Review Article | Open Access
Soumaya Ghodbane, Aida Lahbib, Mohsen Sakly, Hafedh Abdelmelek, "Bioeffects of Static Magnetic Fields: Oxidative Stress, Genotoxic Effects, and Cancer Studies", BioMed Research International, vol. 2013, Article ID 602987, 12 pages, 2013. https://doi.org/10.1155/2013/602987
Bioeffects of Static Magnetic Fields: Oxidative Stress, Genotoxic Effects, and Cancer Studies
The interaction of static magnetic fields (SMFs) with living organisms is a rapidly growing field of investigation. The magnetic fields (MFs) effect observed with radical pair recombination is one of the well-known mechanisms by which MFs interact with biological systems. Exposure to SMF can increase the activity, concentration, and life time of paramagnetic free radicals, which might cause oxidative stress, genetic mutation, and/or apoptosis. Current evidence suggests that cell proliferation can be influenced by a treatment with both SMFs and anticancer drugs. It has been recently found that SMFs can enhance the anticancer effect of chemotherapeutic drugs; this may provide a new strategy for cancer therapy. This review focuses on our own data and other data from the literature of SMFs bioeffects. Three main areas of investigation have been covered: free radical generation and oxidative stress, apoptosis and genotoxicity, and cancer. After an introduction on SMF classification and medical applications, the basic phenomena to understand the bioeffects are described. The scientific literature is summarized, integrated, and critically analyzed with the help of authoritative reviews by recognized experts; international safety guidelines are also cited.
Living organisms are continuously exposed to the natural geomagnetic field of around 20–70 μT that exists over the surface of the Earth and which is implicated in the orientation and migration of certain animal species .
During evolution, living organisms developed specific mechanisms for perception of natural electric and magnetic fields. These mechanisms require specific combinations of physical parameters of the applied field to be detected by biological systems. In order words, the “windows” are means by which discrete MFs are detected by biological systems. Depending on the level of structural organization these mechanisms of detection and response may be seen at different levels, for example, at membrane, cellular, or tissue levels. Sometimes the “windows” function via signal transduction cascade, brain activity, or the central nervous system . The sensitivity of the biological systems to weak MF has been described elsewhere [3–5], mainly in respect to the dependence of bioeffects on the amplitude or the frequency of applied fields.
The frequency of exposure to MFs has increased with rapid advances in science and technology, such as magnetic resonance imaging (MRI) diagnosis, nuclear magnetic resonance (NMR) spectroscopy, and passenger transport systems that are based on magnetic levitation . Therefore, it has become necessary to systematically elucidate the influence of MFs on the body. In an attempt to explain the biological effects of SMFs, it is useful to classify them as weak (<1 mT), moderate (1 mT to 1 T), strong (1–5 T), and ultrastrong (>5 T).
SMFs are time-independent fields whose intensity could be spatially dependent. There are four SMF parameters relevant for the interaction with a biological system: target tissue(s), magnet characteristics, magnet support device, and dosing regimen . SMFs are difficult to shield and can freely penetrate biological tissues . However, not only the field intensity, but also the gradient of the field has important role in biological effects of SMF [9, 10]. SMF can interact directly with moving charges (ions, proteins, etc.) and magnetic materials found in tissues through several physical mechanisms .
Previous research showed that SMF influences biological system in a way that causes proinflammatory changes, as well as an increase in production of reactive oxygen species (ROS) [11, 12]. Throughout the past decades, there have been several experimental results describing the effects of MFs on radical pair recombination.
As reviewed recently by Ueno and Shigemitsu , several biophysical and biochemical effects can be expected when biological systems are simultaneously exposed to SMFs and other forms of energy such as light and radiation [14, 15].
Although there is much speculation about this role, the primary mechanism is thought to be the result of oxidative stress, that is, free radical generation via Fenton reaction, which is the iron-catalyzed oxidation of hydrogen peroxide (H2O2) [16–18].
