Introduction

Initiation and evolution of life involved chemical com-pounds and energy sources, such as the sun and electro-magnetism. Bioelectrical phenomena play a vital role in life processes (1). Among the intrinsic features of living systems are the separation, transport and storage of elec-trical charge (2). The participation of electron transfer (ET) is recognized as one of the essential requirements for electrochemical communication between molecules. An electromagnetic field (EMF) is associated with the mobile, charged electron. In addition to neurotransmis-sion, electrochemistry is involved in electrostatics and electron transport. Electromagnetic forces are primarily responsible for the structure of matter from atoms to more complex substances (3) and have played a dominant role in cell division and other processes in primitive cells as

well as modern eukaryotic ones. As expected, electrical effects have been reported in plant chemistry (4). The pre-ponderance of bioactive substances or their metabolites incorporate ET functionalities, which, we believe, play an important role in physiological responses. The main groups include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced nitroso or hydroxylamine derivatives) and conjugated iminiums (or imines). There are two princi-pal pathways that can result from ET, one being redox cycling with generation of reactive oxygen species (ROS) and oxidative stress (OS). The other involves interaction with the central nervous system (CNS).

ET is probably the most prevalent and important process in chemical transformation. The generality and unifying aspects are demonstrated by involvement in all areas of the physical and biological sciences. Examples

Journal of Receptors and Signal Transduction, 2010; 30(4): 214–226

Address for Correspondence: Peter Kovacic, Department of Chemistry; San Diego State University; San Diego, California, USA. E-mail: pkovacic@sundown.sdsu.edu

R e v i e w a R t i c l e

Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects

Peter Kovacic1, and Ratnasamy Somanathan2

1Department of Chemistry, San Diego State University, San Diego, California, USA, and 2Centro de Graduados e Investigación del Instituto Tecnológico de Tijuana, Apdo postal, Tijuana, B.C. Mexico

abstractElectromagnetic fields (EMFs) played a role in the initiation of living systems, as well as subsequent evolution. The more recent literature on electrochemistry is documented, as well as magnetism. The large numbers of reports on interaction with living systems and the consequences are presented. An important aspect is involvement with cell signaling and resultant effects in which numerous signaling pathways participate. Much research has been devoted to the influence of man-made EMFs, e.g., from cell phones and electrical lines, on human health. The degree of seriousness is unresolved at present. The relationship of EMFs to reactive oxygen species (ROS) and oxidative stress (OS) is discussed. There is evidence that indicates a rela-tionship involving EMFs, ROS, and OS with toxic effects. Various articles deal with the beneficial aspects of antioxidants (AOs) in countering the harmful influence from ROS-OS associated with EMFs. EMFs are useful in medicine, as indicated by healing bone fractures. Beneficial effects are recorded from electrical treatment of patients with Parkinson’s disease, depression, and cancer.

Keywords: Electromagnetic fields (EMFs); electron transfer (ET); oxidative stress (OS); reactive oxygen species (ROS); antioxidants (AOs); cell phones

(Received 17 March 2010; revised 21 April 2010; accepted 21 April 2010)

ISSN 1079-9893 print/ISSN 1532-4281 online © 2010 Informa UK LtdDOI: 10.3109/10799893.2010.488650 http://www.informahealthcare.com/rst

Journal of Receptors and Signal Transduction

2010

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226

17 March 2010

21 April 2010

21 April 2010

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1532-4281

© 2010 Informa UK Ltd

10.3109/10799893.2010.488650

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Electromagnetic fields 215

are receptor chemistry (5) and cell-signaling mechanism (6). Extensive evidence is documented supporting mode of action for carcinogens (7), mitochondrial toxins (8), and major organ toxins (9–14).

Since electrochemistry plays an important role in bio-functioning, including the CNS, more attention should be devoted to this area, particularly fundamental aspects. A neglected topic is determination of reduction potential which provides information concerning the feasibility of ET by exogenous and endogenous agents. If the reduction potential is more positive than −0.5 V, then ET is a pos-sibility in vivo. Requisite electron donors reside mainly in protein side-chains in the form of disulfide, phenolic oxygen, or conjugated amine species.

In the electrochemical category, studies demonstrate a role for electrostatic forces in a variety of areas. The term bioelectrostatics is a label used in the life science area in which widespread participation is documented (4). Energetics appears to play a significant role. Subjects addressed are enzymes, membranes, chromosomes, his-tamine, receptors, the Hofmeister effect, plant chemistry, and evolutionary development. A recent hypothesis pro-poses that electrostatic force is a factor in receptor-ligand action, based on the molecular electrostatic potential associated with ions and dipoles (5). Energetics and bridging may be important actors.

The mechanism of electrostatic action by phosphates and sulfates has been discussed (15). A hypothesis was presented for the basic mode of action of phosphates and sulfates in cell signaling, with phosphorylation being the center of attention. In both cases, the anions provide strong electrostatic fields that are believed to be of major importance. It is probably not coincidental that the phosphates involved are mono- or di-esters containing at least one free hydroxy group in anion form. A similar situation pertains to sulfation in which monoesterifica-tion preserves an anion residue. The field may serve as a link that connects existing electrochemical pathways or as an energy source.

