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21 August 2024

The Role of Oxidative Stress in Hypomagnetic Field Effects

,
,
and
1
Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China
2
College of Earth and Planetary Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
3
Beijing National Observatory of Space Environment, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing 100029, China
*
Author to whom correspondence should be addressed.
Antioxidants2024, 13(8), 1017;https://doi.org/10.3390/antiox13081017
This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress
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Abstract

The geomagnetic field (GMF) is crucial for the survival and evolution of life on Earth. The weakening of the GMF, known as the hypomagnetic field (HMF), significantly affects various aspects of life on Earth. HMF has become a potential health risk for future deep space exploration. Oxidative stress is directly involved in the biological effects of HMF on animals or cells. Oxidative stress occurs when there is an imbalance favoring oxidants over antioxidants, resulting in cellular damage. Oxidative stress is a double-edged sword, depending on the degree of deviation from homeostasis. In this review, we summarize the important experimental findings from animal and cell studies on HMF exposure affecting intracellular reactive oxygen species (ROS), as well as the accompanying many physiological abnormalities, such as cognitive dysfunction, the imbalance of gut microbiota homeostasis, mood disorders, and osteoporosis. We discuss new insights into the molecular mechanisms underlying these HMF effects in the context of the signaling pathways related to ROS. Among them, mitochondria are considered to be the main organelles that respond to HMF-induced stress by regulating metabolism and ROS production in cells. In order to unravel the molecular mechanisms of HMF action, future studies need to consider the upstream and downstream pathways associated with ROS.

1. Introduction

The geomagnetic field (GMF) is crucial for the survival and evolution of life on Earth because it protects against atmospheric escape, solar wind, and cosmic rays. The elimination of the GMF, known as the hypomagnetic field (HMF), poses risks for astronauts during deep space exploration, as well as for all life during geomagnetic reversals. Paleomagnetic studies have indicated that during reversals, the dipole field strength can decrease by up to 90% at Earth’s surface. This weakens the protection of the GMF, leading to increased radiation on the surface of Earth, exposing all life to the HMF and a strong radiation environment for thousands of years [1,2,3]. The change in Earth’s environment has a profound impact on the evolution and survival of living organisms. Therefore, the role of the GMF on life is composed of two different scales: The GMF’s impact on the origins and evolution of life on Earth and its influence on living organisms’ physiology and behaviors. Although the evolutionary effect of GMF reversals on life is still not fully understood, major variations in the GMF correlate with major geological and biological processes [4,5]. As we look towards future space exploration, astronauts will encounter extremely weak magnetic field conditions, such as in interstellar space (2–8 nT), on the Moon (9–300 nT), and on Mars (10 nT–5 µT) [6,7,8]. These weak magnetic fields could have a negative impact on astronauts’ health. In this article, we focus on the influence of the elimination of GMF on various aspects of animals’ health. Numerous studies have shown that HMF exposure causes many adverse biological effects at both a cellular and organism levels, with changes in the intracellular levels of reactive oxygen species (ROS) often occurring in response to HMF exposure [9,10,11].
ROS belong to a large group of oxidants derived from molecular oxygen [12,13]. Oxidative stress occurs when there is an imbalance favoring oxidants over antioxidants, leading to redox signaling disruption and/or molecular damage. In recent years, with a better understanding of the roles of different ROS in cells, “oxidative stress” has come to encompass two meanings: elevated levels of ROS cause molecular damage, known as ‘oxidative stress’, and physiological levels of ROS play key roles in redox signaling through post-translational modifications, known as ‘oxidative eustress’ [14,15]. ROS are essential for cellular signaling and response to stress, which contribute to both physiological and pathological conditions. Moderate ROS levels serve as signaling molecules and are essential for cellular functions and various pathologies [16]. ROS assist the host in combating micro-organisms and also participate in intermicrobial competition. For instance, mouse peritoneal macrophages can be stimulated to release H2O2 against micro-organisms into the extracellular medium [17], while excess ROS levels incur damage to DNA, protein, or lipids, widely associated with dysfunction and disease. The interaction of ROS with nitrogenous bases and deoxyribose results in significant oxidative DNA damage, leading to mutations, carcinogenesis, apoptosis, necrosis, and hereditary diseases [18]. Most cancers are believed to have a direct connection to ROS-induced mitochondrial dysfunction. This direct relationship between ROS and cancer has also been identified in other conditions, such as Alzheimer’s and Type 2 diabetes [19]. Research indicates that HMFs have a significant impact on cellular ROS levels, altering physiological and biological processes in organisms [20,21]. Signaling pathways associated with ROS regulation may be linked to many biological effects caused by HMF exposure. Here, we outline the upstream and downstream signaling pathways of ROS and propose the possible molecular mechanisms underlying the HMF action.