Recent advance of biological science and technology can help us understand MF effects more clearly. Studies on the biological effects of MFs have resulted in significant developments in the medical applications of SMF as well as EMF, after the development of high-strength superconducting magnets. The mainstays of such medical applications are transcranial magnetic stimulation (TMS) and MRI. These techniques have also contributed much to the amazing progress made in understanding brain functions. A guideline for exposure of the human body to SMFs set by the international commission on nonionizing radiation protection (ICNIRP)  suggests 2 T as the ceiling value for body parts, except for arms and legs, in occupational exposure. In the application of clinical MRI, the current exposure level is confirmed to be less than or equal to 2 T. In SMFs at this strength it is not feasible to obtain resonance images, except for hydrogen atoms. There are several reports that strong SMF effects play significant roles in endogenous and exogenous ROS generations. Based on advanced studies of SMF effects on oxidative stress reactions, the potentially hazardous effect of SMF on living organisms is that exposure to SMF can increase the activity, concentration, and life time of paramagnetic free radicals, which might cause oxidative stress, genetic mutation, and/or apoptosis [20–23]. In particular, SMF exposure initiates an iron-mediated process that increases free radical formation in brain cells, leading to the breaking of DNA strands and cell death.
Genotoxic effects of exposure to static magnetic fields have been mostly examined in cell cultures . Few in vivo studies of genotoxicity or possible effects on other carcinogenic processes have been carried out. Animal studies are often used in the evaluation of suspected human carcinogens  either screening for an increased incidence of spontaneous tumors or of the incidence of tumors induced by known carcinogens.
The earlier literature has been summarized by WHO , Kowalczuk et al.  and ICNIRP [28, 29], Repacholi and Greenebaum , IARC , ICNIRP , McKinlay et al. , and Dini and Abbro  whilst more recent studies have been reviewed by Okano , Phillips et al. , and Ueno and Okano .
The focus of this review is on recent studies, where possible. These studies are covered under three main sections: free radical generation and oxidative stress, apoptosis and genotoxicity, and cancer.
The objective of this review is to describe and shed light on some of the most recent information on the biological effects and medical applications of magnetic fields. A discussion of possible implications of these effects on biological systems is also provided.
2. Oxidative Stress
Biological free radicals are most commonly oxygen or nitrogen based with an unpaired electron, leading to the terms ROS, such as superoxide anion (O2−), hydroxyl radical (OH•) and singlet oxygen (1O2), or “reactive nitrogen species (RNS)”, such as nitric oxide (NO) . The ROS and RNS play significant roles in immunological defense , intracellular signaling , and intercellular communication . It is assumed that SMF could change the lifetime of radical pairs, yields of cage products, and escape products. If an SMF affects cells through the radical pair mechanism, an SMF influences the spin of electrons in free radicals, which may lead to changes in chemical reaction kinetics and possibly altering cellular function .
2.1. Moderate-Intensity Static Magnetic Fields and Oxidative Stress
There are several reports showing that moderate SMF could influence the ROS modulation (generation/reduction) from enzymatic reactions in cell-free solutions. The SMF effects also play significant roles in the endogenous and exogenous ROS modulation in biological systems, in vitro and in vivo.
Amara et al.  investigated the effect of SMF exposure on testicular function and antioxidant status in rats. Exposure to SMF (128 mT; 1 h/day for 30 days) has no effect on epididymal sperm count, spermatozoa motility, and genital organ weight. In contrast, SMF induces an increase of malondialdehyde (MDA) in the testis. In the gonad, SMF decreases the catalase (CAT), glutathione peroxidase (GPx), and mitochondrial Mn-superoxide dismutase (Mn-SOD) activities. However, cytosolic CuZn-SOD activity is unaffected.
The latter group also investigated the effects of SMF (128 mT, 1 h/day during 30 consecutive days) exposure on the antioxidative enzymes activity and MDA concentration in male rat brain . The exposure of rats to SMF decreased the GPx, CuZn-SOD, and CAT activities in frontal cortex. The same treatment decreased the CuZn-SOD and Mn-SOD activities in hippocampus. However, the glutathione levels remained unchanged in both brain structures. In the hippocampus, SMF-exposure increased MDA concentration. These results indicated that exposure to SMF induced oxidative stress in rat hippocampus and frontal cortex.