The cell is able to couple the energy of adenosine tri-phosphate (ATP) hydrolysis directly to endergonic proc-esses by transferring a phosphate from ATP to some other molecule, which then becomes more reactive (15,16). Nearly all cellular work depends on energizing by ATP of other molecules via transfer of phosphate. This situation may apply to phosphate insertion by ATP into signaling molecules with resulting enhanced energy.

Reports on electrochemical effects of metal cations mainly involve Mg, Zn, Fe, Ca, and Cu (17). Of these, calcium has received the most attention in relation to cell communication and receptor binding. Calcium and other alkaline earth cations change the electrostatic potential adjacent to negatively charged bilayer mem-branes. Organic cations, such as dimethonium, were also employed in investigations of electrostatic effects.

Electromagnetic phenomena are associated with charged radicals and electrons in motion. Although this idea has been advanced previously, it has attracted little attention. A crude hypothesis for ET involvement in neu-rotransmission was advanced in 1983. Two years later, electron translocation brought about by redox reactions was visualized as being the primary mechanism whereby electric fields are generated in the living cell (18). Fast movement of electrons results in polarization, which establishes an electrical gradient. Electron migration conceivably progresses by means of radical intermedi-ates. In 1996, the ET concept was applied to regulatory action of nitric oxide (NO) in neurotransmission, toxicity, and immunological reactions (19,20).

A 2004 review summarizes the present status of elec-trophysiological effects, and deserves special attention (21). After a burst of research dealing with electrical coupling, gap junctions became less popular among neurobiologists vs. the ionic approach. Recent reports have brought gap junction back into the spotlight, suggesting that this type of cell–cell signaling may be interrelated with, rather than alternative to, chemical transmission.

Besides the trivial primary effects of EMF on ionic charges and dipolar matter, cellular biochemical reaction and channel transport processes are field dependent (22). Interaction of signaling systems with low-energy EMFs may produce metabolic responses in the body (23). The applied field might modify existing signal-transduction processes in cell membranes, thus producing both trans-duction and biochemical amplification of the existing field effects. A practical example comprises the physi-ological effects of the external field in the healing of bone fractures (24).

Investigations of volatile anesthetics provide valuable insight concerning the role of electrostatics (5). At clini-cally relevant concentrations, ethers, alkyl halides, and alcohols enhance agonist action on the GABA (A) recep-tor, whereas alkanes do not. A good correlation exists between dipole moments and receptor activity. Dipole moments are related to electrostatics. Other relevant studies involve local anesthetics.

Electrostatic forces are relatively weak. Can such low levels have an influence in living systems? A recent study provides evidence for involvement. Investigators have gained insight into physiological events in which weak forces, as low as 0.5 picoNewtons, play a regulatory role e.g., in ion channel functioning (25). It is fascinating that at the cellular level, weak forces may be more important than strong ones. Weak magnetic forces that operate over short distances are associated with prevalent radicals. Mounting evidence indicates that energy is a significant factor in electrostatic operation (4). Support is available from studies in a variety of fields both animal and plant, including enzymes, membranes and other systems.

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216 Peter Kovacic and Ratnasamy Somanathan

Living creatures can be regarded as complex electro-chemical systems that evolved over billions of years (6). Organisms interact with and adapted to an environment of electrical and magnetic fields (MFs). Humans are now immersed in a man-made environment of such fields whose long-term effects are unknown.

Useful comparisons can be made with electrical con-ductance in nonbiological systems. In copper, the metal serves as conduit for electrons. The electrical energy is converted into a useful end result. Electrons and holes are also involved in semi-conductor operation. Other examples exist among conducting polymers, e.g., polyaniline.

The present review deals with electromagnetism in biological systems and in medicine. The electrochemi-cal aspects are updated. The magnetic portion is also the center of attention. The approach is in an integrated manner involving general aspects, cell signaling, ET, electromagnetic effects, radicals, OS, and antioxidants (AO). Various toxic manifestations are addressed, as with brain illnesses, electrical power lines and cell phones. A beneficial medical feature is use in bone fracture repair.

It should be emphasized that physiological activity of endogenous and exogenous agents is often complex and multifaceted. There is greater need of interdiscipli-nary approaches of the type in this review. Knowledge of events at the basic molecular level can result in practical application to medicine. This review is representative, rather that exhaustive. Neurotransmission is not included in depth in the major topics. In some cases, original refer-ences are present in the reviews or articles.

Interactions with biological systems (general)

A number of articles present a broad view of the effects of EMFs on living systems. MFs are widely distributed in the environment and their effects are increasing with burgeoning development of electrical machines. It has been suggested that EMF, especially weak ones, may affect various functions of living things and several experiments to evaluate the idea have been carried out (26). Studies in cell biology have demonstrated that weak EMF can affect various cellular functions and important EMF targets in cells are signal-transduction cascades. Furthermore, EMF affects not only specific gene tran-scription and cell growth, but also membrane mediated signal-transduction processes, especially the Ca2+ trans-port system. Effects of MF on mitochondrial functions, cell growth and transformation, signal transduction of neutrophils, cell apoptosis, gene expression and lipid peroxidation of biological membrane were examined. Static strong MF-induced lipid peroxidation of biologi-cal membrane.

