Research - Toxicological - Heat-Shock Response

Although the heat shock response was first recognized in response to temperature elevation, it is an essential mechanism in the protection of cells from a variety of other stresses including heavy metals, exposure to oxidants, inflammation and fever. As part of the response, heat-shock proteins (hsp) are induced and act as molecular chaperones to repair damaged proteins. In addition hsp production is induced by non-stress biological factors such as differentiation, growth factors and the cell cycle, and they play important roles in normal cellular functioning (Laszlo, 2005).

Tian et al. (2002), however, found increased hsp production at SARs above 20 W/kg, and Shallom et al. (2002) also found an increase of hsp 70 at SARs of 1.5 and 2.5 W/kg. The latter authors also found that RF radiation conferred protection against hypoxia in chick embryos and suggested that this beneficial effect might be due to the hsp production. Di Carlo (2002) also found that chick embryos exposed to RFR at1.7 W/kg for 30 or 60 minutes once daily for 4 days had decreased protection against hypoxic stress. Others (Daniells, 1998, de Pomerai, 2000, Kwee, 2001, Weisbrot, 2003) demonstrated an increase in hsps in experiments where target tissues were exposed at very low SARs. De Pomerai’s group, however, reported in 2006 that their earlier reports (Daniells 1998, de Pomerai 2000a, b) of a non-thermal effect of microwaves could not be sustained. They found that at least part of the response is thermal. Leszczynski et al. (2002) reported an increase in hsp27 in response to 900 MHz radiation for 1 hour (average SAR 2W/kg). Czyz et al. (2004) found an increase in hsp70 in one type of cell exposed to GSM 1800 EMF at 217 Hz pulses. This increase was seen in cells exposed for 48 hours, but not in those exposed for 6 hours. These authors did not find any change in other cell types or after exposure to GSM signals modified at 2 or 8 Hz.

On the other hand, Cleary et al. (1997) found no evidence of stress protein induction in cells exposed for 2 hours to RF radiation at high SARs.Capri et al. (2004) found no evidence of increase in hsp 70 levels in human mononuclear cells exposed to 1800 MHz RF fields at SAR of 2 W/kg for 44 hours. . Likewise, Lim et al. (2005) found no evidence of an increase in hsp27 or 70 levels following exposure to either continuous wave or GSM-modulated RFR at 900 MHz for periods up to 1 hour. Miyakoshi (2005) reported similar negative results with 1950 MHz exposure for 1 or 2 hours, at SARs up to 10 W/kg and Lantow found no evidence of hsp70 production after exposure to RFR at 1800 MHz for 45 minutes. Lee (2006) found no evidence of increase in Hsp levels or in stress responses in Hsp70-deficient mice or in wild mice following subchronic exposure. Chauhan(2006a, b) found no increase in Hsp27 or Hsp70 levels after exposure of human lymphoblastoma cells or other human derived cell lines to RFR at SARs of 1 and 10 W/kg. Simko (2006) reported no increase in Hsp70 levels after exposure of monocytes to RFR (CW, modulated, or GSM-nonDTX) at 1800 MHz and SAR of 2 W/kg for 60 minutes. Wang (2006) found that exposure to a 2450 MHz EMF had little or no effect on HSP70 and HSP27 expression, but it may induce a transient increase in HSP27 phosphorylation in A172 cells at very high SAR level (>100 W/kg). Lee (2006) found that, under conditions where ambient temperature was strictly controlled, RFR at 1736 MHz and SAR of either 2 or 20 W/kg did not elicit any stress response. There was no increase in the expression of HSPs or of mitogen-activated protein kinases, which are major participants in stress responses. Hirose (2007) found no evidence of phosphorylation of HSP27 or expression of the HSP gene family in either glioblastoma or fibroblast cells exposed to RFR up to 0.8 W/kg. Sanchez (2007a) reported no effect on HSP expression of a 48-h GSM-1800 exposure at 2W/kg on skin cells, and the same group found no effect on HSP expression when hairless rats were exposed to RFR for 12 weeks (Sanchez 2007b).

Part of the regulation of the production of hsps uses the heat-shock factor (HSF). When the cell is exposed to an inducer, HSF in the cytoplasm is activated and binds to the heat-shock element (HSE), which is found in the promoters of hsp proteins. Therefore, the activation of HSF is a necessary first step in the activation of the stress response. Laszlo et al. (2005) found that exposure to microwaves at 835.62 MHz or 847.74 MHz at either low SAR (0.6 w/kg) or high (5.0 W/kg) for 5-60 minutes or for up to 7 days did not activate the HSF.

French et al. (2001) hypothesize that prolonged exposure to RF radiation could induce formation of heat-shock proteins that could in turn induce or promote cancer. De Pomerai (2003) demonstrated changes in the shape of proteins after exposure to RF radiation, and suggested that these changes may be the stimulus to the formation of hsps that they described in their earlier paper. Cranfield (2004) demonstrated that C. elegans, which had been used in the experiments by their group (de Pomerai, 2000), contains magnetite, and suggested that its presence may have confounding effects on experiments involving electromagnetic fields.