SMF exposure alters antioxidant enzyme activity and the labile zinc fraction in THP1 cells (monocyte line) . Cell culture flasks were exposed to SMF (250 mT) during 1 h, 2 h, and 3 h. Cell viability was slightly lower in SMF-exposed groups compared to a sham-exposed group. However, SMF exposure failed to alter MDA, GPx, CAT, and SOD levels even by 3 h of exposition. Cells stained with zinc-specific fluorescent probes zinpyr-1 showed a decrease of labile zinc fraction in all groups exposed to SMF. SMF exposure (250 mT, during 3 h) did not cause oxidative stress in THP1 cells but altered the intracellular labile zinc fraction.
Chater et al.  evaluated the effects of exposure to SMF on some parameters indicative of oxidative stress in pregnant rat. Exposure to SMF (128 mT; 1 h/day from day 6 to day 19 of pregnancy) failed to alter plasma MDA and GPx activity. Moreover the same treatment did not alter liver concentration of MDA and kidney activities of GPx CAT and SOD. By contrast, SMF induced an increase of liver GSH content. Similar results were reported by Ghodbane et al.  who show that liver GSH concentrations were significantly higher in SMF exposed rats than in the controls, indicating an adaptive mechanism to electromagnetic pollution. GSH levels can be increased due to an adaptive mechanism to slight oxidative stress through an increase in its synthesis. However, a severe oxidative stress may decrease GSH levels due to the loss of adaptive mechanisms and the oxidation of GSH to GSSG.
Exposure to SMF (128 mT; 1 h/day for 5 days) induces a decrease of selenium levels in kidney, muscle, and brain with a decrease of GPx activities in kidney and muscle. By contrast, SMF exposure increased total GSH levels and total SOD activities in liver, while glutathione reductase (GR) activity is unaffected. Selenium supplementation (Na2SeO3, 0.2 mg/L, in drinking water for 4 weeks) in SMF-exposed rats restored selenium levels in kidney, muscle, and brain and elevated the activities of GPx in kidney and muscle to those of control group. In the liver, selenium supplementation failed to bring down the elevated levels of total GSH and SOD activities . Thus, subacute exposure to SMF altered the antioxidant response by decreasing tissues selenium contents, while selenium supplementation ameliorates antioxidant capacity in rat exposed to SMF. Regarding the fate of selenium administration in SMF-exposed rats, it may be assumed that this element minimizes the oxidative stress induced by SMF.
Previous data implicated the SMF in free radical production, like superoxide anions in different cells and organs [22, 47, 48]. However, Ghodbane et al.  showed that SMF exposure failed to alter plasma TBARs and total thiol groups, indicating an adaptive mechanism to slight oxidative stress caused by electromagnetic field as previously shown by Chater et al. . By contrast, Amara et al.  showed an increase in MDA level in liver and kidney, indicating oxidative stress under SMF (128 mT, 1 h/day during 30 consecutive days). This discrepancy may be explained by the intensity and the duration of the exposure. The cellular and molecular modifications induced when SMFs interact with biological materials are, however, dependent on the duration of exposure, intensity, tissue penetration, and the type of cells .
Moreover, Ghodbane et al.  evaluated the effect of selenium (Se) supplementation in SMF-exposed rats. Pretreatment with Se (Na2SeO3, 0.2 mg/L, for 30 consecutive days, per os) prevented plasma α-tocopherol and retinol decrease induced by SMF exposure.
Amara et al.  examined the effect of zinc supplementation on the antioxidant enzymatic system, lipid peroxidation and DNA oxidation in SMF-exposed rats. The exposure of rats to SMF (128 mT, 1 h/day during 30 consecutive days) decreased the activities of GPx, CAT, and SOD activities and increased MDA concentration in liver and kidneys. Zinc supplementation (ZnCl2, 40 mg/L, per os) in SMF-exposed rats restored the activities of GPx, CAT, and SOD in liver to those of control group. However, only CAT activity was restored in kidney. Moreover, zinc administration was able to bring down the elevated levels of MDA in the liver but not in kidneys. The authors suggested that zinc supplementation minimizes oxidative damage induced by SMF in rat tissues.