It is now well established that low-frequency (<300 Hz) EMF fields induce biological changes that include effects ranging from increased enzyme reaction rates to increased transcript levels for specific genes (27). The induction of stress gene HSP70 expression by exposure to EMF provides insight into how these fields interact with cells and tissues. The large amount of pub-lished data available on the heat-induced stress response (i.e., “heat shock”) offers a model for studying and com-paring the EMF-induced stress response. Results from these and other studies have yielded important clues to EMF interaction with cellular systems, particularly at the molecular level.

Insight into the mechanism(s) are also provided by examination of the interaction of EMF with moving charges and their influence on enzyme reaction rates in cell-free systems. In general, biological studies with in vitro model systems have focused on the nature of the signal-transduction pathways involved in response to EMF. Based on evidence of the electron transport/charge flow in DNA, it is likely that EMF interact directly with electrons in DNA to stimulate biosynthesis.

Studies of EMF induction of the stress response pro-teins, point to the application of EM fields in two bio-medical applications: cytoprotection and gene therapy. Therapeutic use of EMFs has met with great success since the early 1970’s in accelerating the healing of bone frac-tures and soft tissue wounds.

Paradoxically, it is the health risk issue that has in recent years dominated EMF research. Epidemiological studies have indicated that EMFs can also induce health adverse effects and EMF are perceived by biological systems as a possible hazard. However, exposure to EMFs also has beneficial effects (28), as understanding of mechanisms expands. Specific requirements for field energies are being defined and the range of treatable ills broadened. These include nerve regeneration, wound healing, graft behavior, diabetes, and myocardial and cerebral ischemia, among other conditions.

Life on earth has evolved in a sea of natural EMFs. Over the past century, this natural environment has sharply changed with introduction of a vast and growing spectrum of man-made EMFs (29). From models based on equilibrium thermodynamics and thermal effects, these fields were initially considered too weak to interact with biomolecular systems, and thus incapable of influ-encing physiological functions. Laboratory studies have tested a spectrum of EMF fields for bioeffects at cell and molecular levels. Modulation of cell-surface chemical events by EMFs indicates a major amplification of ini-tial weak effects is associated with binding of hormones, antibodies, and neurotransmitters to their specific sites. Calcium ions play a key role in this amplification. These studies support new concepts of communication between cells.

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Electromagnetic fields 217

In cellular aggregates that form tissues of higher ani-mals, cells are separated by narrow fluid channels that take on special importance in signaling from cell to cell. These channels act as windows on the electrochemical world surrounding each cell. Hormones, antibodies, neurotransmitters and chemical cancer promoters, for example, move along them to reach binding sites on cell membrane receptors. These narrow fluid “gutters,” typically not more than 150 A wide, are also preferred pathways for intrinsic and environmental EMFs, since they offer much lower electrical impedance than cell membranes. Although this intercellular space (ICS) forms only about 10% of the conducting cross section of typical tissue, it carries at least 90% of any imposed or intrinsic current, directing it along cell membrane sur-faces. Numerous stranded protein molecules protrude from within the cell into this narrow ICS. Their glycopro-tein tips form the glycocalyx, which senses chemical and electrical signals in surrounding fluid. Their negatively charged tips form receptor sites for hormones, antibod-ies, neurotransmitters, and for many metabolic agents, including cancer promoters. These charged terminals form an anatomical substrate for the first detection of weak electrochemical oscillations in pericellular fluid, including field potentials arising in activity of adjacent cells or as tissue components of environmental fields.

If one used electromagnetic energy sensors to view the world from space 100 years ago, the world would have looked quite dim (30). Now the world glows with elec-tromagnetic energy emissions at the nonionizing portion of the spectrum, such as power line fields, radio waves, microwaves, etc.

Living organisms are complex electrochemical systems that evolved over billions of years in a world with rela-tively simple weak MF and with few EM energy emitters. As is characteristic of living organisms, they interact with and adapted to this environment of electric and MFs. One example of this adaptation is the visual system, which is exquisitely sensitive to emissions in the very narrow portion of the EM spectrum that we call light. Organisms also adapt to another portion of the spectrum, the UV, by developing filtering systems in the eye and the skin to protect them from it.

A wide range of living organisms, including humans, adapted by using EM energy to regulate various critical cellular systems; we see this in the complex of circadian rhythms. Fish, birds, and the duckbill platypus developed systems to use EMFs to sense prey and to navigate. EM fields are involved in neural membrane function. Even protein conformation effects involve the interactions of electrical fields.

Thus, it is not surprising that massive introduction of EMF in an enormous range of new frequencies, modula-tions, and intensities in recent years have affected living organisms. In fact, it would be incredible and beyond

belief if these EMF did not affect the electrochemical systems we call living organisms.

Electrification in developed countries has progres-sively increased the mean level of extremely low- frequency EMF to which populations are exposed; these human- made fields are substantially above the naturally occurring ambient electric and MFs of ∼10−4 Vm−1 and ∼10−13 T, respectively (31). Several epidemiology studies have concluded that low-frequency EMF may be linked to an increased risk of cancer, particularly childhood leukemia. These observations have been reinforced by cellular studies reporting EMF-induced effects on biolog-ical systems, most notably on the activity of components of the pathways that regulate cell proliferation. However, the limited number of attempts to directly replicate these experimental findings have been almost uniformly unsuc-cessful, and no EMF-induced biological response has yet been replicated in independent laboratories. Many of the most well-defined effects have come from gene expres-sion studies; several attempts have been made recently to repeat these findings. This review analyzes these studies and summarizes other reports of major cellular responses to EMF and the published attempts at replication.

