EMF and Stress proteins (Hsp)
Richard GAUTIER (Dr en pharmacie), Roger SANTINI (Dr es sciences)
or Heat shock proteins
www.csif-cem.org le 17/06/2003
Increase of synthesis of Hsp by the electromagnetic fields (EMF) generally or by the radio frequencies of the mobile telephony in particular was widely demonstrated. By studying works relative to the cellular biochemistry we realizes that these mechanisms are known (activation of the way of the MAP KINASE and Hsp, deregulation of the protein synthesis, apoptose pathway) and consequences in sanitary terms established, whether it is in term of resistance in anti-cancerous treatments, of confusions of the intellectual activity, infringement of the BHE, the deficit of the immunity, the development of cancer.
Hsp is proteins the synthesis of which increases when the cell is subjected to a stress, thermic or other. The various categories of proteins are characterized by their molecular weight (Hsp 27, Hsp 70 etc.). Their role, after activation by phosphorylation due to kinases, is to repair (where from their other name of 'chaperon') the molecular effects of the stress notably in the denaturation of proteins. (For more details to refer to 42).
Their short-term action is doubtless positive and allows to envisage new therapeutic orientations ( 48 ) but their long-term obstinacy it is openly negative (48).
Works showing an increase of Hsp by the electromagnetic Fields (EMF)
Numerous teams showed that low frequency ( ELF) or radio frequencies ( RF) some those of the mobile telephony provoke an increase of the synthesis of Hsp and their activation ( 3,4 ) whether it is on animal cells ( 1,2,6,7,9,10 ) or on human cells ( 3,4,5,11 ). The specific activation of the way of the MAP KINASES was also demonstrated (4,8,9,10).
It is necessary to note that a team, French, of researchers ( 13 ) does not find any Hsp's increase in any cellular lineage studied after exhibition in radiations GSM.
Mechanism of cellular stress
Note: numerous studies quoted here do not arise from searches concerning the EMF but the effects of the others stress, the mechanisms of activation of which are identical (Hsp, way of the MAP KINASES) or still works of cellular biochemistry. It is this extension which allows to understand really the set of mechanisms, it allows also well to encircle consequences already established. Searches are very active in this domain for years because they open interesting perspectives in mechanisms and treatment of tumors.
A stress, such as that represented with the EMF either still the stress oxydatif or to the UV or to the heat, give so in some minutes the activation of the way of the MAP KINASES (SAPK1-C-JUN N-TERMINAL KINASE, SAPK2-P38, ERK) (14,33,48) and in some hours the increase of the synthesis of Hsp (above and 14), mainly Hsp27 and Hsp70.
The way of the MAP KINASES give then the activation of Hsp by phosphorylation, mainly by p38 (14,15,17,18,46). It is necessary to note here that the alone increase of the intracellular calcium can explain the increase of the synthesis of Hsp ( 19,20,39 ), it was also demonstrated that of weak radiation of microwaves (15-20 mW / kg) can alter proteins explaining the activation of the way of stress ( 47 ). Otherwise for the complete mechanisms : activation of the way of the MAP KINASES, refer to (16) or to the various publications of Pr Landry ( 36 ) or those of Pr Cecchelli ( 33 ).
Once activated Hsp, they can play their role of 'chaperon' to repair damages in proteins, but this activation has the other consequences by freezing of various activity of the concerned proteins by preventing for example the way of the apoptose ( 4,8,11,15,23,24 ) by which an abnormal cell should owe ' autodestruction ', or by activating this way (8,15,34) what can bring to the fragmentation of the pit ( 15 ).
The activation of the way of MAP KINASES also has many of the other biochemical consequences ( 16 ) : modifications of the cellular reproduction, resistance in stress following, by modulation of the protein syntheses, increase as in the case of Hsp or decrease for the other proteins (= deregulation of bothers).
Effects on the protein syntheses ( 44 ) and modifications of cellular cycle are moreover informed well (8,9,11,16,19,22) by noting well that the time of exhibition and the time of reading after the beginning of the exhibition are very important if one wants to see effects (details in 11);
As well as effects in altering the Blood Brain Barrier by increase of the transcytose by phosphorylation (32,33) and reorganization of the micro-strands of actine (4,25,26,27,34) this altering having been shown as consequence of an exhibition to radio frequencies (to see chapter on radio frequencies and BBB).