The mechanism by which SMF induced oxidative stress in rat tissues is not well understood. A change in radical pair recombination rates is one of the few mechanisms by which an SMF can interact with biological systems such as a cell-free system. The SMF increases the concentration and/or lifetime of free radicals that escape from the radical pair so that the critical radical concentration, needed to initiate membrane damage and cause cell lysis, is reached sooner .
Exposure to SMF (128 mT, 1 h/day, during 5 consecutive days) induced sympathetic neurons system hyperactivity associated with hypoxia-like status  and elevated plasma corticosterone and metallothionein concentrations and enhanced apoptosis [53, 54]. Hashish et al.  indicate that there is a relation between the exposure to SMF and the oxidative stress through distressing redox balance leading to physiological disturbances. SMF exposure induced probably the disruption of mineral divalent element homeostasis, contributing to their deficiency in tissues [43, 44, 46, 50]. Agay et al.  have demonstrated that alteration of antioxidant trace elements (Zn, Se, and Cu) disrupts the activities of antioxidant enzymes. Duda et al.  reported a change in liver and kidneys concentration of copper, manganese, cobalt and iron in rats exposed to static and low-frequency magnetic fields. SMF probably induces a conformational change of antioxidant enzymes that leads to loss of their catalytic activity .
A few studies concerning the supplemental antioxidants vitamins C and E have focused on the preventive and curative properties in damage induced by SMF exposure . Jajte et al.  reported the effect of melatonin and vitamin E on the level of lipid peroxidation in rat blood lymphocytes exposed to iron ions and/or SMF. When cells were treated with melatonin or vitamin E and then exposed to iron ions and SMF, the level of lipid peroxidation was significantly reduced.
Sullivan et al.  reported that SMF (230–250 mT) exposure stimulates ROS production in human fetal lung cells (WI-38) during the first 18 h period when cells are attaching to the culture vessel. These results support the hypothesis that increased ROS formation may account for SMF effects on cell attachment. However, SMF decreases growth in cell when the increase in ROS was abated, suggesting that other mechanisms account for SMF effects on cell growth.
Kabuto et al.  showed that an SMF (5–300 mT for 40 min) had no effect on the accumulation of TBARS in mouse brain homogenates induced by FeCl3. In contrast, when the homogenates were incubated with FeCl3 in an SMF (2–4 mT), the accumulation of TBARS was decreased. The accumulation of TBARS in phosphatidylcholine solution incubated with FeCl3 and H2O2 was also inhibited by the SMF exposure. These results suggest that the SMF could have an inhibitory effect on Fe2+-induced lipid peroxidation, and the effectiveness of this SMF suppression on Fe2+-induced ROS generation is restricted to a “window” of field intensity of 2 to 4 mT.
Currently, environmental and industrial pollution causes multiple stress conditions; the combined exposure to magnetic field and other toxic agents is recognized as an important research area, with a view to better protecting human health against their probable unfavorable effects. Amara et al.  investigated the effect of coexposure to SMF and cadmium (Cd) on the antioxidant enzymes activity and MDA concentration in rat skeletal and cardiac muscles. The exposure of rats to SMF (128 mT, 1 h/day during 30 consecutive days) decreased the activities of GPx and CuZn-SOD in heart muscle. Exposure to SMF increased the MDA concentration in rat cardiac muscle. The combined effect of SMF and Cd (CdCl2, 40 mg/L, per os) disrupted more the antioxidant enzymes activity in rat skeletal and cardiac muscles.
The combined effect of SMF (128 mT, 1 hour/day for 30 consecutive days) and CdCl2 (40 mg/L, per os) decreased SOD activity and glutathione level and increased MDA concentration in frontal cortex as compared with Cd-exposed rats .
In pregnant rats coexposed to cadmium (CdCl2, 3.0 mg/Kg body weight) and SMF (128 mT/1 h/day) for 13 consecutive days as from the 6th to 19th day of gestation, no effects on activities of antioxidant were observed in both tissues compared to cadmium-treated group . However, the association between SMF and Cd decreased plasma MDA concentration, suggesting that a homeostatic defense mechanism was activated when SMF was associated to Cd in pregnant rats.
