4. Cell studies

Microwave irradiation can produce genotoxic effects in human cells [38]. Induction of micronuclei in human lymphocytes with wide interindividual variability after exposure in vitro to 1800 MHz [39] has been observed and is correlated with specific chromosomal aberrations (acentric fragments and dicentric chromosomes) [40]. Exposure of human peripheral blood lymphocytes to EMR associated with cell phones (830 MHz) leads to chromosomal instability, specifically aneuploidy, which is known to increase cancer risk [41]. Aneuploidy among other kinds of DNA damage can result in p53-mediated postmitotic apoptosis in human cells [42]. EMR from cell base stations has also been reported to increase the frequency of DNA strand breaks in the lymphocytes of cellphone users and in individuals residing near cell base stations [43, 44].

DNA damage like aneuploidy can result in cell cycle arrest and activation of apoptosis.

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The generation of reactive oxygen species in response to microwave radiation has been observed in various studies. Certain carcinogens like UV rays exert some of their carcinogenic effects via the generation of reactive oxygen species in the cell [55]. This is true of X-rays, as well [56]. Certain oncogenic proteins such as Ras also produce elevations in ROS upon stimulation. Many genes and proteins that respond to conditions of oxidative stress within the cell subsequently trigger apoptosis. Because mitochondria are important regulators of cellular redox status, the induction of oxidative stress exhibits its effects upon these organelles to trigger the intrinsic

Moreover, an increase in the efflux of calcium ions has been observed in human neuroblastoma cells at extremely low levels of microwave radiation, and this cellular calcium imbalance may reflect the release of calcium ions from internal organelles. In this regard, lead perturbs and alters the release of intracellular calcium stores from organelles like the endoplasmic reticulum (ER) and mitochondria [59, 60]. Mitochondria can accumulate large amounts of calcium, for example, in the presence of inorganic phosphate. The rise in calcium results in an upregulation of energy metabolism and an increase in mitochondrial membrane potential. Then, the release of this accumulated calcium through a special channel, permeability transition pore (PTP), can cause mitochondrial depolarization. According to the model of glutamate toxicity, mitochondrial calcium accumulation and resultant membrane depolarization are clearly linked to the

Microwaves can also affect chromatin conformation and histone phosphorylation in human lymphocytes. Interestingly, in addition to causing genetic damage via oxidative and nonoxidative mechanisms (DNA adducts), certain carcinogenic heavy metals can cause significant epigenetic changes in cells such as DNA methylation and histone modifications. These can result in gene silencing or reactivation of gene expression [63]. MicroRNAs (miRNAs) are highly conserved, noncoding small RNAs regulating the expression of broad gene networks at the posttranscriptional level and may represent another epigenetic control mechanism. In many cases, the specific effects of such epigenetic changes still appear to be unknown and could conceivably impact major cellular functions like cell death and/or proliferation [64].

Apoptosis is involved in maintaining cell number in tissues, and, although increased cell proliferation is necessary, it is not sufficient for cell transformation to take place. Normally, in multicellular organisms, a dynamic balance exists between cell birth and cell death to retain constant cell numbers throughout adult life. This homeostasis depends on an integrated balance between apoptosis (cell death) and mitosis (cell division) such that these two activities are counterbalanced and equivalent. In fact, this homeostatic balance may contribute a critical

A permanent loss in homeostatic equilibrium between cell division and cell death may be a critical determinant in the transition to tumorigenesis. The increased proliferation in preneoplastic lesions is often accompanied by a parallel increase in cell death, at least in the initial stages of transformation to cancer. Quantitative histological studies in the rat liver model

defense mechanism of the cell to various genotoxic agents such as carcinogens [65].

Double-strand breaks in DNA caused by radiation can also signal apoptosis.

apoptotic pathway via cytochrome c release and caspase cascade activation [57, 58].

initiation of a cell death pathway in mitochondria [61, 62].

Cellphone radiation can increase c-fos proto-oncogene activity by more than 40% in embryonic mouse cells and alter c-jun proto-oncogene activity in rat cells [45, 46]. However, there is some conflicting data on this subject, and reports can be inconsistent, while data in humans appear to be lacking. Additionally, there is no evidence to suggest that microwaves can cause point mutations, which are associated with oncogene activation in humans and other mammals [47]. Nevertheless, the c-fos protein can induce cellular apoptosis, and the c-jun gene product has been found to be necessary for neuronal apoptosis in human and other mammalian cells [48, 49]. Microwaves can affect chromatin conformation and histone phosphorylation in human lymphocytes, as well, which may be associated with epigenetic mechanisms at the cellular level [50]. A significant increase in the efflux of calcium ions has been observed in human neuroblastoma cells at extremely low levels of microwave radiation indicating a high degree of sensitivity [51]. This cellular calcium imbalance may reflect the release of calcium ions from internal organelles like mitochondria and the endoplasmic reticulum [ER] as occurs in response to certain heavy metals, and this process is linked to an apoptotic pathway [11].

Microwaves have been reported to induce ERK-mediated apoptosis and cell cycle arrest in a dose-dependent manner in a human natural killer cell line (NK-92) just 1 hour after exposure, which could lead to general immune suppression and the development of tumors [13]. Activation of the Ras/Raf/ERK pathway has been associated with both the intrinsic mitochondrial and the extrinsic death receptor apoptotic pathways [52]. Continuous microwave irradiation (2.45 GHz) can cause Fas-induced apoptosis via the extrinsic death receptor pathway in a human Jurkat T-cell line [14]. Fas is a member of the tumor necrosis factor receptor (TNFR)/ nerve growth receptor (NGR) family. In another recent study, microwave radiation exposure from a GSM cellphone simulator (900 MHz) also resulted in a significant increase in the apoptotic rate of a human T-cell line (Jurkat cells) [53]. In addition, the formation of ROS in normal human peripheral blood mononuclear cells can stimulate apoptosis in response to 900 MHz cellphone radiation. In this case, apoptosis is induced via the mitochondrial pathway and is mediated by ROS [54]. Finally, apoptosis can be stimulated in human brain glioblastoma cells directly in response to microwaves. EMR exposure in the cell base station frequency range [1800 MHz] induces apoptosis-related events such as ROS bursts and oxidative DNA damage, which in turn promote p53-dependent caspase-3 activation through release of cytochrome c from mitochondria [12].