Geomagnetic fields can serve as the combined MF, affecting different biochemical ions in cells (32). Also influenced are electrostatic processes including phos-phate group transfer. Ligand-receptor effects can be due to field influence on substances abundant in the cell, as well as on molecules participating in intracellular sign-aling and membrane transport whose perturbation can be amplified by enzyme cascades or ion fluxes. Weak extremely low-frequency MF effects can be amplified by nonlinear mechanisms.

A recent review concentrates on findings described in the recent literature on the response of cells and tissues to EMFs (33). Models of the interaction between differ-ent forms of EMF and ions, biomolecules in the cell and cell-surface recognition are discussed. Naturally occur-ring electric fields are not only important for cell-surface interactions, but are also pivotal for the normal develop-ment of the organism and its physiological functions. The review also bridges the gap between recent cell biological studies (EMF actions) and aspects of EMF-based therapy, e.g., in wounds and bone fractures.

OS

A study demonstrated the effects of 900-MHz EMF emit-ted from cellular phone on brain tissues and also blood malondialdehyde, glutathione (GSH), retinol, vitamin D3, tocopherol, and catalase enzyme activity of guinea pigs (34). Results indicated production of OS in brain tissue. A similar study showed 900-MHz mobile phone-induced oxidative endometrial impairment (35). The modulation

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218 Peter Kovacic and Ratnasamy Somanathan

of OS with vitamin E and C reduces the endometrial damage, both at biochemical and histological levels. Similar exposure also enhanced lipid peroxidation and H

2O

2 content accompanied by diminished antioxidative

enzyme activity, indicating OS could be partly due to reduced activities of AO enzymes in duckweed (36). Rats exposed to EMF showed increase in malondialdehyde levels and decrease in GSH levels (37). A study demon-strated protective effects of melatonin and caffeic acid phenethyl ester (CAPE) against retinal OS in long-term use of mobile phone (38). Mobile phone-induced myo-cardial OS protection by the AO CAPE was shown (39). CAPE may prevent the 900-MHz EMF-induced oxida-tive changes in liver by ROS reducing and increasing AO enzyme activities (40). Radio frequency-electromagnetic radiation from mobile phones induces OS and reduces sperm motility in rats (41). Thus, semen quality and male fertility may be negatively affected. The protective effects of the AOs N-acetyl-l-cysteine and epigallocatecin-3-gallate on electric field-induced hepatic OS was reported (42). Results indicate significant increase in the levels of oxidative products e.g., malondialdehyde, and significant decrease in the AO enzyme superoxide dismutase (SOD); GSH-peroxidase GSH-Px activity was affected on expo-sure to EMF. Addition of AOs resulted in the reduction of OS prior to EMF application.

ROS

Results demonstrate 60-Hz sinusoidal MF-activated cell growth inhibition of prostate cancer in vitro (43). Apoptosis together with cell cycle arrest were the domi-nant causes of the MF-elicited cell growth inhibition, mediated by MF-induced ROS. These results suggest pos-sibility of using 60-Hz MF in radiation therapy of prostate cancer. There is formation of ROS in cells after exposure to 900-MHz radio frequency radiation (44). Results showed that hydrogen peroxide is produced in aqueous solutions under exposure to electromagnetic radiation as a result of the influence of heat and thermoacoustic waves (45). The induction of intracellular ROS by blue light implies that redox effects may mediate the cellular responses. This result suggests the opportunity to mitigate any effects of direct or coincident exposure during dental treatment via AO (46). A recent study suggests that 872 MHz RF radia-tion might enhance chemically induced ROS production and thus cause secondary DNA damage (47).

AOs

A study suggests that mobile telephone radiation leads to OS in corneal and lens tissues and the AOs, such as vitamin C, can help to prevent these effects (48). Mobile

phones caused oxidative damage biochemically by increasing the levels of malondialdehyde, carbonyl groups, xanthine oxidase activity and decreasing catalase activity, and that treatment with melatonin significantly prevented oxidative damage in the brain (49). Increase in malondialdehyde levels of renal tissue and also the decrease in renal SOD, catalase, GSH-Px activities demonstrate the role of OS induced by mobile phone exposure. Melatonin, via its free radical scavenging and AO properties, ameliorated oxidative tissue injury in rat kidney (50). A similar study suggested that EMF at the fre-quency generated by a cell phone causes OS and peroxi-dation in the ertythrocytes and kidney tissues from rats. In the erythrocytes, vitamin C seems to protect against the OS (51). A citrus flavoglycoside, naringin protects mouse liver and intestine against the radiation-induced damage by elevating the AO status and reducing the lipid peroxidation (52).