2.2. Strong and Ultrastrong Static Magnetic Fields and Oxidative Stress
Although strong SMF is supposed to have the potential to affect biological systems, the effects have not been evaluated sufficiently.
Sirmatel et al.  investigated the effects of a high-strength magnetic field produced by an MRI apparatus on oxidative stress. The effects of SMF (1.50 T) on the total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) in male subjects were investigated. In this study, 33 male volunteers were exposed to SMF for a short time, and the TAC, TOS, and OSI of each subject were determined using the methods of Erel. Magnetic field exposure was provided using a magnetic resonance apparatus; radiofrequency was not applied. TAC showed a significant increase in postexposures compared to preexposures to the magnetic field (). OSI and TOS showed a significant decrease in postexposures compared to preexposures to SMF (for each of two, ). The 1.50 T SMF used in the MRI apparatus did not yield a negative effect; on the contrary, it produced the positive effect of decreasing oxidative stress in men following short-term exposure.
The Nakagawa research group [65, 66] measured and evaluated a ROS scavenger, metallothionein (MT), a ROS product, and lipid peroxidation in the liver, kidneys, heart, lung, and brain of 8-week-old male BALB/c mice in vivo. The mice were exposed to an SMF of 3.0 and 4.70 T for 1–48 h. A 4.70 T SMF exposure for 6–48 h increased both MT and lipid peroxidation levels in the liver alone. A 3.0 T SMF exposure for 1–48 h did not induce any changes in both MT and lipid peroxidation levels in all the tissues. A single subcutaneous injection of CCl4 (0.5 mL/kg) increased both MT and lipid peroxidation levels in the liver, and the combination of CCl4 administration and a 4.70 T SMF for 24 h potentiated both MT and lipid peroxidation levels. The increase in activities of both glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) caused by CCl4 administration was also enhanced by the SMF exposure. It is concluded that exposure to a high SMF induces the increase of both MT and lipid peroxidation levels in the liver of mice and enhances the hepatotoxicity caused by CCl4 injection.
3. Genotoxicity, DNA Damage, and Apoptosis
Health and environmental concerns have been raised because the SMF effects on oxidative stress leading to genetic mutation and apoptosis/necrosis have been found. It seems to take place from free radical generation.
Several experiments have been shown, and they discussed how SMF can influence the immune function or oxidative DNA damage via the ROS formation process.
One possibility is that DNA is damaged by free radicals that are formed inside cells. Free radicals affect cells by damaging macromolecules, such as DNA, protein, and membrane lipids. Several reports have indicated that SMF enhances free radical activity in cells [67–71], particularly via the Fenton reaction . The Fenton reaction is a process catalyzed by iron in which hydrogen peroxide, a product of oxidative respiration in the mitochondria, is converted into hydroxyl free radicals, which are very potent and cytotoxic molecules.
3.1. Genotoxic Effects of Moderate-Intensity Static Magnetic Fields
Amara et al.  investigated the effect of SMF exposure in DNA damage in THP1 cells (monocyte line). Cell culture flasks were exposed to SMF (250 mT) during 1 h, 2 h, and 3 h. The results showed that cell viability was slightly lower in SMF-exposed groups compared to a sham-exposed group. DNA analysis by single cell gel electrophoresis (comet assay) revealed that SMF exposure did not exert any DNA damage by 1 and 2 h. However, it induced a low level of DNA single strand breaks in cells after 3 h of exposition. To further explore the oxidative DNA damage, cellular DNA was isolated, hydrolyzed, and analyzed by HPLC-EC. The level of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) remained unchanged compared to the sham-exposed group (+6.5%, ). The results showed that SMF exposure (250 mT, during 3 h) did not cause oxidative stress and DNA damage in THP1 cells.
Exposure of rats to SMF (128 mT, 1 h/day during 30 consecutive days) increased metallothioneins level in frontal cortex, while the 8-oxodGuo concentration remained unaffected, indicating the absence of DNA oxidation. Metallothionein induction protected probably DNA against oxidative damage . The same treatment elevated the 8-oxodGuo in kidneys but not in liver. Zinc supplementation (ZnCl2, 40 mg/L, per os) attenuated DNA oxidation induced by SMF in kidneys to the control level .