Genotoxicity, Teratogenicity and Mutagenicity of Sulfur Mustard Poisoning
Sulfur Mustard (SM) or mustard gas is the most widely used chemical weapons throughout the history. It has been used in World War 1 and recently in Iran-Iraq conflict. Disabilities produced by SM are continuing problems and various cancers as a consequence of SM exposure were reported. Different in vitro and in vivo studies showed DNA damage and mutations following sulfur mustard exposure. These findings along with the other reported delayed complications as cancer following SM toxicity, suggest instability in the genetic system. The most accepted theory of SM toxicity is alkylation reactions with DNA, RNA and proteins in the cell. DNA is the main target for SM toxicity and DNA cross links and adducts constitute 15 % and 85 % of DNA damages respectively. Several studies have documented the mutagenic effects of SM in mammalian cells, in vivo and in vitro test systems. Measurement of DNA damage, measurement of proteins involved in DNA damage and repair signalling, measurement of markers of oxidative stress and evaluation of chromosomal aberration are among the most important tests for evaluating of SM genotoxicity. There is no treatment for SM toxicity yet, therefore, increasing our knowledge about the mechanisms of SM genotoxicity, would help us better understanding about prevention and treatment of SM toxicity in human. Few studies are available regarding the reproductive effects of SM in animals and humans and the results are controversial.
KeywordsSulfur Mustard Genotoxicity DNA damage Telomere Chromosomal aberration
An adduct is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product.
ATP is a nucleoside triphosphate used in cells as a coenzyme and transports chemical energy within cells for metabolism.
The attachment of an alkyl group to an organic compound, usually by the addition or substitution of a hydrogen atom or halide group
A natural process of self-destruction by degradative enzymes in certain cells. Also called programmed cell death.
A substance or agent that can cause cancer.
The cell cycle, or cell-division cycle, is the series of events that take place in a cell leading to its division and duplication (replication).
A chemical agent or toxin, such as mustard gas, lewisite, or sarin, that has been prepared for release on the battlefield or within a civilian population in sufficient concentration to cause widespread illness or death.
A chromosomal aberration reflects on a typical number of chromosomes or a structural abnormality in one or more chromosomes.
A cross-link is a bond that links one polymer chain to another. They can be covalent bonds or ionic bonds.
Deoxyribonucleic acid (DNA) is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms.
The breaking of a (DNA) into smaller parts.
DNA replication is the process of producing two identical copies from one original DNA molecule.
An electron-deficient chemical compound or group that is attracted to electrons and tends to accept electrons.
A domain of organisms having cells, each with a distinct nucleus within the genetic material is contained.
Genotoxicity describes the property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer.
A molecule that acts as a co-enzyme in cellular oxidation-reduction reactions.
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called “blasts”.
The addition of a methyl group to a cytosine residue on double- stranded DNA, a process which plays a major role in regulating gene expression.
A change in the nucleotide sequence of the genome of an organism or virus, sometimes resulting in the appearance of a new character or trait not found in the parental type.
Nicotinamide adenine dinucleotide is a coenzyme and signaling molecule, whose oxidized form is NAD+.
Increased oxidant production in animal cells characterized by the release of free radicals and resulting in cellular degeneration.
P53 is a tumor suppressor protein that is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer.
PARP is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.
The prokaryotes are a group of organisms whose cells lack a membrane-bound nucleus (karyon).
Several processes by which genetic material of different origins becomes combined. It most commonly occurs between the two sets of parental chromosomes during production of germ cells
Ribonucleic acid (RNA) is a ubiquitous family of large biological molecules that perform multiple vital roles in the coding, decoding, regulation, and expression of genes.
Sister chromatid exchange (SCE) is the exchange of genetic material between two identical sister chromatids. Used as a mutagenic testing of many products.
The process by which sperm develop to become mature sperm, capable of fertilizing an ovum.
A class of related cytotoxic and vesicant chemical warfare agents with the ability to form large blisters on the exposed skin and in the lungs
A telomere is a region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes.
Any agent or factor that induces or increases the incidence of abnormal prenatal development.
Transcription is the first step of gene expression, in which a particular segment of DNA is copied into RNA by the enzymes, RNA polymerase.
A substance that has no intrinsic carcinogenic potential, but which, when applied repeatedly, amplifies cancer-inducing effects of other (initiator) substances.
A gene that its function is to limit cell proliferation and loss of function leads to cell transformation and tumor growth. Also called antioncogene.