Electromagnetic radiation triggered extracellular–signal-regulated kinase-survival signaling and activated JNK-apoptotic signaling in Dorsophila (53). Near-infrared increased ROS production independent of ischemia and reperfusion, and this effect was blocked by N-acetylcysteine. Near-infrared electromagnetic radia-tion also enhanced NO generation during early reper-fusion (54). Radio frequency-electromagnetic radiation in both power density and frequency of mobile phones enhances mitochondrial ROS generation by human spermatozoa, decreasing the motility and vitality of these cells while stimulating DNA base adduct formation and, ultimately DNA fragmentation. These findings have clear implications for the safety of extensive mobile phone use by males of reproductive age, potentially affecting both their fertility and health, as well as wellbeing of their off-spring (55). There is ample evidence that radio frequency-electromagnetic radiation can alter the genetic material of exposed cells in vivo and in vitro and in more than one way (56). This genotoxic action may be mediated by microthermal effects in cellular structures, formation of free radicals, or an interaction with DNA-repair mecha-nisms. A study showed the gene expression of rat neuron could be altered by exposure to radio frequency EMF under experimental conditions (57). EMF is a stressor agent that induces an imbalance between ROS genera-tion and AO defense response (58). Calcium ions may play a pivotal role in enhancing OS, proinflammatory reactions and apoptosis associated with EMF exposure.

Cell signaling

There is extensive literature on the relationship of elec-tromagnetic effects on cells. Interaction with signaling systems is a potential mechanism by which very low-energy EMFs might produce metabolic responses in the

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Electromagnetic fields 219

body (59). Hormone and neurotransmitter receptors are specialized protein molecules that use a variety of biochemical processes to pass chemical signals from the outside of a cell across the plasma membrane to the inte-rior. Since many low-energy EMFs have too little energy to directly traverse the membrane, it is possible that they may modify the existing signal-transduction process in cell membranes, thus providing both transduction and biochemical amplification of the effects of the field itself. As an example, one metabolic process in which the physi-ological effects of low-energy EMFs is well established in the healing of bone fractures. The process of regulation of bone turnover and healing is reviewed in the context of clinical applications of electromagnetic energy to the healing process. A hypothetical molecular mechanism is presented that might account for the observed effects of EMF on bone cell metabolism in terms of the field interference with signal-transduction events involved in the hormonal regulation of osteoblast function and differentiation.

There are miscellaneous, additional articles dealing with cell signaling. Exposure of murine cells to pulsed EMFs rapidly activates the mammalian target of rapamy-cin signaling pathway (60). These findings suggest that pulsed EMF exposure might function in a manner analo-gous to soluble growth factors by activating a unique set of signaling pathways. A recent study reported that pulsed EMF treatment of osteoblastic cells stimulated the rapid phosphorylation of the mammalian target rapamycin and its downstream mediators (61). Exposure to 900-MHz EMF induces an unbalance between pro-apoptotic and pro-survival signals in leukemia cells (62). Pulsed electric fields with long durations can induce cell fusion or introduce xenomolecules into cells (63). As the pulse duration decreased, plasma membrane electroporation decreased and appearance of apoptosis markers were delayed. The results suggest that with decreasing pulse durations, nanosecond pulsed electric fields modulate cell signaling from plasma membrane to intracellu-lar structures and functions. Injection of electric field pulses of high intensity and short duration increases the membrane permeability due to reversible electrical breakdown of the cell membrane. Such pulses lead to apoptosis in Jurkat T-lymphoblasts and in HL-60 cells including DNA fragmentation and cleavage of poly(ADP ribose) polymerase (64).

Studies with human hematopoietic cell line TF-1 suggest multifarious effects of EMF on lipid signal transduction, with doses of 30 or 40 pulses having an anti-proliferative effect (65). Changes in the lipid second messengers and shift in some molecular species, such as phosphates, were observed. Static MF (SMF) on normal human neuronal cell culture induced dramatic changes of morphology, formed vortex of cells and exposed branched neuritis featuring synaptic buttons (66). Inositol

lipid signaling was significantly reduced. Endothelin-1 release from FNC-B4 cells was also dramatically reduced. Results suggest fields below 0.5T have significant biologi-cal effects on human neurons.

Various reports show interaction of EMF and tyrosine kinase. Exposure of lymphoma cells to low-energy EMF results in tyrosine kinase-dependent activation of phos-pholipase leading to increased inositol phospholipids turnover (67). Exposure of human skin fibroblasts and rat osteoblasts to extremely low-frequency EMF induced increase in protein kinase activity (68). A similar study showed extremely low-frequency MFs initiate protein tyrosine phosphorylation of the T-cell receptor complex (69). Findings are in line with earlier reports on how MF exposure affects signal transduction in Jurkat. In a related study it was shown that extremely low-frequency MFs alter the intracellular calcium concentrations in the human leukemia T-cell line Jurkat (70).

There is extensive literature on calcium in cell signal-ing. Numerous reports demonstrate that weak EMFs can elicit in vivo and in vitro bioeffects from several different biological systems (71). Of particular interest are those studies that report the existence of “window” effects or resonance-type response of biological systems to the amplitude and frequency of EMF. The significance of DC MFs for “window” or “resonance” effects was pointed out two decades ago. The importance of weak EMF bioeffects is now well established. The phenomenon of signal trans-duction is central to a wide range of cellular activities triggered by ligand-gated binding of hormones, antigen molecules, growth factor and other cell-surface agonists which are key pathways for the activation, differentiation and proliferation of many cell types. Calcium ions appear to be essential in the first steps of transduction coupling of exogenous physical signals at the cell membrane and in the ensuing steps of calcium-dependent signaling in intracellular enzyme systems. The early modulation of calcium signaling by EMF has, thus, been suggested to be a plausible candidate for activation of a number of biochemical reactions. EMF coupling with cellular tar-gets may occur via highly cooperative steps. For exam-ple, calcium-dependent steps in the target pathway may include: (i) initial detection of EMF with resultant electrochemical changes at specific binding sites; (ii) membrane bound proteins signaling to the cell interior; (iii) EMF coupling with the cytoskeleton and other sub-cellular constituents.

