mice. Curr Biol 2002; 12:1605-1610.

24. Korkmaz A, Tanand D, Russel J. Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies. Interdiscip Toxicol 2008; 1:22–26.

25. Papirmeister B, Gross CI, Meier HL, Petrali JP,Johnson JB. Molecular basis of mustard-induced vesication. Fundam Appl Toxicol 1985; 5:134-139.

26. Balali M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 2006; 99:273–284.

27. Pour-Jafari H. Fetal deaths and parental exposure to chemical warfare agents. Med J Islamic Rep Iran 1992; 6:87-88.

28. Hackett PL, Rommereim RL, Burton FG, Buschbom RL, Sasser LB. Teratology studies on lewisite and sulfur mustard agents: Effects of sulfur mustard in rats and rabbits: Final Report: Frederick, MD: U.S. Army Medical Research and Development Command, Department of the Army. AD-A 1987; 187- 495.

29. McNamara BP, Owens EJ, Christensen MK, Vocei FJ, Ford DF, Rozimarek N. Toxicological basis for controlling levels of mustard in the environment. EB-SP-74030. Edgewood Arsenal. Aberdeen Proving Grounds, MD. Proving Ground, MD. 1975.