These mechanisms explain so perfectly the harmful influence of a prolonged exhibition ( 4,11,12,16,22,29 ), Hsp on one hand not being able to increase infinitely without consequences ( 18,26,30,48 ), MAP KINASES pathway on the other hand undergoing a regulation which eventually been extended beyond or bringing to a decrease of the synthesis of Hsp ( 6 ). Kyra and coll. (16) having for example noted that exhibition is chronic or not on one of the kinase ( ERK) will determine if the answer of a cell is growth or differentiation!
Of even though an exhibition in short EMF ( 2 days) protects chicks against a hypoxy ( 7 ) a longer exhibition ( 4 days) deprotect ( 6 ). What confirms that if the surexpression of Hsp is considered generally as defender for a following stress (31) it is not valid for every stress, so Lee's works and coll. (30) for which astrocytes with high level Hsp 70 is more resistant in a shock ischemic but less in a hypoglycaemia or those of Plateel and coll. (34) where the hypoxy decreases resistance in a stress oxydatif.
Current knowledge on the consequences of a prolonged exhibition
About level : If in short exhibition minimum level having shown an effect in the cellular calcium or the cycles of reproduction are 0.15 mW / kg (37,38) (2 mW / kg on human cells 11) or about 0,4 microW / cm2 ( 1,2 V/m) mechanisms above show well that in chronic exhibition thresholds giving an effect are much lower. No more the mechanisms which bring in way of enzymes and their system of regulation explains perfectly the notion of ' window of action ' in dose or in time.
- Resistance in the anti-cancerous treatments because of the action defender of activated Hsp (21,29,36,40,41)
- Headache, neuro-degenerative diseases (Alzheimer, Parkinson, ALS) by altering the BBB then destruction of nerve cells following the inflammation and\or following the apoptose ( 45 ), and one can note that the ALS was epidemiologically connected with the electromagnetic fields ( 35 ) and headache to mobil phone (to see chapter on BBB)
- Confusions of the sleep, cognition, tire, depression, suicide by deficit of the synthesis of neurotransmitters and it is necessary to note that depression and suicide were epidemiologically connected with the EMF ( 43 ) and confusions of the sleep, tires in the brilliances of base station (to see chapter on EEG).
- Immunizing deficits by lesser synthesis of antibods and lesser differentiation of immunity cells
- Leukaemia (indicated by: 19,35,36) by deficit of the way apoptotic and cellular proliferation, certain leukaemia showing Hsp's 27 ( 21 ) surexpression and it is necessary to note that leukaemia were epidemiologically connected with the electromagnetic fields ( 35,43 )
- Cancer (indicated by: 4,11,29,35,36) by deficit of the apoptotic way and cellular proliferation, certain cancers showing Hsp's 27 ( 21 ) surexpression and it is necessary to note that certain cancers were epidemiologically connected with the electromagnetic fields ( 35,43 )
- miscarriages by stop of multiplication of the embryonic cells and it is necessary to note that the miscarriages were epidemiologically connected with the CEM ( 35 )
So in constant or chronic applications, as at the local residents of base station of phones, broadcasting station Wi-Fi, high-tension lines, electric transformers, the electromagnetic fields giving modification of the cellular physiology with for consequence increase of disease described above.
(1) David de Pomerai et coll. EFFECTS OF MICROWAVE RADIATION MAY NOT BE LIMITED TO HEATING. The Lancet Volume 355, Number 9217. 20 May 2000
(2) David de Pomerai Microwave induction of a heat-shock response in Caenorhabditis elegans : insights from mutants. COST 281 Workshop on "Subtle Temperature Effects of RF-EMF", London, November 12-13, 2002.
(3) Leszczynski et coll. PHOSPHORYLATION OF HSP27 - THE MOLECULAR MECHANISM FOR MOBILE PHONE EXPOSURE TO MOBILE PHONE RADIATION INDUCES CELLULAR STRESS RESPONSE. BEMS 2001
(4) Leszczynski et coll. Non-thermal activation of the hsp27/p38MAPK stress pathway by mobile phone radiation in human endothelial cells: Molecular mechanism for cancer- and blood-brain barrier-related effects. Differentiation 2002 May;70(2-3): 120-9
(5) Sontag et coll. EXTREMELY LOW FREQUENCY MAGNETIC FIELDS INDUCE HEAT SHOCK PROTEINS IN HL-60 CELLS.