Calcium influx increased during mitogen-activated signal transduction in thymic lymphocytes exposed to a MF (72), providing evidence for an electric field metric and site of interaction involving the calcium ion chan-nel. A similar study showed a membrane mediated Ca2+ signaling process is involved in the mediation of EMF in the immune system (73). High-frequency (900 MHz) low amplitude (5 Vm−1) EMF stimulus affects transcription,

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220 Peter Kovacic and Ratnasamy Somanathan

translation, calcium, and energy charge in tomato (74). Within minutes of exposure to electromagnetic stimulation, stress-related mRNA (clamodulin, calcium-dependent protein kinase inhibitor) accumulated in a rapid, large and three-phase manner typical of an envi-ronmental stress response. Extremely low frequency, time-varying fields act in combination with SMFs to alter calcium signaling in the lymphocytes (75) and inhibits calcium influx triggered by the mitogen Concanavalin A. Only mitogen-activated cells undergo calcium signal-ing and exhibit field response. The interaction of low-intensity MF predicts the occurrence of biological effects at specific values for the frequency and field intensity of the EMF and SMFs. In a similar study calcium influx was elevated 1.5-fold when lymphocytes were exposed to Concanavalin A plus MF (76). The signal-transduction hypothesis is supported by experimental evidence for a general biological framework for understanding MF interactions with the cell through signal transduction. MFs can act as a co-stimulus at suboptimal levels of mitogen; pronounced physiological changes in lym-phocytes, such as calcium influx and c-MYC mRNA induction, were not triggered by weak mitogenic signal unless accompanied by a MF. Thus, MFs have the ability to potentiate or amplify cell signaling. In a study using radioactive 45Ca2+ and murine leukemia cell line, signifi-cant increase of calcium influx was shown when exposed to EMF (77).

In a study, the influence 50-Hz EMFs in combination with a tumor promoting phorbol ester on protein kinase C (PKC) and cell cycle in human cells was carried out; results indicated lower concentration of phorbol ester induces a less maximum effect on PKC pathway, which can be enhanced by the applied EMF (78).

Effects of 50-Hz MFs on the signaling pathways of N-formyl-meth-leu-phe-induced shape changes in inver-tebrate immunocytes and the activation of an alternative “stress pathway” were discussed (79). Exposure of Mytilus galloprovincialis to MFs in the range of 200–1000 μT provokes intensity-correlated effects on potassium and calcium channels of immunocytes. An intensity of 200 μT was ineffective, whereas 300 and 400 μT provoked a temporary damage, and above this level damage pro-gressively became permanent.

The fundamental mechanistic aspects of cell signaling have been addressed (80).

EMF and cell phones

In a study, detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the extracellular-signal regu-lated kinase cascade and how it induces transcription and other cellular processes were described (81). Upon

irradiation (mobile phone frequencies) on mitogen-activated protein kinase cascades and extracellular signal-regulated kinase are rapidly activated in response to various frequencies and intensities of EMF. The first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS. These ROS then directly stimulate matrix metalloproteinases and allow them to cleave and release heparin-binding epider-mal growth factor, which, in turn, further activates the extracellular-signal regulated kinase cascade. Mobile phone radiation-induced activation of hsp27 may (i) facilitate the development of brain cancer by inhib-iting the cytochrome c/caspase-3 apoptotic pathway and (ii) cause an increase in blood-brain barrier per-meability through stabilization of endothelial cell stress fibers (82). Authors postulate that these events, when occurring repeatedly over a long period of time, might become a health hazard because of the possible accu-mulation of brain tissue damage. Furthermore, other brain damaging factors may co-participate in mobile phone radiation-induced effects.

Bone repair

Appreciable attention has been paid to the practical, medical effects of electrical field exposure on bone injury. There has been renewed interest in the use of magnets for enhancing tooth movements (83). The major premise upon which magnetic effects alter cell reactions is based upon electrically based theories of cellular signaling or perturbation of polar proteins within the cell mem-brane. The two major theories are based upon electrically based phenomena, i.e., piezoelectricity and streaming potentials.

Both mechanical and electrical signals have been shown to regulate the synthesis of extracellular matrix and may do so through the stimulation of signaling pathways at the cell membrane resulting in the appear-ance of intracellular second messengers, particularly cyclic nucleotides (84). The therapeutic use of electric fields is derived from the observation that when bones are placed under mechanical load (stress) the defor-mation (strain) is accompanied by an electrical signal and the signal is related to strain characteristics. This strain-related or straingenerated electric potential has been hypothesized to consist of information transfer to the osteocyte regarding the nature of its mechanical environment and the state of the extracellular matrix. The origin of the electric signal was thought initially to be related to defamation of the crystalline structure of extracellular matrix collagen, involving the piezoelec-tric effect. Other data, however, have suggested that alterations in fluid flow might produce electrokinetic events, specifically streaming potentials, which might

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Electromagnetic fields 221

be partly or wholly responsible for the observed electric potential.

