This study aimed to examine the effects of short and long term exposures to 81 mG EMF intensity. It focused on the roles ofROS, Ca2+ and calcium channel blocker (CCB) on the rat brain. Rats were exposed to 81 mG EMF intensity at the mobile phone base station for one and four weeks (2 hr/day, EMF exposed group). Another group of rats was pretreated with CCB (amlodipine 20 mg/ kg) for four weeks and similarly exposed to EMF (EMF + amlodipine group). Sham exposed and amlodipinecontrol groups were used. At the end of the study, Ca2+ as well as pro-inflammatory and oxidative stress markers were measured. Immunohistochemical staining for Bax in brain samples was carried out. Short term exposure evoked a cellular adaptation response. This was evident by a transient increase in brain levels of Ca2+, glutathione (GSH) and serum tumor necrosis factor alpha (TNFalpha). Long term exposure to EMF was lethal; progressive oxidative damage, and a prolonged increase in the Ca2+ levelaccompanied by a marked pro-inflammatory reaction (TNFalpha and CRP) were demonstrated. These alterations were ameliorated by pre- and con-comitant treatment with amlodipine. Furthermore, it restored the EMF induced apoptosis in brain tonear normal. In conclusion, EMF is a stressor agent that induces an imbalance between ROS generation and antioxidant defense response. Calcium ions may play a pivotal role in enhancing oxidative stress, pro-inflammatory reactions and apoptosis associated with EMF exposure. Therefore calcium channel blockade seems to play a role in brain protection.
electromagnetic field; calcium; oxidative stress; apoptosis; amlodipine; rats
Ahmed AE, Hussein GI, Loh JP, Abdel-Rahman SZ: Studies on the mechanism of haloacetonitrile-induced gastrointestinal toxicity - interaction of dibromoacetonitrile with glutathione and glutathione -S-transferase in rats. J Biochem Toxicol 6:115-121, 1991.
Annuziato L, Amoroso S, Pannaccione A, Cataldi M, Pignataro G, D'Alessio A, Sirabella R, Secondo A, Sibaud L, Di Renzo GF: Apotosis induced in neuronal. cells by oxidative stress: role played by caspases and intracellular calcium ions. Toxicol Lett 139:125-133, 2003.
Bancroft D, Steven A: Theory and Practice of Histological Techniques. 4th ed. Churchill Livingstone. New York, London and Tokyo, 1996, pp. 435-465.
Berridge MJ, Bootman MD, Lipp P: Calcium a life and death signal. Nature 395:645-648, 1998.
Brown DM, Donaldson K, Borm PJ, Schins RP, Dehnhardt M, Gilmour P, Jimenez LA, Stone V: Calcium and ROS-mediated activation of transcription factors and TNF-cytokine gene expression in macrophages exposed to ultrafine particles. Am J Physiol Lung Cell Mol Physiol 286:L344-L353, 2004.
Buge JA, Aust SD: Microsomal lipid peroxidation. Methods Enzymol 52:302-310, 1978.
Campillo N, Vinas P, Garcia L, Cordoba H: Selenium determination in biological fluids using Zeeman background correction electrothermal atomic absorption spectrometry. Anal Biochem 280:195-200, 2000.
Bediz CS, Baltaci AK, Mogulkoc R, Oztekin E: Zinc supplementation ameliorates electromagnetic field- induced lipid peroxidation in the rat brain. J Exp Med 208:133-140, 2006.
Chromy V, Fischer J: Photometric determination of total protein in lipemic sera. Clin Chem 23:754-756, 1977.
Drury RA, Wallington EA: Histological techniques. 5th edn. Oxford university press, Oxford, 1980, pp. 27-29.
Ermak G, Davies KJ: Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol 38:713-721, 2002.
Frumkin H, Jacobson A, Gansler T, Thun MJ: Cellular phones and risk of brain tumors. CA Cancer J Clin 51:137-141, 2001.
Fukuo K, Yang J, Yasuda O: Nifedipine indirectly up regulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways. Circulation 106:356-361, 2002.
Hassoun EA, Stohs SJ: Cadmium-induced production of superoxide anion oxide, DNA single strand breaks and lactate dehydrogenase leakage in J774A.1 cell cultures Toxicol 112:219-226, 1996.
Highton J, Hessian P: A solid-phase enzyme immunoassay for C-reactive protein: clinical value and the effect of rheumatoid factor. J Immunol Methods 68:185-192, 1984.
