Extremely Low-Frequency Electromagnetic Fields Cause G1 Phase Arrest through the Activation of the ATM-Chk2-p21 Pathway

In daily life, humans are exposed to the extremely low-frequency electromagnetic fields (ELF-EMFs) generated by electric appliances, and public concern is increasing regarding the biological effects of such exposure. Numerous studies have yielded inconsistent results regarding the biological effects of ELF-EMF exposure. Here we show that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, inhibiting cell proliferation. To present well-founded results, we comprehensively evaluated the biological effects of ELF-EMFs at the transcriptional, protein, and cellular levels. Human HaCaT cells from an immortalized epidermal keratinocyte cell line were exposed to a 1.5 mT, 60 Hz ELF-EMF for 144 h. The ELF-EMF could cause G1 arrest and decrease colony formation. Protein expression experiments revealed that ELF-EMFs induced the activation of the ATM/Chk2 signaling cascades. In addition, the p21 protein, a regulator of cell cycle progression at G1 and G2/M, exhibited a higher level of expression in exposed HaCaT cells compared with the expression of sham-exposed cells. The ELF-EMF-induced G1 arrest was diminished when the CHK2 gene expression (which encodes checkpoint kinase 2; Chk2) was suppressed by specific small interfering RNA (siRNA). These findings indicate that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, resulting in cell cycle arrest at the G1 phase. Based on the precise control of the ELF-EMF exposure and rigorous sham-exposure experiments, all transcriptional, protein, and cellular level experiments consistently supported the conclusion. This is the first study to confirm that a specific pathway is triggered by ELF-EMF exposure.

• Publication year

  2014

• Venue

  PLoS ONE

• Publication date

  2014-08-11

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1371/journal.pone.0104732PMID 25111195PMCID 4128733
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Radiation Therapy-Induced Tumor Invasiveness Is Associated with SDF-1-Regulated Macrophage Mobilization and Vasculogenesis

  2013cited by this paper
• Control of cell cycle transcription during G1 and S phases

  2013cited by this paper
• Comparative Transcriptome Profiling of an SV40-Transformed Human Fibroblast (MRC5CVI) and Its Untransformed Counterpart (MRC-5) in Response to UVB Irradiation

  2013cited by this paper
• Intra- and Inter-Individual Variance of Gene Expression in Clinical Studies

  2012cited by this paper
• Corrigendum to “Effects of 50 Hz sinusoidal electromagnetic fields of different intensities on proliferation, differentiation and mineralization potentials of rat osteoblasts” [Bone 49 (2011) 753–761]

  2012cited by this paper
• The Proliferative Response of NB69 Human Neuroblastoma Cells to a 50 Hz Magnetic Field is mediated by ERK1/2 Signaling

  2012cited by this paper
• Genome‐wide transcription analysis of Escherichia coli in response to extremely low‐frequency magnetic fields

  2012cited by this paper
• Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines.

  2012cited by this paper
• Using model organism Saccharomyces cerevisiae to evaluate the effects of ELF‐MF and RF‐EMF exposure on global gene expression

  2012cited by this paper
• Gene expression in the mammary gland tissue of female Fischer 344 and Lewis rats after magnetic field exposure (50 Hz, 100 μT) for 2 weeks

  2012cited by this paper
• Repeated Small Perturbation Approach Reveals Transcriptomic Steady States

  2011cited by this paper
• Effects of 50 Hz sinusoidal electromagnetic fields of different intensities on proliferation, differentiation and mineralization potentials of rat osteoblasts.

  2011cited by this paper
• Inactivation of ataxia telangiectasia mutated gene can increase intracellular reactive oxygen species levels and alter radiation-induced cell death pathways in human glioma cells

  2011cited by this paper
• UVB Radiation Induces Persistent Activation of Ribosome and Oxidative Phosphorylation Pathways

  2009cited by this paper
• Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production

  2008cited by this paper
• Cell-cycle control and cortical development

  2007cited by this paper
• Cell type specific redox status is responsible for diverse electromagnetic field effects.

  2007cited by this paper
• Gene expression profiling of human endothelial cells exposed to 50-Hz magnetic fields fails to produce regulated candidate genes

  2006cited by this paper
• Gene expression analysis of ELF-MF exposed human monocytes indicating the involvement of the alternative activation pathway.

  2006cited by this paper
• p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2

  2005cited by this paper
• Cell type-specific genotoxic effects of intermittent extremely low-frequency electromagnetic fields.

  2005cited by this paper
• Extremely Low-Frequency Electromagnetic Fields do not Affect DNA Damage and Gene Expression Profiles of Yeast and Human Lymphocytes

  2005cited by this paper
• Mammalian cyclin-dependent kinases.

