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

With the rapid increase in the number of mobile phone users, the potential adverse effects of the electromagnetic field radiation emitted by a mobile phone has become a serious concern. This study demonstrated, for the first time, the blood-brain barrier and cognitive changes in rats exposed to 900 MHz electromagnetic field (EMF) and aims to elucidate the potential molecular pathway underlying these changes. A total of 108 male Sprague-Dawley rats were exposed to a 900 MHz, 1 mW/cm(2) EMF or sham (unexposed) for 14 or 28 days (3h per day). The specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). In addition, the Morris water maze test was used to examine spatial memory performance determination. Morphological changes were investigated by examining ultrastructural changes in the hippocampus and cortex, and the Evans Blue assay was used to assess blood brain barrier (BBB) damage. Immunostaining was performed to identify heme oxygenase-1 (HO-1)-positive neurons and albumin extravasation detection. Western blot was used to determine HO-1 expression, phosphorylated ERK expression and the upstream mediator, mkp-1 expression. We found that the frequency of crossing platforms and the percentage of time spent in the target quadrant were lower in rats exposed to EMF for 28 days than in rats exposed to EMF for 14 days and unexposed rats. Moreover, 28 days of EMF exposure induced cellular edema and neuronal cell organelle degeneration in the rat. In addition, damaged BBB permeability, which resulted in albumin and HO-1 extravasation were observed in the hippocampus and cortex. Thus, for the first time, we found that EMF exposure for 28 days induced the expression of mkp-1, resulting in ERK dephosphorylation. Taken together, these results demonstrated that exposure to 900 MHz EMF radiation for 28 days can significantly impair spatial memory and damage BBB permeability in rat by activating the mkp-1/ERK pathway.

[1]  Jike Lu,et al.  Analgesic effect of electroacupuncture on chronic neuropathic pain mediated by P2X3 receptors in rat dorsal root ganglion neurons , 2012, Neurochemistry International.

[2]  C. Yardin,et al.  Apoptosis is Induced by Radiofrequency Fields through the Caspase-Independent Mitochondrial Pathway in Cortical Neurons , 2008, Radiation research.

[3]  Ian C. Hsu,et al.  Extremely Low-Frequency Electromagnetic Fields Cause G1 Phase Arrest through the Activation of the ATM-Chk2-p21 Pathway , 2014, PloS one.

[4]  Ersan Odaci,et al.  Effects of prenatal exposure to a 900 MHz electromagnetic field on the dentate gyrus of rats: a stereological and histopathological study , 2008, Brain Research.

[5]  Bertil R. R. Persson,et al.  Blood-Brain Barrier Permeability and Nerve Cell Damage in Rat Brain 14 and 28 Days After Exposure to Microwaves from GSM Mobile Phones , 2008, Electromagnetic biology and medicine.

[6]  P. Andersen,et al.  Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  P. Radermacher,et al.  Involvement of heme oxygenase-1 (HO-1) in the adaptive protection of human lymphocytes after hyperbaric oxygen (HBO) treatment. , 2001, Carcinogenesis.

[8]  Frank S. Prato,et al.  Magnetic resonance imaging temporarily alters blood-brain barrier permeability in the rat , 1987, Neuroscience Letters.

[9]  Riccardo Russo,et al.  Does acute exposure to mobile phones affect human attention? , 2006, Bioelectromagnetics.

[10]  S. J. Martin,et al.  The rodent hippocampus and spatial memory: from synapses to systems , 2007, Cellular and Molecular Life Sciences.

[11]  M. Mailankot,et al.  Spatial Memory Perfomance of Wistar Rats Exposed to Mobile Phone , 2009, Clinics.

[12]  A. Guy,et al.  Opioid receptor subtypes that mediate a microwave-induced decrease in central cholinergic activity in the rat. , 1992, Bioelectromagnetics.

[13]  Jacob Eberhardt,et al.  Cognitive impairment in rats after long‐term exposure to GSM‐900 mobile phone radiation , 2008, Bioelectromagnetics.

[14]  Y. Mei,et al.  Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE2 and EP Receptor-Mediated cAMP/PKA Pathway , 2013, PloS one.

[15]  Wei Chen,et al.  Differential regulation and properties of MAPKs , 2007, Oncogene.