Huang BS, Leenen FH: Sympatho-inhibitory and depressor effects of amlodipine in spontaneously hypertensive rats. J Cardiovasc Pharmacol 42:153-160, 2003.
Hwang S, Kim GH: Biomarkers for oxidative stress status of DNA, lipids, and proteins in vitro and in vivo cancer research. Toxicol 229:1-10, 2007.
Hyland G : Physics and biology of mobile telephony. Lancet 356:1833-1836, 2000.
Julius S, Kieldsen SE, Weber M: Outcome in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the value randomized trial. Lancet 363:2022-2031, 2004.
Kataoka C, Egashira K, Ishibashi M, Inoue S, Ni W, Hiasa K, Kitamoto S, Usui M, Takeshita A: Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis. Am J Physiol Heart Circ Physiol 286:H768-74, 2004.
Kaune WT, Dovan T, Kavet RI, Savitz DA, Neutra RR: Study of high and low current configuration homes from the 1988 Denver childhood cancer study. Bioelectromagnetics 23:177-188, 2002.
Kim S, Rome D, Yoo Y, Park K: Transforming growth factor beta expression in normal and pathological condition. Horm Res 42:5-8, 1994.
Krjukow AA, Semenkova GN, Cherenkevich SN, Gerein V: Activation of redox-systems of monocytes by hydrogen proxide. Biofactors 26:283-292, 2006.
Kwee S, Raskmark P, Velizarov S: Changes in cellular proteins due to environmental non-ionizing radiation and heat shock proteins. Electro Mangetobiol 20:165-176, 2001.
Lai H, Singh NP: Magnetic field induced DNA strand breaks in brain cells of the rat. Environ. Health perspect 112:687-694, 2004.
Lantow M, Scheudere J, Hartwig C, Simko M: Free radical release and HSP70 expression in two human immune-relevant cell lines after exposure to 1800 MHz radiofrequency radiation. Radiat Res 165:88-94, 2006.
Leszczynski D, Joenvaara S, Reivinen J, Kuokka R: Non-thermal activation of the hsp27/p38 MAPK stress pathway by mobile phone radiation in human endothelial cells: molecular mechanism for cancer and blood brain barrier related effects. Differentiation 70:120-129, 2002.
Mak IT, Zhang J, Welgicki WB : Productive effects of dihydropyridine Ca-blockers against endothelial cell oxidative injury due to combined nitric oxide and superoxide. Pharmacol Res 45:27-33, 2002.
Minelli TA, Balduzzo M, Milone FF, Nofrate V:Modleing cell dynamics under mobile phone radiation. Nonlinear Dynamics Psychol Lif Sci 11:197-218, 2007.
Moshage H, Hok B, Huizenga JB, Jansen PLM: (1995) Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 41:892-896, 1995.
Mostafa YM, Moustafa RM, Belac, A, Abou-El-Ela SH, Ali FM: Effects of acute exposure to the radiofrequency fields of cellular phones on plasma lipid peroxide and anti-oxidative activities in human erythrocytes. J Pharm Biomed Anal 26:605-608, 2001.
Muth JN, Varadi G, Schwartz A : Use of transgenic mice to study voltage-dependent Ca2+ channels. Trends pharmacol Sci 22:526-532, 2001.
Oelze M, Warnholt, A, Faulhaber J, Wenzel P, Kleschyov AL, Coldewey M, Hink U, Pongs O, Fleming, I, Wassmann S, Meinertz T, Ehmke H, Daiber A, Munzel T: NADPH oxidase accounts for enhanced superoxide production and impaired endothelium-dependent smooth muscle relaxation in BKbeta1-/-mice. Arterioscler Thromb Vasc Biol 26:1753-1759, 2006.
Orendacova J, Orendac M, Racekova E, Marsala J: Neurological effects of microwave exposure: a review focused on morphological findings in experimental animals. Arch Ital Biol 145:1-12, 2007.
Ozguner F, Bardak Y, Comlecki S: Protective effects of melatonin and caffeic acid phenylethyl ester against retinal oxidative stress in long-term use of mobile phone: a comparative study. Mol Cell Biochem 282:83-88, 2006.
Qiu C, Fratiglioni L, Karp A, Winblad B, Bellander T: Occupational exposure to electromagnetic fields and risk of Alzheimer's disease. Epidemiology 15:687-694, 2004.