  2005cited by this paper
• C/EBPα Is a DNA Damage-Inducible p53-Regulated Mediator of the G1 Checkpoint in Keratinocytes

  2004cited by this paper
• Absence of genotoxicity in human blood cells exposed to 50 Hz magnetic fields as assessed by comet assay, chromosome aberration, micronucleus, and sister chromatid exchange analyses

  2004cited by this paper
• Comment on: Non-ionizing radiation, Part 1: Static and extremely low-frequency electric and magnetic fields, International Agency for Research on Cancer (IARC) Monograph (Vol. 80), 2002.

  2003cited by this paper
• Effects of extremely low frequency (50 Hz) magnetic field on morphological and biochemical properties of human keratinocytes

  2002cited by this paper
• Analysis of the ultraviolet B response in primary human keratinocytes using oligonucleotide microarrays

  2002cited by this paper
• Non-ionizing radiation, Part 1: static and extremely low-frequency (ELF) electric and magnetic fields.

  2002cited by this paper
• Genomic scale analysis of the human keratinocyte response to broad‐band ultraviolet‐B irradiation

  2002cited by this paper
• Non-ionizing Radiation, Part 1: Static and Extremely Low-frequency (elf) Electric and Magnetic Fields,

  2002cited by this paper
• Haemopoietic cell proliferation in murine bone marrow cells exposed to extreme low frequency (ELF) electromagnetic fields.

  2001cited by this paper
• Rays and arrays: the transcriptional program in the response of human epidermal keratinocytes to UVB illumination

  2001cited by this paper
• Inhibition of proliferation of human lymphoma cells U937 by a 50 Hz electromagnetic field.

  2001cited by this paper
• Identification by cDNA microarray technology of genes modulated by artificial ultraviolet radiation in normal human melanocytes: relation to melanocarcinogenesis.

  2001cited by this paper
• Experimental design for gene expression microarrays.

  2001cited by this paper
• Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.

  2000cited by this paper
• KEGG: Kyoto Encyclopedia of Genes and Genomes

  2000cited by this paper
• Exposure to 60-Hz magnetic fields and proliferation of human astrocytoma cells in vitro.

  2000cited by this paper
• p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells

  1998cited by this paper
• Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1.

  1998cited by this paper
• Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.

  1998cited by this paper
• Effects of IL-3 gene expression on tumor response to irradiation in vitro and in vivo.

  1997cited by this paper
• CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.

  1997cited by this paper
• Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism.

  1995cited by this paper
• Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray

  1995cited by this paper
• G2/M-phase arrest and release in ataxia telangiectasia and normal cells after exposure to ionizing radiation.

  1994cited by this paper
• The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.

  1993cited by this paper
• p53 mutations in human immortalized epithelial cell lines.

  1993cited by this paper
• Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line

  1988cited by this paper

• The effect of 4.3 GHz high-power microwave exposure on human corneal epithelial cells

  2026cites this paper
• The Frequency of a Magnetic Field Determines the Behavior of Tumor and Non-Tumor Nerve Cell Models

  2025cites this paper
• Cellular and Molecular Effects of Magnetic Fields

  2024influential citation
• 50 Hz magnetic field influences caspase-3 activity and cell cycle distribution in ionizing radiation exposed SH-SY5Y neuroblastoma cells

  2024influential citation
• The Cellular Response Is Determined by a Combination of Different ELF-EMF Exposure Parameters: A Scope Review

  2024cites this paper
• The DNA damage and regulatory strategy in hematopoietic stem cells after irradiation exposure: Progress and challenges

  2023cites this paper
• Biological Effects of Magnetic Storms and ELF Magnetic Fields

  2023cites this paper
• Investigation of processes in a set for biocell modification by means of a magnetic field using an alternative current source with high output resistance

  2022cites this paper
• The distinguishing electrical properties of cancer cells.

  2022cites this paper
• Extremely Low Frequency Magnetic Fields Induce mTOR and Hsa_Circ_100338 Expression Changes in Gastric Cancer and Normal Fibroblast Cell Lines

  2022influential citation
• Differential biological responses of adherent and non-adherent (cancer and non-cancerous) cells to variable extremely low frequency magnetic fields

  2022cites this paper
• An overview of the biological effects of extremely low frequency electromagnetic fields combined with ionizing radiation.

  2022cites this paper
• Regulation of skeletal myogenesis in C2C12 cells through modulation of Pax7, MyoD, and myogenin via different low-frequency electromagnetic field energies

  2022cites this paper
• Biomaterial-based strategies for in vitro neural models.