(6) Di Carlo et coll. Chronic electromagnetic field exposure decreases HSP70 levels and lowers cytoprotection. J Cell Biochem 2002;84(3):447-54
(7) Shallom et coll. Microwave exposure induces Hsp70 and confers protection against hypoxia in chick embryos. J Cell Biochem 2002;86(3):490-6
(8) Pacini et coll. Exposure to global system for mobile communication (GSM) cellular phone radiofrequency alters gene expression, proliferation, and morphology of human skin fibroblasts. Oncol Res 2002;13(1):19-24
(9) Weisbrot et coll. Effects of mobile phone radiation on reproduction and development in Drosophila melanogaster. J Cell Biochem 2003 May 1;89(1):48-55
(10) Goodman et coll. Cell Phone Radiation Increases hsp70 Levels, SRE-binding and Phosphorylation of ELK1 During Development and Growth in Drosophila melanogaster. COST 281 Workshop on "Subtle Temperature Effects of RF-EMF", London, November 12-13, 2002
(11) Kwee et coll. NON-THERMAL EFFECTS OF ELECTROMAGNETIC FIELDS ON CELLULAR SIGNAL TRANSDUCTION. COST 281 Workshop on "Subtle Temperature Effects of RF-EMF", London, November 12-13, 2002.
(12) Kwee et coll. Changes in cellular proteins due to environmental non-ionizing radiation. 1. Heat-shock proteins, Electromagnetobiology 20(2):141-152, 2001.
(13) Poulletier de Gannes et coll. Heat shock proteins as sensors of nonthermal effects? COST 281 Workshop on "Subtle Temperature Effects of RF-EMF", London, November 12-13, 2002
(14) Sonia Dorion and Jacques Landry. Activation of the mitogen-activated protein kinase pathways by heat shock. Cell Stress & Chaperones: Vol. 7, No. 2, pp. 200–206
(15) Deschesnes, R.G., J. Huot, K. Valerie, et Landry, J.. Involvement of p38 in apoptosis-associated membrane blebbing and nuclear condensation. Mol Biol Cell. 12:1569-1582, 2001.
(16) Kyra et coll. Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress. The Journal of Experimental Biology 206, 1107-1115 (2003).
(17) Landry et coll. Human Hsp27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II, J. Biol Chem. 267: 794-803, 1992.
(18) Huot et coll. Oxidative Stress-Induced Actin Reorganization Mediated by the p38 Mitogen-Activated Protein Kinase/Heat Shock Protein 27 Pathway in Vascular Endothelial Cells. Circulation Research. 1997;80:383-392
(19) Apati et coll. Calcium induces cell survival and proliferation through the activation of MAPK pathway in a human hormone-dependent leukaemia cell line (TF-1). J Biol Chem 2003 Mar 14;278(11):9235-43.
(20) Danciu et coll. Calcium regulates the PI3K-Akt pathway in stretched osteoblasts. FEBS Lett 2003 Feb 11;536(1-3):193-7
(21) Ciocca et coll. Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J Natl Cancer Inst 1993 Oct 6;85(19):1558-70
(22) Kwee et coll. Radiofrequency electromagnetic fields and cell proliferation, in Electricity and Magnetism in Biology and Medicine, F.Bersani, ed., Kluwer Academic/Plenum Publishers, New York, 187-190, 1999.
(23) Desbiens et coll. c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of Ask1 in the p38 signaling cascade. Biochem. J. 372:631-641, 2003.
(24) Charette et coll. Inhibition of Daxx-mediated apoptosis by heat shock protein 27. Mol Cell Biol. 20:7602-7612, 2000
(25) Guay et coll. Regulation of actin filament dynamics by p38 MAP kinase-mediated phosphorylation of heat shock protein 27. J. Cell Sci. 110: 357-368, 1997
(26) Huot et coll. Oxidative stress-induced actin reorganization mediated by the p38 Mitogen-Activated Protein kinase/heat shock protein 27 pathway in vascular endothelial cells. Circ. Res . 80: 383-392, 1997.