In a review of the subject, Cotgreave (2005) concluded that many of the studies "are flawed by inconsistencies in exposure models, cell types used and the independent reproducibility of the findings". He went on to say "Therefore, the validity of these effects in human health risk assessment remain unsubstantiated".

Authors
Ammari M, Gamez C, Lecomte A, Sakly M, Abdelmelek H, De Seze R.
Title
GFAP expression in the rat brain following sub-chronic exposure to a 900 MHz electromagnetic field signal.
Journal
Int J Radiat Biol. (2010). 86(5):367-75.

Authors
Brescia F, Sarti M, Massa R, Calabrese ML, Sannino A, Scarfì MR.
Title
Reactive oxygen species formation is not enhanced by exposure to UMTS 1950 MHz radiation and co-exposure to ferrous ions in Jurkat cells.
Journal
Bioelectromagnetics. May 27, 2009. Ahead of print.

Authors
Capri M, Scarcella E, Bianchi E, Fumelli C, et al. (2004):
Title
1800 MHz radiofrequency (mobile phones, different Global System for Mobile Communication modulations) does not affect apoptosis and heat shock protein 70 level in peripheral blood mononuclear cells from young and old donors.
Journal
Int J Radiat Biol 80:389-397.
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Authors
Chauhan V, Mariampillai A, Bellier PV, Qutob SS, et al.
Title
Gene expression analysis of a human lymphoblastoma cell line exposed in vitro to an intermittent 1.9 GHz pulse-modulated radiofrequency field.
Journal
Radiat Res 2006;165:424-429.
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Authors
Chauhan V, Mariampillai A, Gajda GB, Thansandote A, et al.
Title
Analysis of proto-oncogene and heat-shock protein gene expression in human derived cell-lines exposed in vitro to an intermittent 1.9 GHz pulse-modulated radiofrequency field.
Journal
Int J Radiat Biol 2006b;82:347-354.
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Author
Cleary SF, Cao G, Liu L-M, Egle PM, et al. (1997)
Title
Stress proteins are not induced in mammalian cells exposed to radiofrequency or microwave radiation.
Journal
Bioelectromagnetics 18:499-505.
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Author
Cranfield CG, Dawe A, Karloukovski V, Dunin-Borkowski RE, et al. (2004)
Title
Biogenic magnetite in the nematode caenorhabditis elegans.
Journal
Proc Biol Sci 271 Suppl 6:S436-9.
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Authors
Czyz J, Guan K, Zeng Q, Nikolova T, et al. (2004):
Title
High frequency electromagnetic fields (GSM signals) affect gene expression levels in tumor suppressor p53-deficient embryonic stem cells.
Journal
Bioelectromagnetics 25:296-307.
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Authors
Dawe AS, Smith B, Thomas DWP, Greedy S, et al. (2006):
Title
A small temperature rise may contribute towards the apparent induction of heat-shock gene expression in the nematode Caenorhabditis Elegans.
Journal
Bioelectromagnetics 27:88-97.
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Author
De Pomerai D, Daniells C, David H, Allan J, et al. (2000)
Title
Non-thermal heat-shock response to microwaves.
Journal
Nature 405:417-418.
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Authors
De Pomerai DI, Smith B, Dawe A, North K, et al. (2003)
Title
Microwave radiation can alter protein conformation without bulk heating.
Journal
FEBS Letters 543:93-97.
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Authors
Di Carlo A, White N, Guo F, Garrett P, et al. (2002):
Title
Chronic electromagnetic field exposure decreases HSP70 levels and lowers cytoprotection.
Journal
J Cell Biochem 84:447-454.
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Authors
Ding GR, Wang XW, Li KC, Qiu LB, Xu SL, Tan J, Guo GZ.
Title
Comparison of Hsps expression after radio-frequency field exposure in three human glioma cell lines.
Journal
Biomed Environ Sci. (2009) 22(5):374-80.

Authors
Finnie JW, Chidlow G, Blumbergs PC, Manavis J, Cai Z.
Title
Heat shock protein induction in fetal mouse brain as a measure of stress after whole of gestation exposure to mobile telephony radiofrequency fields.
Journal
Pathology. (2009). 41(3):276-9.

Authors
Franzellitti S, Valbonesi P, Contin A, Biondi C, Fabbri E.
Title
HSP70 expression in human trophoblast exposed to different 1.8 GHz mobile phone signals.
Journal
Radiat Res 2008;170(4):488-497.