  2022cites this paper
• Evaluation of the PTEN and circRNA-CDR1as Gene Expression Changes in Gastric Cancer and Normal Cell Lines Following the Exposure to Weak and Moderate 50 Hz Electromagnetic Fields

  2021cites this paper
• Magnetic field-induced Ca2+ intake by mesenchymal stem cells is mediated by intracellular Zn2+ and accompanied by a Zn2+ influx.

  2021cites this paper
• The effect of extremely low frequency electromagnetic fields following on upregulation of miR-21 and miR-29 in gastric cancer cell line

  2021cites this paper
• Wound Repair and Extremely Low Frequency-Electromagnetic Field: Insight from In Vitro Study and Potential Clinical Application

  2021cites this paper
• Effect of 50-Hz Magnetic Fields on Argyrophilic Nucleolar Organizer Regions in Bone Marrow Cells

  2021cites this paper
• The genotoxic effects of contrast enhanced abdominopelvic 3-tesla magnetic resonance imaging on human circulating leucocytes.

  2020cites this paper
• A novel magnetic field generating machine with a wide range of tunable parameters to study in vitro cells

  2020cites this paper
• In vitro 50 Hz magnetic field long-term exposure: Cytogenetic tests on human lymphoblastoid TK6 cells and validation of the test environment

  2020cites this paper
• Insights in the biology of extremely low-frequency magnetic fields exposure on human health

  2020cites this paper
• Evaluation of the effect of radiofrequency electromagnetic waves on radiosensitivity

  2019cites this paper
• Exploring the radiosensitizing potential of magnetotherapy: a pilot study in breast cancer cells

  2019cites this paper
• Electromagnetic Fields, Genomic Instability and Cancer: A Systems Biological View

  2019cites this paper
• DNA damage from long-term occupational exposure to extremely low frequency electromagnetic fields among power plant workers.

  2019cites this paper
• Neuroprotective Effects of Melatonin and Omega-3 on the Central Nervous System Exposed to Electromagnetic Fields in the Pre- and Postnatal Periods

  2019cites this paper
• The molecular mechanism of cell cycle arrest in the Bursa of Fabricius in chick exposed to Aflatoxin B1

  2018cites this paper
• Magnetocarcinogenesis: is there a mechanism for carcinogenic effects of weak magnetic fields?

  2018cites this paper
• The antitumor effect of static and extremely low frequency magnetic fields against nephroblastoma and neuroblastoma

  2018cites this paper
• Extremely low frequency variable electromagnetic fields affect cancer and noncancerous cells in vitro differently: Preliminary study

  2018cites this paper
• The Protective Role of Selenium in AFB1-Induced Tissue Damage and Cell Cycle Arrest in Chicken’s Bursa of Fabricius

  2018cites this paper
• Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway.

  2017cites this paper
• Pulsed or continuous electromagnetic field induce p53/p21-mediated apoptotic signaling pathway in mouse spermatogenic cells in vitro and thus may affect male fertility.

  2017cites this paper
• Modification of p21 level and cell cycle distribution by 50 Hz magnetic fields in human SH-SY5Y neuroblastoma cells

  2017influential citation
• Activation of Signaling Cascades by Weak Extremely Low Frequency Electromagnetic Fields

  2017cites this paper
• Effect of Environmental Extremely Low-Frequency Electromagnetic Fields Exposure on Inflammatory Mediators and Serotonin Metabolism in a Human Neuroblastoma Cell Line.

  2016cites this paper
• Effects of electromagnetic fields on the metabolism of lubricin of rat chondrocytes

  2016cites this paper
• The Role of Telomere Maintenance in Adult Mammalian Acute Central Nervous System Injury and Retinal Ganglion Cell Apoptosis

  2016cites this paper
• Puerarin, an isoflavone compound extracted from Gegen (Radix Puerariae Lobatae), modulates sclera remodeling caused by extremely low frequency electromagnetic fields.

  2016cites this paper
• Exposure to 900 MHz electromagnetic fields activates the mkp-1/ERK pathway and causes blood-brain barrier damage and cognitive impairment in rats.

  2015cites this paper
• Extremely low frequency electromagnetic fields affect proliferation and mitochondrial activity of human cancer cell lines

  2015cites this paper
• mTOR Activation by PI3K/Akt and ERK Signaling in Short ELF-EMF Exposed Human Keratinocytes

  2015cites this paper
• Extremely Low-Frequency Electromagnetic Fields Affect the miRNA-Mediated Regulation of Signaling Pathways in the GC-2 Cell Line

  2015cites this paper
• Effects of extremely low frequency electromagnetic field (ELF-EMF) on catalase, cytochrome P450 and nitric oxide synthase in erythro-leukemic cells.

  2015cites this paper
• Distinct Epidermal Keratinocytes Respond to Extremely Low-Frequency Electromagnetic Fields Differently

  2014cites this paper