to various nuclear proteins. In case of severe DNA injury, overactivation of PARP-1 depletes the cellular stores of NAD+, an essential cofactor in the glycolytic pathway, the tricarboxylic acid cycle, and the mitochondrial electron transport chain. As a result, the loss of NAD+ leads to a marked reduction in the cellular pools of ATP, resulting in cellular dysfunction and cell death via the necrotic pathway. Experimental evidence has established that the PARP-1 pathway of cell death plays a pivotal role in tissue injury and organ dysfunction in mustard-induced acute toxicity (Kehe et al., 2007; Korkmaz et al., 2008). Beneficial Effects of Melatonin Against Acute SM Toxicity There is a large body of evidence that melatonin is major scavenger of both oxygen and nitrogen based radicals including ONOO–. Several metabolites of this indolamine also have the capability to detoxify free radicals and their derivatives (Tan et al., 2007). Melatonin, possesses genomic actions and regulates the expression of several genes includ- ing those for SOD and GSH-Px. Melatonin influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes under both physiological conditions and during elevated oxidative stress (Reyes-Toso et  al., 2004). These two features in a single molecule are unique for an antioxidant and both actions protect against pathologically- produced free radicals after SM exposure. In many inflammatory processes, ONOO– rather than oxygen-based radicals is the predominant molecule which decides the fate of cells. Once formed, ONOO– cannot be scavenged by conventional antioxidants. As a multifunc- tional antioxidant, however, melatonin and its metabolites have unique features over the usual antioxidants includ- ing iNOS inhibition and ONOO– scavenging properties against mustard-induced acute toxicity (Sadir et al., 2007; Topal et al., 2005; Ucar et al., 2007; Yildirim et al., 2004). Melatonin has been shown to ameliorate inflammation by blocking transcriptional factors and pro-inflammatory cytokines (Mei et al., 2002; Sasaki et al., 2002; Wang et al., 2004) and preserves cellular energy production and ATP level in several pathologic circumstances (Dugo et al., 2001; Lopez et  al., 2006; Tan et  al., 2005). Thus, melatonin is the only medically suitable versatile antioxidant and anti- inflammatory agent which defeats the cells against all levels of acute mustard toxicity. Proposed Mechanism of Delayed SM Toxicity Unfortunately, it is not clear how mustard gas causes severe multi-organ damage years after even a single exposure (Balali-Mood and Hefazi, 2006). Most metabolites of mus- tard agents are excreted in the urine within a few weeks after exposure and they do not accumulate within the cells (Somani and Babu, 1989). Cellular acute effects of mustards and several other drugs including acetaminophen and doxo- rubicin disappear after the exposure ceases. SM is the only Interdisciplinary Toxicology. 2008; Vol. 1(1): 22–26 Also available online on setox.eu/intertox 23 warfare agent which has severe delayed effects and causes progressive incapacitation of victims. 34 000 Iranians have been examined 13–20 years after exposure to SM, and it was found that lungs (42.5%), eyes (39%), and skin (24.5%) of victims are affected and these pathologies are almost incur- able even with extensive treatments (Khateri et al., 2003). A possible explanation of the delayed mechanism would be epigenetic perturbations caused by SM even after single exposure. The term epigenetic describes the study of inherit- able alterations in gene expression that occur in the absence of changes in genome sequence. This is in contrast to genet- ics, which deals with the transmission of information based on differences in DNA sequence. Therefore, epigenetic gene regulation requires molecular mechanisms that encode information in addition to the DNA base sequence and can be propagated through mitosis and meiosis. Our current understanding of epigenetic regulation of gene expression involves basically two classes of molecular mechanisms: histone modifications and DNA methylation. A variety of enzymes are involved in this process including most importantly histone deacetylases (HDACs), histone acetyl transferases (HATs) and DNA methyltransferases (DNMTs) (Miremadi et  al., 2007). Alteration of the structure of chromatin is critical to the regulation of gene expression. Chromatin is made up of nucleosomes, which are particles consisting of DNA associated with an octomer of two molecules each of the core histone proteins (H2A, H2B, H4 and H4), around which 146 base pairs of DNA are wound. In resting conditions, DNA is wound tightly around these basic core histones, excluding the binding of the enzyme RNA polymerase II, which activates the formation of mes- senger RNA. This conformation of the chromatin structure is described as closed, and is associated with the suppression of gene expression. DNA methylation is another regulation, in which a cytosine base is modified by a DNMT at the C5 position of cytosine, a reaction that is carried out by various members of a single family of enzymes. CpG islands are CG-rich sequences located near coding sequences and serve as promoters for the associated genes and methylation of CpG sites is maintained by DNMTs. DNA methylation is commonly associated with gene silencing and contributes to transcriptional regulation of tissue-specific genes during cellular differentiation. The methylation status of CpG islands within promoter sequences works as an essential regulatory element by modifying the binding affinity of transcription factors to DNA binding sites. Gene transcrip- tion only occurs when the chromatin structure is opened up, with unwinding and properly methylated of DNA so that RNA polymerase II and basal transcription complexes can now bind to the naked DNA to initiate transcription. The epigenotype can be transmitted from a parent cell to a daughter cell maintaining a specific epigenotype within cell lineages. Thus, the phenotype is a result of the genotype, the specific DNA sequence, and the epigenotype. The geno- type must exist in a particular chromatin configuration, the epigenotype, which allows a secondary level of fine control over gene expression. The epigenotype shows far greater plasticity than the genotype, and it has been speculated that Copyright © 2010 Slovak Toxicology Society SETOX