Interdisc Toxicol. 2008; Vol. 1(1): 22–26. doi: 10.2478/v10102-010-0027-x Published online in: www.intertox.sav.sk & www.versita.com/science/medicine/it/ Copyright © 2010 Slovak Toxicology Society SETOX This is an Open Access article distributed under the terms of the Creative Commons Attribu- tion License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. r EVIEW Art Icl E interdisciplinary Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies Ahmet Kor KmAz 1,2, Dun-Xian TAn 2 and r ussel J. r eiTer 2 1 Department of Physiology, School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey 2 Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA ITX010108R06 • Received: 16 May 2008 • Revised: 17 May 2008 • Accepted: 19 May 2008 • Electronic Publication: November 2010 Abstr Act Sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. The toxicity of SM as an incapacitat- ing agent is of much greater importance than its ability to cause lethality. Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. Therefore melatonin shows beneficial effects against acute SM toxicity in a variety of manner. It scavenges most of the oxygen- and nitrogen-based reac- tants, inhibits inducible nitric oxide synthase, repairs DNA damage and restores cellular energy depletion. The delayed toxicity of SM however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to genetic mutations, epimutations can also involve in the pathogenesis of a variety of human diseases. Several actions of melatonin are now delineated by epigenetic actions including modulation of histone acetylation and DNA methylation. Future studies are warranted to clarify whether epigenetic mechanisms are involved in pathogenesis of delayed sulfur mustard toxicity and melatonin alleviates delayed toxicity of this warfare agent. KEY WOr Ds : sulfur mustard; acute toxicity; delayed toxicity; melatonin; epigenetic aberrations Introduction Among the available chemical warfare agents, sulfur mus- tard (SM), also known as mustard gas, has been a widely used chemical weapon. Because of its devastating toxicity, its use during the World War I earned it the sobriquet “king of the battle gases”. Other compounds such as nitrogen mustard (HN2) were developed during World War II, but found to be unsuitable as a munition. Soon after discovering HN2, it became the first non-hormonal agent used in cancer chemo- therapy. A number of HN2 derivatives including cyclophos- phamide (CP), ifosfamide, mechlorethamine, melphalan and chlorambucil are valuable cytotoxic and radiomimetic agents for the treatment of cancer (Kehe and Szinicz, 2005). Summary of Acute SM Toxicity Acute toxicity of SM shares almost the same pathophysi- ologic mechanisms with other toxic agents including CP, Correspondence address: Ahmet Korkmaz, MD. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA e-mail: korkmaz@uthscsa.edu; drakorkmaz@gmail.com paraquat, acetaminophen and doxorubicin. Recent data consistently proves that reactive oxygen species (ROS) (Ozcan et al., 2005), nitric oxide (NO•) (Korkmaz et al., 2003) produced by inducible nitric oxide synthase (iNOS) (Oter et al., 2004), and most importantly peroxynitrite (ONOO–) (Korkmaz et  al., 2005; Yaren et  al., 2007) are involved in initial detrimental effects of all mustards (Korkmaz et al., 2007; Korkmaz et al., 2006). ONOO– is per se not a radical but is a powerful nitrosat- ing agent. ONOO– interacts with and covalently modifies all major types of biomolecules including membrane lipids, thiols, proteins and DNA. ONOO– activates matrix metalloproteinases (MMPs) and triggers the expression of selectins and cellular adhesion molecules, via enhanc- ing nuclear factor (NF)-κB and activator protein (AP)-1 activation, thereby promoting pro-inflammatory responses including most importantly tumor necrosis factor (TNF)-α and interleukin (IL)-1β. ONOO– also induces apoptosis and necrosis in cells depending on the exposure concentration. In case of higher concentration, a DNA repair enzyme poly (ADP ribose) polymerase-1 (PARP-1), mediates ONOO–-induced necrosis (Korkmaz et  al., 2006). PARP-1 detects and signals DNA strand breaks induced by a variety of genotoxic insults. PARP transfers ADP-ribose units from the respiratory coenzyme nicotinamide adenine dinucleotide (NAD+)