(27) Huot et coll. Hsp27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res 56: 273-279,1996.
(28) Lavoie et coll. Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J.Biol. Chem. 268:24210-24214, 1993.
(29) French et coll. (2001) Differentiation 67(4-5)-.93-97
(30) Lee et coll. Differential neuroprotection from human heat shock protein 70 overexpression in in vitro and in vivo models of ischemia and ischemia-like conditions. Exp Neurol 2001 Jul;170(1):129-39
(31) Yenari et coll. The neuroprotective potential of heat shock protein 70 (HSP70). Mol Med Today 1999 Dec;5(12):525-31
(32) Goldberg et coll. p38 MAPK activation by TGF-1 increases MLC phosphorylation and endothelial monolayer permeability. Am J Physiol Lung Cell Mol Physiol 282: L146-L154, 2002.
(33) Rapport de recherche 2000 de l'équipe du Pr Cecchelli (Unité Mixte Institut Pasteur de Lille - Université d'Artois - EA 2465) : http://www.pasteur-lille.fr/france/recherche/pdf/bhe.pdf (fichier pdf)
(34) Plateel et coll. Hypoxia increases the susceptibility to oxidant stress and the permeability of the blood-brain barrier endothelial cell monolayer. J Neurochem. 1995 Nov;65(5):2138-45.
(35) Neutra et coll. The Risk Evaluation An Evaluation of the Possible Risks
From Electric and Magnetic Fields (EMFs) From Power Lines, Internal Wiring,
Electrical Occupations and Appliances (2002) California EMF program.
(36) Rapport de recherche Mars 2003 de Jacques Landry (Centre de recherche en cancérologie de l'Université Laval) sur : http://188.8.131.52/landry.htm#Projet-2
(37) Schwartz et coll. Exposure of frog hearts to CW or amplitude-modulated VHF fields: selective efflux of calcium ions at 16 Hz. Bioelectromagnetics 1990;11(4):349-58
(38) Kwee et coll. RF electromagnetic fields and cell
proliferation in 5th Nordic Workshop on Biological Effects of Low
Frequency Electromagnetic Fields. A. Johnsson and G. Oftedal eds.
Norwegian Radiation Protection Authority Strålevern rapport 1997:6
(39) Ding et coll.
1996. Increases in HSF1 translocation and synthesis in
human epidermoid A-431 cells, role of protein kinase C
and [Ca2+], J. Investig. Med. 44, 144-153.
(40) Oesterreich et coll. 1992. Association between
heat shock proteins and drug resistance in human
breast cancer [abstract]. Breast Cancer Res. Treat 23 : 178.
(41) Hettinga J.V.E., Lemstra W., Meijer C., Los G., Devrier
E.G.E., Konings A.M.T., Kampinga H.H., 1996. Heat shock
protein expression in cisplatin sensitive and resistant
human tumor cells. Int. J. Cancer. 67, 800-807.
(42) J.C. DAVID, J.F. GRONGNET Les protéines de stress. INRA Prod. Anim.,
2001, 14 (1), 29-40
(43) Henshaw DL. Does our electricity distribution system pose a serious risk to public health ? Med Hypotheses 2002 Jul;59(1):39-51
(44) Maercker et coll. GENE EXPRESSION PROFILING STUDIES ON GLOBAL cDNA ARRAYS SHOW SENSITIVITY OF HUMAN AND MOUSE CELL LINES TO ELF-EMF EXPOSURE. BEMS 2002
(45) Saporito et coll. Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. Prog Med Chem 2002;40:23-62.
(46) Bensaude et coll. 1996. Heat shock induced protein modifications and
modulation of enzyme activities. Stress inducible cellular
responses ; ed. by U. Feige, R.I. Morimoto, I. Yahara and
B. Polla Birhauser Verlag. 199-219.
(47) De Pomerai et coll. Microwave radiation can alter protein conformation without bulk heating. FEBS Lett. 2003 May 22;543(1-3):93-7.
(48) Pockley AG. Heat shock proteins as regulators of the immune response. The Lancet online April 29, 2003.