Quinn SJ, Kifor O, Kifor I, Butters RB, Brown EM: Role of the cytoskeleton in extracellular calcium-regulated OTH release. Biochem Biophys Res Commun 354:8-13, 2006.
Rollwiz J, Lupke M, Simko M: Fifty-hertz magnetic fields induce free radical formation in mouse bone marrow-derived monocytes and macrophages. Biochim Biophys Acta 1974:231-238, 2004.
Ronit L, Asher S, Harry F, Vladimir S, Ophra R, Maor E, Doron K, Rachel L: Low energy visible light induces reactive oxygen species generation and stimulates an increase of intracellular calcium concentration in cardiac cells. J Biological Chem 278:40917-40922, 2003.
Roy-Byrine PP: The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. J Clin Psychiatry 66 (Suppl 2):14-20, 2005.
Salford LG, Brun AE, Eberhardt JL, Malmgren L, Bertil R : Nerve cell damage in mammalian brain after exposure to microwaves from GSM mobile phones, Environmental Health Prespectives V 111:881-883, 2003.
Sasaki H, Watanabe F, Murano T, Moyashita Y, Shirai K: Vascualr smooth muscle cell apoptosis induced by 7-ketocholesterol was mediated via Ca2+ and inhibited by the calcium channel blocker nifedipine. Metabolism 56:357-362, 2007.
Shibko P, Koivistoenen C, Tratnyet A, Newhall C, Friendman L: A method for sequential quantitative separation and determination of protein, RNA, DNA, lipid, and glycogen from a single rat liver homogenate or from a subcellular fraction. Anal Biochem 19:514-528, 1967.
Simko M, Hartwig C, Lantow M, Lupke M, Mattsson MO, Rahman Q, Rollwitz J: HSP 70 expression and free radical release after exposure to non-thermal radio-frequency electromagnetic fields and ultrafine particles in human Mono Mac 6 cells. Toxicol Lett 161:73-82, 2006.
Snedecor GW, Cochran WG: Statistical methods 7th ed Iowa Uni Press Ames Iowa USA, 1981, pp: 175-191.
Sun LX, Yao K, Jiang H, He JL, Lu DQ, Wang KJ, Li HW: DNA damage and repair induced by acute exposure of microwave from mobile phone on cultured human lens epithelial cells. Zhonghua Yan Ke ZA Zhi 42:1084-1088, 2006.
Toba H, Nakagawa Y, Miki S, Shimizu T, Yoshimura A, Inoue R, Asayama J, Kobara M, Nakata T: Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of endothelial nitric oxide synthetase and the inhibition of angiotensin converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood pressure-lowering effects of amlodipine and manidipine. Hypertens Res 28:689-700, 2005.
Uccelletti D, Farina F, Inton P, Goffrini P, Mancini P, Talora C, Rizzuto R, Palleschi C: The Golgi Ca2+ ATPase function is required for oxidative stress response by controlling the expression of the heat-shock element HSP60 in Kluyveromuyces lactiss. Mo Biol. Cell 16:4636-4647, 2005.
Yeniterzi M, Avunduk MC, Baltaci AK, Aribas OK, Gormus N, Tosun E: The histopathological changes in the rats caused by magnetic field of 50Hz frequency. Selcuk J Med 19:39-51, 2002.
Yokus B, Cakir DU, Akdag MZ, Sert C, Mete N: Oxidative DNA damage in rats exposed to extremely low frequency electromagnetic fields. Free Radic Res. 39:317-323, 2005.
Yoshii T, Iwa M, Li Z, Chen R, Ide A, Fukunaga S, Oshita A, Mogi M, Higaki J, Horiuchi M: Regression of atherosclerosis by amlodipine via anti-oxidative stress actions. Hypertens Res 29:457-466, 2006.
Yoshikawa T, Tanigawa M, Imai A, Hongo H, Kondo M: Enhancement of nitric oxide generation by low frequency electromagnetic field. Pathophysiology 7:131-135, 2000.
Yoshitaka H, Yoshikuni K, Masatsugu N, Yoji S, Koji I, Kenji S: Amoldipine-induced reduction of oxidative stress in the brain is associated with sympatho-inhibitory effects in stroke-prone spontaneously hypertensive rats. Hypertens Res 29:49-56, 2006.
Zhou X, Yang W, Li J: Ca2+ and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthetase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J Biol Chem 281:31337-31347, 2006.
Kovacic P, Somanathan R. Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects. J Recept Signal Transduction. 30: 214-226, 2010.