Oxidative Stress and NADPH Oxidase: Connecting Electromagnetic Fields, Cation Channels and Biological Effects

Abstract

Oxidative Stress and NADPH Oxidase: Connecting Electromagnetic Fields, Cation Channels and Biological Effects Christos D Georgiou, Lukas H Margaritis. Oxidative Stress and NADPH Oxidase: Connecting Electromagnetic Fields, Cation Channels and Biological Effects. Int J Mol Sci. 2021 Sep 17;22(18):10041. doi: 10.3390/ijms221810041. Abstract Electromagnetic fields (EMFs) disrupt the electrochemical balance of biological membranes, thereby causing abnormal cation movement and deterioration of the function of membrane voltage-gated ion channels. These can trigger an increase of oxidative stress (OS) and the impairment of all cellular functions, including DNA damage and subsequent carcinogenesis. In this review we focus on the main mechanisms of OS generation by EMF-sensitized NADPH oxidase (NOX), the involved OS biochemistry, and the associated key biological effects. Conclusions On the basis of the above findings, an EMF mechanism can involve ROS formation due to membrane and voltage-gated cation channel function deterioration [2,3,7,8] followed by stress activation and heat-shock protein overexpression [56], which may be associated with behavioural and physiological effects such as blood– brain barrier disruption, memory malfunction, changes in gene expression [53], autophagy, apoptosis [53,84] (especially due to modulation [85]), lifespan reduction, DNA damage, and cancer [18]. Theory and Research Perspectives for a Conclusive Linking of EMFs with ROS/RNS EMF induction of OS via increased concentration of free radicals, has been challenged (by ICNIRP) mainly due to (i) the claimed non-ionizing nature of EMF (ELF/RF), where no covalent bonds are broken at non-thermal intensities, or so the argument goes, and because (ii) the measurement of OS is performed by non-specific methods. Indeed, OS is measured, either by methods that are not specific to the identification of generated free radicals, or indirectly by certain oxidative modifications they cause on key biological molecules (e.g., DNA damage, lipid/protein peroxidation, etc.). Man-made EMFs do not possess high enough energy to generate free radicals, e.g., on freely moving single H2O molecules by a single photon. However, the individual EMF of such photons are fully synchronized (in terms of frequency, polarization, phase, and propagation direction), thereby producing cumulative macroscopic electric and magnetic fields and electromagnetic radiation (EMR). Nonetheless, these may be additively high enough to break covalent bonds and may directly generate free radicals. Secondly, concentrations of naturally occurring free radicals can increase by the prevention of either (i) reactions between them (e.g., appearing as the aforementioned reactants •NO + O2•− and products •OH + •NO2), or (ii) the reassociation of free radical pairs generated enzymically as transition states. Such prevention can be assisted by the EMF-induced free radical pair mechanism [86,87]. Here, EMFs can prevent the reassociation of free radical pairs by reversing the spin direction of the single electron in one of these free radicals by flipping the direction of its magnetic field component. Thus, the magnetically affected free radical pair ends up consisting of two free radicals, the electron spins of which have become parallel, thereby preventing their re-binding and indirectly increasing their concentration. The free radical pair mechanism has been accounted for by the International Agency for Research on Cancer for the classification of the RF EMFs in the Group 2B category of “possibly carcinogenic to humans” [88]. These two mechanisms of free radical-concentration increase corroborate with the preliminary finding that ELF EMFs increase the concentration of O2•− by many fold in various organs of mice exposed to the ICNIRP limit of 100 µT at 50 Hz (pending publication by Dr. Georgiou’s lab). Therefore, methods for the in vivo specific detection of the key biological free radicals •OH and O2•− ([89,90]) are needed in order to unequivocally prove the generation of carcinogenic OS by EMFs. Open access paper: mdpi.com

AI evidence extraction

Main findings

This review proposes that EMFs can disrupt membrane electrochemical balance and voltage-gated cation channel function, which may trigger increased oxidative stress via EMF-sensitized NADPH oxidase (NOX) and lead to downstream cellular effects including DNA damage and carcinogenesis. It discusses proposed mechanisms for increased free-radical concentrations (including a free radical pair mechanism) and notes challenges raised about non-thermal EMF-induced oxidative stress and limitations of oxidative stress measurement specificity.

Outcomes measured

• oxidative stress (OS)
• reactive oxygen species (ROS) / reactive nitrogen species (RNS)
• NADPH oxidase (NOX) activation/sensitization
• membrane electrochemical balance disruption
• voltage-gated cation channel dysfunction
• DNA damage
• carcinogenesis/cancer
• heat-shock protein overexpression
• blood–brain barrier disruption
• memory malfunction
• gene expression changes
• autophagy
• apoptosis
• lifespan reduction

Limitations

• Narrative review; no primary study methods or quantitative synthesis described in the abstract.
• The abstract notes that EMF induction of oxidative stress has been challenged due to the non-ionizing/non-thermal argument and because oxidative stress is often measured with non-specific or indirect methods.
• Calls for in vivo specific detection methods for key radicals (•OH and O2•−) to more conclusively demonstrate EMF-induced oxidative stress.

Suggested hubs

• who-icnirp (0.62)
  Abstract explicitly discusses challenges raised by ICNIRP and references ICNIRP exposure limits.

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