2. Types of ROS

ROS encompass molecules derived from O2, including superoxide (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH). Superoxide dismutases (SODs) catalyze the dismutation of O2•− to H2O2. H2O2 is reduced by many kinds of enzymes (antioxidants), including catalase, peroxiredoxins (PRDXs), glutathione peroxidases (GPXs), and other peroxidases (cytochrome c). Catalase is one of the key antioxidant enzymes that destroys cellular hydrogen peroxide to produce water and oxygen to relieve oxidative stress [22]. O2•− can damage various cellular components and indirectly affect signaling pathways [18,23]. H2O2 serves as a signaling molecule through the reversible oxidation of cysteine residues within proteins, which is involved in redox signaling at specific concentrations. For example, the thiolate anion of cysteine residues is oxidized to sulfenic form (Cys-SOH) by low levels of H2O2, which alters the function of protein during redox signaling [24,25], while higher levels of H2O2 further oxidize thiolate anions to sulfinic (SO2H) or sulfonic (SO3H) species to cause permanent protein damage [18]. The most harmful effect of H2O2 is its reaction with transition metals such as ferrous iron (Fe2+) to produce hydroxyl radicals (•OH), known as the Fenton reaction. •OH is a powerful oxidant that indiscriminately oxidizes lipids, proteins, and DNA, causing significant damage and genomic instability. In addition, other oxygen-containing free radicals can also cause oxidation of essential cellular components, including peroxynitrite, lipid hydroperoxides (LOOH), alkoxyl radical (RO•), peroxyl radical (ROO•), sulfate radical (SO4•−), and Fenton reaction intermediates [26,27]. Here, we mainly discuss two types of ROS involved in the biological effects of HMF: O2•− and H2O2.

3. ROS Homeostasis

ROS levels are strictly controlled by multiple ROS-generating and ROS-eliminating systems, which actively maintain the intracellular redox state in cells. Production of O2•− is primarily from the mitochondrial respiratory chain and the NADPH oxidases (NOXs) in cells. NOXs are transmembrane enzymes responsible for the production of O2•− via electron transfer across membranes from NAD(P)H to molecular oxygen [28]. NOXs produce superoxide primarily on the intracellular side of membranes. The human NOXs family consists of Nox1–5, Duox1, and Duox2. The classic activity control of Nox enzymes is exerted by calcium or protein–protein interactions and post-translational modifications (PTMs). Phosphorylation, acetylation, methylation, and glycosylation are the most studied PTMs in cells. The activities of Nox5 and the Duox enzymes are calcium-dependent, and the activity controls of Nox1, Nox2, and Nox3 are regulated through interactions with the cytosolic proteins, such as the small GTPase Rac [29]. Interactions between different oxidases or oxidase systems play key roles in oxidative stress. Activation of NOX induces activation of downstream secondary oxidase systems, including uncoupled endothelial nitric oxide synthase and xanthine oxidase [30].
Mitochondrial electron transport chain (ETC) complexes I and III are the main sites of O2•− production where the leaking O2 is reduced to O2•−. The NADH and FADH2 donate electrons to the ETC. Thus, the ratio of NADH to NAD+ regulates O2•− production [22,31]. Therefore, there is a close relationship between mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial ROS (mtROS) generated by the ETC. The mtROS production depends on the metabolic state of mitochondria in cells [32]. In response to the electron transport, protons (H+) are pumped from the matrix into the intermembrane space to form mitochondrial membrane potential (ΔΨm). ATP synthase uses the energy of proton gradient to produce ATP. However, uncoupling proteins (UCPs) break the perfect coupling between proton gradient and ATP synthase, mediating a small amount of H+ to flow into the matrix to reduce ATP synthesis. Therefore, UCPs are able to reduce the efficiency of OXPHOS, thereby reducing ROS production [33]. Other than mitochondria and NOXs, other sources of ROS production include xanthine oxidase (XO) and cyclooxygenases (COXs) [34].
ROS are counterbalanced by antioxidant networks, which modulate ROS levels to allow their physiological roles. ROS-eliminating systems and antioxidants include GPXs, thioredoxin peroxidases (TRXPs), SODs, PRDXs, glutathione (GSH), thioredoxin 2 (TRX2), glutaredoxin 2 (GRX2), ascorbic acid, tocopherol, vitamin E, and carotene [35]. For example, SODs convert O2•− to H2O2, which can then be converted by catalase to harmless H2O [32,36].