[16]  Fabrizio Mancinelli,et al.  Electromagnetic fields at mobile phone frequency induce apoptosis and inactivation of the multi‐chaperone complex in human epidermoid cancer cells , 2005, Journal of cellular physiology.

[17]  H. Konno,et al.  Forebrain ischemia induced by temporary bilateral common carotid occlusion in normotensive rats , 1989, Journal of the Neurological Sciences.

[18]  Yanjun Zeng,et al.  Effects of long-term electromagnetic field exposure on spatial learning and memory in rats , 2013, Neurological Sciences.

[19]  Jianhong Luo,et al.  Chronic exposure to GSM 1800-MHz microwaves reduces excitatory synaptic activity in cultured hippocampal neurons , 2006, Neuroscience Letters.

[20]  Matti Laine,et al.  Pulsed and continuous wave mobile phone exposure over left versus right hemisphere: Effects on human cognitive function , 2007, Bioelectromagnetics.

[21]  K. Muraszko,et al.  Role of Iron in Brain Injury After Intraventricular Hemorrhage , 2011, Stroke.

[22]  R. de Seze,et al.  Effect of an acute 900MHz GSM exposure on glia in the rat brain: a time-dependent study. , 2007, Toxicology.

[23]  Antti Juvonen,et al.  Mobile Phone Radiation and the Developing Brain: Behavioral and Morphological Effects in Juvenile Rats , 2007, Radiation research.

[24]  Jacob Raber,et al.  Radiation-Induced Cognitive Impairments are Associated with Changes in Indicators of Hippocampal Neurogenesis , 2004, Radiation research.

[25]  H. Kimelberg,et al.  Neuronal–glial interactions and behaviour , 2000, Neuroscience & Biobehavioral Reviews.

[26]  C. Paz,et al.  Modulation of albumin-induced endoplasmic reticulum stress in renal proximal tubule cells by upregulation of mapk phosphatase-1. , 2013, Chemico-biological interactions.

[27]  Yi Zhang,et al.  Exposure to 1950-MHz TD-SCDMA Electromagnetic Fields Affects the Apoptosis of Astrocytes via Caspase-3-Dependent Pathway , 2012, PloS one.

[28]  Jacob Eberhardt,et al.  Increased blood-brain barrier permeability in mammalian brain 7 days after exposure to the radiation from a GSM-900 mobile phone. , 2009, Pathophysiology : the official journal of the International Society for Pathophysiology.

[29]  S. Vandenberg,et al.  Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice , 2004, Experimental Neurology.

[30]  M. Pallàs,et al.  A new method for determining blood–brain barrier integrity based on intracardiac perfusion of an Evans Blue–Hoechst cocktail , 2008, Journal of Neuroscience Methods.

[31]  E. Odacı,et al.  Chronic prenatal exposure to the 900 megahertz electromagnetic field induces pyramidal cell loss in the hippocampus of newborn rats , 2009, Toxicology and industrial health.

[32]  P. Dimbylow,et al.  SAR calculations in an anatomically realistic model of the head for mobile communication transceivers at 900 MHz and 1.8 GHz. , 1994, Physics in medicine and biology.

[33]  Val Gebski,et al.  Effect of long‐term mobile communication microwave exposure on vascular permeability in mouse brain , 2002, Pathology.

[34]  R. Morris,et al.  Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning , 1990, The European journal of neuroscience.

[35]  R. Morris.  Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[36]  Niyazi Acer,et al.  900 MHz electromagnetic field exposure affects qualitative and quantitative features of hippocampal pyramidal cells in the adult female rat , 2009, Brain Research.

[37]  Süleyman Kaplan,et al.  Purkinje cell number decreases in the adult female rat cerebellum following exposure to 900MHz electromagnetic field , 2010, Brain Research.

[38]  Leeka Kheifets,et al.  EMF and health. , 2005, Annual review of public health.

[39]  L. Noble,et al.  Induction of heme oxygenase-1 after hyperosmotic opening of the blood-brain barrier , 1998, Brain Research.

[40]  C. Kamei,et al.  Interaction between hippocampal gamma-aminobutyric acid(A) and N-methyl-D-aspartate receptors in the retention of spatial working memory in rats. , 2010, Biological & pharmaceutical bulletin.