enzyme activities via interaction with calmodulin, which in turn modulates epigenetic activation leading to gene expression (Tomas-Zapico et  al., 2005; Tomas-Zapico and Coto-Montes, 2005). A number of known anti-inflammatory effects of melatonin, such as selective inhibition of iNOS and/ or cyclooxygenase-2 and MMPs clearly derive from mela- tonin and epigenetic cross-talk and modification through suppression of NF-κB binding (Esposito et al., 2008) and/or p300-HAT expression within the nucleus (Deng et al., 2006). The action of melatonin in advanced cancer patients (Lissoni et al., 2001) also seems to result from a combination of effects on histone modification and DNA methylation (Cui et al., 2006; Korkmaz and Reiter, 2008). Recently, direct evidence of epigenetic actions for melatonin including nuclear receptors, co-regulators and histone acetylating enzymes has been reported (Sharma et  al., 2008). In this study, melatonin significantly increased mRNA expression for various HDAC isoforms and increased histone H3 acety- lation in neural stem cell lines. Concluding Remarks Despite 75 years of research, there is still no antidote for mustard. This fact is especially crucial when we consider that probably at least a dozen countries have mustard in their arsenals today. Melatonin has been administered in both physiological and pharmacological amounts to humans and animals, and there is widespread agreement that it is a non-toxic molecule. In pregnant rats, maternal lowest no observed effect level has been found to be 200mg/ kg/day and developmental no observed adverse effect level is ≥ 200 mg/kg/day (Jahnke et al., 1999). Melatonin is easily synthesized in pharmacologically pure form, non- patentable, inexpensive and affordable; therefore, it has a great potential to improve the public health (Reiter, 2006) as a multi-tasking molecule. Melatonin has non-genomic, genomic and epigenetic actions; all these actions may be beneficial in both acute and delayed mustard toxicity. REf EREn CES Adcock IM, Ito K, Barnes PJ. (2004) Glucocorticoids: effects on gene transcrip- tion. Proc Am Thorac Soc 1: 247–254. Balali-Mood M, Hefazi M. (2006) Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 99: 273–282. Barnes PJ. (2006) How corticosteroids control inflammation: Quintiles Prize Lec- ture 2005. Br J Pharmacol 148: 245–254. Bombail V, Moggs JG, Orphanides G (2004) Perturbation of epigenetic status by toxicants. Toxicol Lett 149: 51–58. Cui P, Luo Z, Zhang H, Su Y, Li A, Li H, Zhang J, Yang Z, Xiu R. (2006) Effect and mechanism of melatonin’s action on the proliferation of human umbilical vein endothelial cells. J Pineal Res 41: 358–362. Deng WG, Tang ST, Tseng HP, Wu KK. (2006) Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibit- ing p52 acetylation and binding. Blood 108: 518–524. Dugo L, Serraino I, Fulia F, De Sarro A, Caputi AP, Cuzzocrea S. (2001) Effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in an acute model of inflammation. J Pineal Res 31: 76–84. Interdisciplinary Toxicology. 2008; Vol. 1(1): 22–26 Also available online on setox.eu/intertox 25 Emad A, Emad V. (2007) Elevated levels of MCP-1, MIP-alpha and MIP-1 beta in the bronchoalveolar lavage (BAL) fluid of patients with mustard gas-induced pulmonary fibrosis. Toxicology 240: 60–69. Emad A, Rezaian GR. (1999) Characteristics of bronchoalveolar lavage fluid in patients with sulfur mustard gas-induced asthma or chronic bronchitis. Am J Med 106: 625–628. Esposito E, Iacono A, Muia C, Crisafulli C, Mattace Raso G, Bramanti P, Meli R, Cuzzocrea S. (2008) Signal transduction pathways involved in protective ef- fects of melatonin in C6 glioma cells. J Pineal Res 44: 78–87. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD. (2004) The nature of small-airway obstruc- tion in chronic obstructive pulmonary disease. N Engl J Med 350: 2645–2653. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Ad- cock IM, Hogg JC, Barnes PJ. (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352: 1967–1976. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. (2001) Cigarette smok- ing reduces histone deacetylase 2 expression, enhances cytokine expres- sion, and inhibits glucocorticoid actions in alveolar macrophages. Faseb J 15: 1110–1112. Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM. (2006) Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med 203: 7–13. Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C. (1999) Maternal and de- velopmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci 50: 271–279. Jiang YH, Bressler J, Beaudet AL. (2004) Epigenetics and human disease. Annu Rev Genomics Hum Genet 5: 479–510. Kehe K, Raithel K, Kreppel H, Jochum M, Worek F, Thiermann H. (2007) Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mus- tard (SM)-induced cell death in HaCaT cells. Arch Toxicol [Epub ahead of print] Kehe K, Szinicz L. (2005) Medical aspects of sulphur mustard poisoning. Toxicology 214: 198–209. Khateri S, Ghanei M, Keshavarz S, Soroush M, Haines D. (2003) Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime ex- posure to mustard agent. J Occup Environ Med 45: 1136–1143. Korkmaz A, Kurt B, Yildirim I, Basal S, Topal T, Sadir S, Oter S. (2008) Effects of Poly(ADP-Ribose) Polymerase Inhibition in Bladder Damage Caused by Cyclo- phosphamide in Rats. Exp Biol Med (Maywood) 233: 338–343. Korkmaz A, Oter S, Deveci S, Ozgurtas T, Topal T, Sadir S, Bilgic H. (2003) Involve- ment of nitric oxide and hyperbaric oxygen in the pathogenesis of cyclo- phosphamide induced hemorrhagic cystitis in rats. J Urol 170: 2498–2502. Korkmaz A, Oter S, Sadir S, Coskun O, Topal T, Ozler M, Bilgic H. (2005) Peroxyni- trite may be involved in bladder damage caused by cyclophosphamide in rats. J Urol 173: 1793–1796. Korkmaz A, Reiter RJ. (2008) Epigenetic regulation: a new research area for me- latonin? J Pineal Res 44: 41–44. Korkmaz A, Topal T, Oter S. (2007) Pathophysiological aspects of cyclophosph- amide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 23: 303–312. Korkmaz A, Yaren H, Topal T, Oter S. (2006) Molecular targets against mustard toxicity: implication of cell surface receptors, peroxynitrite production, and PARP activation. Arch Toxicol 80: 662–670. Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. (2001) Anti-an- giogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett 22: 45–47. Lopez LC, Escames G, Ortiz F, Ros E, Acuna-Castroviejo D. (2006) Melatonin re- stores the mitochondrial production of ATP in septic mice. Neuroendocrinol Lett 27: 623–630. Loppow D, Schleiss MB, Kanniess F, Taube C, Jorres RA, Magnussen H. (2001) In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Respir Med 95: 115–121. Marwick JA, Kirkham PA, Stevenson CS, Danahay H, Giddings J, Butler K, Don- aldson K, Macnee W, Rahman I. (2004) Cigarette smoke alters chromatin re- modeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol 31: 633–642. McLachlan JA, Burow M, Chiang TC, Li SF. (2001) Gene imprinting in develop- mental toxicology: a possible interface between physiology and pathology. Toxicol Lett 120: 161–164. Mei Q, Yu JP, Xu JM, Wei W, Xiang L, Yue L. (2002) Melatonin reduces colon im- munological injury in rats by regulating activity of macrophages. Acta Phar- macol Sin 23: 882–886. Copyright © 2010 Slovak Toxicology Society SETOX