4. Changes in Cellular ROS Levels Caused by HMF

The effects of HMF on living organisms are diverse, including different effects ranging from cells, tissues, and organs to organisms. For instance, HMF has significant negative effects on early development, circadian rhythms, and the central nervous system in animals [9,37]. However, the mechanisms underlying these effects are still not well understood. Here, we summarize published studies on the effects of HMFs on ROS within animal cells or organisms (Table 1), excluding studies on plants or micro-organisms. HMF generally reduced H2O2 levels within cells, accompanied by changes in cell behavior and gene expression in in vitro studies (Table 1). HMF in the range of 0.2–0.5 μT inhibited the proliferation and eNOS expression in endothelial cells [38], while HMFs (0.5–2 μT) suppressed H2O2 production in cancer cells and bovine pulmonary artery endothelial cells (PAEC). This effect can be inhibited by antioxidants like catalase and SOD mimetic MnTBAP [39]. HMF (<0.2 μT) reduced H2O2 levels in human neuroblastoma cells by inhibiting the activity of CuZn-SOD, and the enhanced cell proliferation caused by HMF can be remedied by additional H2O2 supplementation [40]. HMF (20 nT) also reduced ROS production in mice peritoneal neutrophils by affecting NOX activity and mitochondrial ETC [41,42]. However, an in vitro study of mouse skeletal muscle cells showed that HMF (<3 μT) could cause an increase in its ROS levels, leading to a decrease in cell function [43].
Table 1. ROS changes caused by HMF at cellular level.
As shown in Table 2, we have found that HMF (0.29 ± 0.01 μT) reduced endogenous ROS in adult hippocampal neural stem cells, further affecting cognitive function of the hippocampus in mice [11]. ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors. Further, in vivo research on other hippocampal cells in the mouse hippocampus revealed that HMF (31.9 ± 4.5 nT) significantly increased its ROS levels by decreasing the expression of antioxidant genes, which may cause oxidative stress damage to the overall hippocampus and further affect anxiety and cognitive behavior in mice [44,45]. HMF can cause bone loss in mammals. For instance, HMF (<300 nT) promotes additional bone loss in the mouse femur during mechanical unloading, likely due to iron overload, exacerbating oxidative stress and thereby inhibiting osteoblast activity [46,47]. Other research showed that under particular conditions of oxidative stress, HMF (0.192 μT) could disrupt the functional state of erythrocytes and promote cell death in rats [48]. In addition, neuroinflammation regulates stem cell niches, particularly neural stem/progenitor cells in mammals. We have found that HMF (31.1 ± 2.0 nT) may also cause neuroinflammation in the hippocampus of mice, manifested by the activation of microglia and upregulation of GFAP expression in astrocytes [49]. This may be closely related to the increase in ROS in hippocampal cells [44,45]. In the biological effects of HMF, changes in ROS levels in cells are often accompanied by changes in cell number, proliferation, and survival; changes in the expression level of antioxidant genes; and even behavioral abnormalities, such as a decline in cognitive and orientation abilities, in animals (Table 1 and Table 2). The different results of HMF affecting ROS levels may be related to the differences in magnetic strength, duration of exposure, cell type, or method of HMF generation.
Table 2. ROS changes caused by HMF at organism level.

6. Conclusions

HMF has been found to cause cognitive dysfunction, anxiety-related behaviors, circadian disorders, gut dysbiosis, reproductive and developmental abnormalities, and osteoporosis in animals [37]. These functional abnormalities in animals may be linked to cellular-level effects caused by HMF. For example, HMF inhibited adult hippocampal neurogenesis, led to high ROS levels and inflammation in the hippocampus, and altered the concentrations of melatonin and norepinephrine in animals. These effects may collectively contribute to cognitive impairment in the animals. HMF also leads to osteoporosis by inhibiting osteoblast differentiation and mineralization. ROS may play key roles in the regulatory mechanisms behind these HMF effects through one or more signaling pathways. However, the question of which biological effects caused by HMF are regulated by ROS-regulated signaling pathways needs to be confirmed in future studies. Mitochondria are considered to be the primary organelles responding to HMF-induced stress. Changes in NOX activity and mitochondrial dynamics and function caused by HMF affect the cellular ROS level. H2O2 acts as a second messenger molecule or oxidative stress, leading to a series of downstream cascades. To reveal the molecular mechanism of HMF effects, the upstream and downstream pathways related to ROS need to be considered in future studies. Therapeutic methods targeting oxidative stress and mitochondrial dysfunction could be developed to mitigate the negative effects of HMF in the future.

Author Contributions

Conceptualization, L.T.; writing—original draft preparation, L.T.; writing—review and editing, L.T., Y.L., J.R. and C.Z.; visualization, L.T. and Y.L.; supervision, L.T.; project administration, L.T.; funding acquisition, L.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China, grant numbers 42388101 and 42274099, and the CAS Project for Young Scientists in Basic Research, grant number YSBR-097.

Acknowledgments

We would like to thank Juan Wan for the helpful discussion.

Conflicts of Interest

The authors declare no conflicts of interest.

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