There are different transduction pathways for ultra-sound and pulsed EMF stimulation that lead to an upgrade of osteoblast proliferation, with their pathways all leading to an increase in cytocolic Ca2+ and activation of calmodulin (85). These findings offer a biochemi-cal mechanism to support the process of ultrasound and pulsed EMF-induced enhanced healing of bone fractures.

Pulsed EMFs affect phenotype and connexin 43 pro-tein expression (86). The mechanism by which EMFs affect bone turnover are unclear. They can directly affect osteoclastic cells, and there is evidence that cells in the osteoblast lineage are sensitive to EMFs. Pulsed EMF can influence MG63 osteoblst-like cells by increas-ing transforming growth factor-β1 (TGF-β1), levels but decreasing levels of prostaglandin E

2 in the conditioned

media. Pulsed EMFs also increase TGF-β1 production by atrophic and hypertrophic nonunion cells. Others have shown that EMFs increase ostoblastic proliferation, extra-cellular matrix production.

Miscellaneous

A study showed EMF-induced stimulation of mouse bone marrow-derived macrophages (87). Furthermore, a sig-nificant increase in superoxide production after exposure to EMF was detected. Extremely low-frequency EMF can partially block the differentiation of Friend erythroleuke-mia cells, and this results in a larger population of cells remaining in the undifferentiated, proliferative state (88).

Nonadditivity of electrostatic and hydrophobic interactions on protein in membrane interfaces was studied (89). The specific ligand-binding sites are gen-erally flanked by basic and/or hydrophobic side-chains which mediate electrostatic and hydrophobic interac-tions responsible for the nonspecific component of binding.

Biophysical input, including electric and EMFs, regulate the expression of genes in connective tissues for structural extracellular matrix proteins resulting in an increase in cartilage and bone production (90). Electric and EMFs increase gene expression for, and synthesis of, growth factors and this may function to amplify field effects through autocrine and paracrine signaling. Electric and EMFs can produce a sustained upregulation of growth factors, which enhance bone formation.

Microwaves generated by an EMF can affect three dimensional structure of eukaryotic proteins, also sug-gesting possible biological effects in living cells (91). Moreover, it has been demonstrated that prolonged

exposure to low-intensity microwave fields can induce heat-shock responses.

EMFs affect transcript levels of apoptosis-related genes in embryonic neural cells (92). EMF exposure of neural progenitor cells transiently affects the transcript level of genes related to apoptosis and cell cycle control.

Individuals occupationally exposed to EMFs undergo an increased risk of brain tumors, particularly astro-cytomas (93). For example, a study revealed more risk of brain tumors in electric utility workers linked in a dose-dependent manner to exposure to EMF. A related study, particularly compelling, showed employment in occupations that entail exposure to EMF presents an elevated risk of 1.7 for all gliomas, and a risk of 10.3 for astrocytomas. Though a recent study did not support the hypothesis of an increased risk of brain cancer associated with occupational exposure to MFs, a metaanalysi of 52 studies recently concluded that there is a small, pervasive association between brain cancer and exposure to EMF. The biological basis for such association, i.e., the cellular and molecular mechanisms underlying these effects of EMF, are, however, poorly understood.

A prevailing hypothesis is that EMF may not cause cancer initiation, but may instead act as a promoter (93). Several studies suggest possible mechanisms to explain the association between EMF exposure and cancer. One of the most interesting and unifying hypotheses involves interaction of EMF with signal-transduction systems. Specifically, EMF may influence the signal-transduction cascade at the level of the cell membrane, trigger changes in calcium influx and/or receptor binding, and induce gene expression and protein synthesis, which may ulti-mately lead to cell proliferation. Preliminary evidence also suggests that exposure to EMF causes an increase in PKC activity. PKC is recognized as a key component of the cellular signal-transduction cascade and has been implicated in modulating the expression of certain genes and regulating cell proliferation.

MFs increase cell survival by inhibiting apoptosis via modulation of Ca2+ influx (94). The rescue of damaged cells may be the mechanism explaining why MFs that are not mutagenic per se are often able to increase mutation and tumor frequencies.

Recent studies investigating changes in susceptibility to apoptosis with regard to EMF exposure have reported both decreased and increased susceptibility (95). Interestingly, previous studies involving DNA repair and EMF exposure have reported no effect.

The interaction of SMFs with living organisms is a rap-idly growing field of investigation (96). However, despite an increasing number of studies on the effects of the inter-action of SMFs with living organisms, many gaps in our knowledge still remain. One reason why it is extremely important to understand the mode of action of MFs on living organisms, is the need to protect human health

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222 Peter Kovacic and Ratnasamy Somanathan

in consideration of the increasing introduction of new technologies, such as magnetically levitated trains and the therapeutical use of MFs (e.g., magnetic resonance imaging, coupling of MF exposure with chemotherapy).