- Balali-Mood M, Balali-Mood B (2009) Sulphur mustard poisoning and its complications in Iranian veterans. Iran J Med Sci 34:155–171Google Scholar
- Boulware S, Fields T, Mcivor E, Powell KL, Abel EL, Vasquez KM, Macleod MC (2012) 2,6-dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog. Toxicol Appl Pharmacol 263:203–209PubMedPubMedCentralCrossRefGoogle Scholar
- Gregus Z, Klaassen CD (2001) Mechanisms of toxicity. In: Casarett and Doull’s toxicology: the basic science of poisons. McGraw-Hill Professionals, New YorkGoogle Scholar
- Hackett P, Sasse RL, Rommereim R, Cushing J, Buschbom R, Kalkwarf D (1987) Teratology studies of lewisite and sulfur mustard agents: effects of lewisite in rats and rabbits. Pacific Northwest Laboratory, Richland, AD-A 198 423Google Scholar
- Hassan ZM, Noori Daloii MR, Nadery Manesh H, Bidaky SK, Rostamzadeh J, Jalilian N, Rezwani HR (2002) Immunohaematological and cytogenetical studies on human population exposed to sulfur mustard. J Sci I R Iran 13:303–309Google Scholar
- IARC (1994) Overall evaluations of carcinogenicity: an updating of IARC monographs volumes 1 to 42. IARC, Lyon, 1987. IARC monographs on the evaluation of carcinogenic risks to humansGoogle Scholar
- Jostes R, Rausch R, Miller B, Sasser L, Dacre J (1989) Geno-toxicity of lewisite in Chinese hamster ovary cells. Toxicologist 9:232Google Scholar
- Karami A, Arjmand S, Khalil PA, Beyrami JF, Ghaneei M, Eshraghi M (2007) New p53 gene mutation in non-cancerous mustard gas exposed lung. Iran J Basic Med Sci 10:111–117Google Scholar
- Kolle, Susanne (2012) Genotoxicity and carcinogenicity. BASF The Chemical Company. http://www.alternative-methods.basf.com/
- Kornberg A, Baker TA (1980) DNA replication. W.H. Freeman, San FranciscoGoogle Scholar
- Lichtfouse E, Schwarzbauer J, Robert D (2012) Environmental chemistry for a sustainable world. Springer, New YorkGoogle Scholar
- Maynard RL (1995) Chemical warfare agents. In: General and applied toxicology. Ballantyne, B, Stockton Press, New YorkGoogle Scholar
- Mcnamara BP, Owens EJ, Christensen MK, Vocci FJ, Ford DF, Rozimarek H, Sidell FR (1975) Clinical notes on chemical casualty care. In: Toxicological basis for controlling levels of mustard in the environment. Aberdeen Proving Ground, Md: Edgewood Arsenal Biomedical LaboratoryGoogle Scholar
- National Research Council (1997) Acute exposure guideline levels for selected airborne chemicals, subcommittee on acute exposure guideline levels. The National Academies Press. Washington, D.CGoogle Scholar
- Papirmeister B, Feister AJ, Robinson SI, Ford RD (1991) In: Medical defense against mustard gas: toxic mechanisms and pharmacological implications. CRC Press, Boca Raton, Florida, USAGoogle Scholar
- Pechuta CM, Rall DP (1993) Relationship of mustard agent and lewisite exposure to carcinogenesis. In: Veterans at risk, the health effects of mustard gas and lewisite. The National Academies Press, Washington, D.C, pp 81–111Google Scholar
- Pour-Jafari H (1992) Fetal deaths and parental exposure to chemical warfare agents. Med J Islamic Rep Iran 6:87–88Google Scholar
- Pour-Jafari H, Farhud D, Hashemzadeh Chaleshtori M (2011) Fetal deaths and congenital malformations in progenies of Iranian chemical victims. J Res Health Sci 3:18–21Google Scholar
- Saenger W (1984) Principles of nucleic acid structure. Springer-Verlag, BerlinGoogle Scholar
- Sharma DR, Sunkaria A, Bal A, Bhutia YD, Vijayaraghavan R, Flora SJ, Gill KD (2009) Neurobehavioral impairments, generation of oxidative stress and release of pro-apoptotic factors after chronic exposure to sulphur mustard in mouse brain. Toxicol Appl Pharmacol 240:208–218PubMedCrossRefGoogle Scholar
- Stewart DL, Sass E, Fritz L, Sasser L (1989) Toxicology studies on lewisite and sulfur mustard agents: mutagenicity of lewisite in the salmonella histidine reversion assay, Pacific Northwest Laboratory, Richland, USA. Supported by U.S. Army Medical Research and Development Command Fort Detrick, Frederick, USAGoogle Scholar
- Williams GM, Weisburger JH (1991) Chemical carcinogenesis. In: Klaassen CD, Amdur MO, Doull J (eds) Casarett and Doull’s toxicology: the basic science of poisons, 4th edn. Pergamon Press, New York, pp 127–200Google Scholar