Author
French PW, Penny R, Laurence JA, McKenzie DR (2001)
Title
Mobile phones, heat shock proteins and cancer.
Journal
Differentiation 67:93-97.
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Authors
Hirose H, Sakuma N, Kaji N, Nakayama K, et al. (2007)
Title
Mobile phone base station-emitted radiation does not induce phosphorylation of Hsp27.
Journal
Bioelectromagnetics 28:99-108.
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Authors
Kim KB, Byun HO, Han NK, Ko YG, Choi HD, Kim N, Pack JK, Lee JS.
Title
Two-Dimensional Electrophoretic Analysis of Radio Frequency Radiation-Exposed MCF7 Breast Cancer Cells.
Journal
J Radiat Res (Tokyo). (2010). 51(2):205-13

Author
Kwee S, Raskmark P, Velizarov S (2001)
Title
Changes in cellular proteins due to environmental non-ionizing radiation. I. Heat-shock proteins.
Journal
Electro- and Magnetobiology 20:141-152.
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Authors
Lantow M, Schuderer J, Hartwig C, Simko M (2006):
Title
Free radical release and HSP70 expression on two human immune-relevant cell lines after exposure to 1800 MHz radiofrequency radiation.
Journal
Radiation Research 165:88-94
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Authors
Laszlo A, Moros EG, Davidson T, Bradbury M, et al. (2005)
Title
The heat-shock factor is not activated in mammalian cells exposed to cellular phone frequency microwaves.
Journal
Radiat Res 164:163-172.
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Authors
Lee J-S, Huang J-J, Lee J-J, Pack J-K, et al. (2005)
Title
Subchronic exposure of hsp 70.1-deficient mice to radiofrequency radiation.
Journal
Int J Radiat Biol 81:781- 792.
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Authors
Lee J-s, Huang T-Q, Kim T-H, Kim JY, et al. (2006):
Title
Radiofrequency radiation does not induce stress response in human T-lymphocytes and rat primary astrocytes.
Journal
Bioelectromagnetics 27:578-588.
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Authors
Leszczynski D, Joenvaara S, Reivinen J, Kuokka R (2002)
Title
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.
Journal
Differentiation 70:120-129.
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Authors
Lim HB, Cook GG, Barker AT, Coulton LA (2005)
Title
Effect of 900 MHz electromagnetic fields on nonthermal induction of heat-shock proteins in human leukocytes.
Journal
Radiat Res 163:45-52.
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Authors
Miyakoshi J, Takemasa K, Takashima Y, Ding G-R, et al. (2005)
Title
Effects of exposure to 1950 MHz radio frequency field on expression of Hsp70 and Hsp27 in human glioma cells.
Journal
Bioelectromagnetics 26:251-257.
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Authors
Nylund R, Tammio H, Kuster N, Leszczynski D.
Title
Proteomic Analysis of the Response of Human Endothelial Cell Line EA.hy926 to 1800 GSM Mobile Phone Radiation.
Journal
J Proteomics Bioinform. (2009). 2:455-462.

Authors
Sanchez S, Haro E, Ruffie G, Veyret B et al. (2007):
Title
In vitro study of the stress response of human skin cells to GSM-1800 mobile phone signals compared to UVB radiation and heat shock.
Journal
Radiation Research 167:572-580.
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Authors
Sanchez S, Masuda H, Ruffie G, Poulletier De Gannes F, et al. (2007b)
Title
Effect of GSM-900 and -1800 signals on the skin of hairless rats. III: Expression of heat shock proteins.
Journal
Int J Radiat Biol 84:61-68.
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Authors
Shallom JM, Di Carlo AL, Ko D, Penafiel LM, et al. (2002)
Title
Microwave exposure induces Hsp 70 and confers protection against hypoxia in chick embryos.
Journal
J Cell Biochem 86:490-496.
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Authors
Simko M, Hartwig C, Lantow M, Lupke M, et al.
Title
Hsp70 expression and free radical release after exposure to non-thermal radio-frequency electromagnetic fields and ultrafine particles in human Mono Mac 6 cells.
Journal
Toxicology Letters 2006;161:73-82.
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Authors
Tian F, Nakahara T, Wake K, Taki M, et al. (2002)
Title
Exposure to 2.45 GHz electromagnetic fields induces hsp 70 at a high SAR of more than 20 W/kg but not at 5 W/kg in human glioma M054 cells.
Journal
Int J Radiat Biol 78:433-460.
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Authors
Wang J, Koyama S, Komatsubara Y, Suzuki Y, et al. (2006):
Title
Effects of a 2450 MHz high-frequency electromagnetic field with a wide range of SARs on the induction of heat-shock proteins in A172 cells.
Journal
Bioelectromagnetics 27:479-486.
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Authors
Weisbrot D, Lin H, Ye L, Blank M, et al. (2003)
Title
Effects of mobile phone radiation on reproduction and development in
Drosophilia melanogaster
Journal
J Cell Biochem 89:48-55
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Authors
Yan JG, Agresti M, Zhang LL, Yan Y, Matloub HS.
Title
Qualitative effect on mRNAs of injury-associated proteins by cell phone like radiation in rat facial nerves.
Journal
Electromagn Biol Med. (2009). 28(4):383-90.