The lack of knowledge of the morphological modifica-tions brought about by exposure to moderate-intensity SMFs prompted the authors to investigate the bioeffects of 6 mT SMFs on different cell types, by means of light and electron microscopy, confocal laser scanning microscopy and immuno- or cytochemistry (96). The morphological modifications related to cell shape, cell surface, cytoskel-eton, and plasma membrane expression of molecules and carbohydrate residues were studied. The effects of expo-sure to moderate-intensity SMF on apoptosis, apoptotic related gene products, macrophagic differentiation and on phagocytosis of apoptotic cells in primary cell cultures were studied. Results showed moderate-intensity (6 mT) SMFs induced modifications of cell shape, cell surface and cytoskeleton. Apoptosis was influenced in all cell type-dependent manner.

Several physical mechanisms have been proposed to account for the initial interactions with cells (97). MFs interact with moving charges in cells and change their velocities, as in the classic interaction of MF with any moving charge. Charge flow associated with a biological function, as for enzyme activity, has been demonstrated in Na, K-ATPase and cytochrome oxidase reactions.

Interaction of weak EMF with living cells is a most important, but unresolved biophysical problem (98). Regulation of ion and substrate pathways through micro-villi provides a possible theoretical basis for the compre-hension of physiological effects of even extremely low MFs.

Erythroleukemia K562 cells and lentil root protoplasts have been subjected to pore-forming electric fields suit-able for transfection experiments (99). Evidence showed the amount of hydroperoxides formed in cell membranes of both cell types is a function of field strength applied. On the other hand, electroporation-induced lipid per-oxidation paralleled the enhancement of membrane permeability and was associated with greater membrane fluidity. The membrane hydroperoxides formed upon electric shock enhanced cell luminescence, and lipoxy-genase activity appeared to be involved in the process.

A recent book on cell signaling contains only limited material on electrochemistry (100). Electrical signaling is involved with changes in membrane potential and electrical impulses in nerve cells for use in communica-tion with other cells. The process entails conversion of electrical signals into chemical ones. There is knowledge of phosphorylations that affects enzyme activity solely by electrostatic effects.

There is speculation that biomolecular radicals are the basis for a magnetosensitive compass that guides migrating birds. The magnetosensitivity of photo-induced

radical pairs serve as a probe of protein substrate inter-actions (101). The technique, involving a weak magnet, may be used to gain information on molecular dynam-ics, diffusion on surface, charge interactions and surface potentials.

A novel hypothesis about visual perception and imagery has been proposed recently, which states that external electromagnetic visible photons are converted into electrical signals in the retina and are then conveyed to the V1 area (102). These electrical signals can be con-verted subsequently to bioluminescent photon signals. There is a role for ROS and reactive nitrogen species.

Very complex MFs rotating around and within the brain can interact with cerebral processes generating consciousness (103). Evidence is presented showing that transcranial magnetic stimulation represents a promis-ing tool for elucidating the pathophysiological sequelae of impaired consciousness with the potential for thera-peutic interaction (104). The literature provides related studies involving magnetic stimulation (105–110).

Various studies are reported on electrical therapy for Parkinson’s disease. Rapid electrical stimulation is safe and efficient in treatment of patients (111,112). The lit-erature contains similar findings (113,114).

Favorable results occur in electrotherapy of patients with depression. Electrical treatment obtained good outcomes with high safety and tolerability (115). There is evidence for electrical nerve stimulation as the treatment of choice for pain and depression (116). Another inves-tigation deals with the influence of transcranial current stimulation coupled with repetitive electrical stimulation on depression (117).

There is application of magnetic nanoparticles as ther-mal agents in hyperthermic treatment of cancer (118,119). Gold nanoparticles efficiently convert the absorbed light into localized heat which can be exploited for the selec-tive laser photothermal therapy of cancer (120).

There are recent articles dealing with electric and EMFs that regulate extracellular matrix synthesis and stimulate repair of fractures and nonunions (121). The study suggests that exposure to EMFs can accomplish the following: (i) regulate proteoglycan and collagen synthesis and increase bone formation in models of endochondral ossification, (ii) accelerate bone forma-tion and repair, (iii) increase union rates in fractures, and (iv) produce results equivalent to bone grafts. Chang et al. demonstrated that pulsed EMF with dif-ferent intensities could regulate osteoclastogenesis, bone resorption, osteoprotegrin, NFkappaB-ligand, and macrophage-colony-stimulating factor in marrow culture system (122). A clinical study with 64 patients undergoing hindfoot arthrodesis (144 joints) showed, if all parameters are equal, the adjunctive use of pulsed EMF increases the rate and speed of radiographic union of joints (123). A similar study with 100 patients

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Electromagnetic fields 223

with symptomatic pseudarthrosis lumber spine fusion, pulsed EMF was shown to be an effective nonoperative salvage approach to achieving fusion (124).

Conclusion

There is considerable literature devoted to electromag-netism in the life sciences and medicine. However, many workers in these areas have little knowledge of the subject and its importance. This review documents the many interactions of EMFs with biological systems and the consequences. Cell signaling has been the subject of much attention in this connection. Using an integrated approach, interaction is demonstrated involving ROS and OS, which may lead to toxicity and high levels of the harmful radicals. The unresolved question of danger associated with man-made EMFs is included. Beneficial effects of EMFs are discussed, such as in the healing of bone fracture, Parkinson’s disease, depression, and cancer.

Acknowledgements

Editorial assistance by Thelma Chavez is acknowledged.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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