Deficits in water maze performance and oxidative stress in the hippocampus and striatum induced by extremely low frequency magnetic field exposure.

Abstract

The exposures to extremely low frequency magnetic field (ELF-MF) in our environment have dramatically increased. Epidemiological studies suggest that there is a possible association between ELF-MF exposure and increased risks of cardiovascular disease, cancers and neurodegenerative disorders. Animal studies show that ELF-MF exposure may interfere with the activity of brain cells, generate behavioral and cognitive disturbances, and produce deficits in attention, perception and spatial learning. Although, many research efforts have been focused on the interaction between ELF-MF exposure and the central nervous system, the mechanism of interaction is still unknown. In this study, we examined the effects of ELF-MF exposure on learning in mice using two water maze tasks and on some parameters indicative of oxidative stress in the hippocampus and striatum. We found that ELF-MF exposure (1 mT, 50 Hz) induced serious oxidative stress in the hippocampus and striatum and impaired hippocampal-dependent spatial learning and striatum-dependent habit learning. This study provides evidence for the association between the impairment of learning and the oxidative stress in hippocampus and striatum induced by ELF-MF exposure.

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Deficits in Water Maze Performance and Oxidative Stress
in the Hippocampus and Striatum Induced by Extremely
Low Frequency Magnetic Field Exposure
Yonghua Cui1., Zhiqiang Ge1., Joshua Dominic Rizak2., Chao Zhai1, Zhu Zhou1, Songjie Gong1, Yi Che1*
1Medical College of Soochow University, Suzhou, People’s Republic of China, 2Laboratory of Primate Neuroscience Research, Key Laboratory of Animal Models, Kunming
Institute of Zoology, Chinese Academy of Science, Kunming, People’s Republic of China
Abstract
The exposures to extremely low frequency magnetic field (ELF-MF) in our environment have dramatically increased.
Epidemiological studies suggest that there is a possible association between ELF-MF exposure and increased risks of
cardiovascular disease, cancers and neurodegenerative disorders. Animal studies show that ELF-MF exposure may interfere
with the activity of brain cells, generate behavioral and cognitive disturbances, and produce deficits in attention, perception
and spatial learning. Although, many research efforts have been focused on the interaction between ELF-MF exposure and
the central nervous system, the mechanism of interaction is still unknown. In this study, we examined the effects of ELF-MF
exposure on learning in mice using two water maze tasks and on some parameters indicative of oxidative stress in the
hippocampus and striatum. We found that ELF-MF exposure (1 mT, 50 Hz) induced serious oxidative stress in the
hippocampus and striatum and impaired hippocampal-dependent spatial learning and striatum-dependent habit learning.
This study provides evidence for the association between the impairment of learning and the oxidative stress in
hippocampus and striatum induced by ELF-MF exposure.
Citation: Cui Y, Ge Z, Rizak JD, Zhai C, Zhou Z, et al. (2012) Deficits in Water Maze Performance and Oxidative Stress in the Hippocampus and Striatum Induced by
Extremely Low Frequency Magnetic Field Exposure. PLoS ONE 7(5): e32196. doi:10.1371/journal.pone.0032196
Editor: Paul A Adlard, Mental Health Research Institute and the University of Melbourne, Australia
Received July 16, 2011; Accepted January 24, 2012; Published May 3, 2012
Copyright: ? 2012 Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by National Basic Research Program of China, Chinese National Science Foundation (31172089). The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: cheyiwenshan@sina.com
. These authors contributed equally to this work.
Introduction
The exposures to extremely low frequency magnetic field (ELF-
MF) in our environment have dramatically increased, which
include both occupational exposure and general exposure to
sources, such as power lines, household electrical wiring and
medical devices [1]. Epidemiological studies suggest that there is
a possible association between ELF-MF exposure and increased
risks of cardiovascular disease, cancers and neurodegenerative
disorders [2–6]. Additionally, animal studies have shown that
ELF-MF exposure (50 Hz, 1 mT) generated behavioral and
cognitive disturbances, and produced deficits in attention,
perception and spatial learning in rats [7]. Our research group
has also demonstrated that ELF-MF exposure (50 Hz, 1 mT)
induced significant impairments in detour learning and one-trial
passive avoidance learning in chicks [8,9].
Although, many research efforts have been focused on the
interaction between ELF-MF exposure and the central nervous
system, the mechanism of interaction is still unknown [10,11].
Some reports suggested that ELF-MF exposure may affect
biological systems by increasing the life span and concentration
of reactive oxygen species (ROS) and free radicals [12,13,14]. Lai
and Singh reported that ELF-MF exposure (60 Hz, 0.01 mT)
caused DNA damage in rat brain cells with the involvement of
oxygen free radical processes [15], Ravera et al. reported that ELF-
MF exposure (75 Hz, 0.74 mT) decreased the activity of different
membrane-anchored enzymes [16], Amara et al. reported that
subchronic static magnetic fields exposure (128 mT) induced
oxidative stress in the rat hippocampus and frontal cortex [17],
and Jelenkovic et al. reported that ELF-MF exposure (50 Hz,
0.5 mT) was harmful to the brain, especially to the basal forebrain
and frontal cortex due to development of lipid peroxidation [18].
It is well known that the increases of free radicals lead to
oxidative damage in major cell macromolecules such as proteins,
lipids, and nucleic acids. The brain tissues, especially the
hippocampal and striatum neurons, are considered particularly
vulnerable to oxidative damage because of their high lipid content,
enrichment in mitochondria, comparatively high oxygen utiliza-
tion, and modest antioxidant defences [19].
Previous studies have emphasized the effects of ELF-MF
exposure on learning behavior and on the antioxidant status of
various tissues and organs. However, no reports have been found
in the literature to provide direct evidence that the impairment of
learning induced by ELF-MF exposure involves oxidative stress.
Therefore, it seemed reasonable to verify the hypothesis that ELF-
MF exposure induces oxidative stress in some brain areas,
damages the brain structure and function, and then impairs
learning ability. The present investigation was designed to evaluate
the effects of chronic ELF-MF exposure on habit learning which is
dependent on striatum [20,21], and on spatial learning which is
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dependent on hippocampus [20,22], as well as evaluate some
parameters indicative of oxidative stress in these two structures.
We believe that this study may provide more evidence for the
hypothesis that the impairment of learning induced by ELF-MF
exposure involves oxidative stress.
Materials and Methods
Ethics Statement
All experiments were conducted during the light phase, and in
accordance with procedures approved by Animal Experimental
Committee, Soochow University, and with the National Institutes
of Health Guidelines for the Care and Use of Laboratory Animals
(NIH Guidelines).
Subjects
Seventy-two adult male C57BL/6 mice weighing 19,21 g at
the beginning of the experiment were housed in pairs in plexiglas
cages with food and water ad libitum throughout the experimental
period. The mice were maintained in a climate-controlled colony
room at 24uCon a 12/12 h reverse light/dark cycle. All mice were
allowed 1 week adaptation to the housing rooms prior to the
initiation of treatment. After adapting, mice received ELF-MF
exposure 4 hours/day for 12 consecutive weeks. Mice were
randomly assigned to three groups (n=24 animals/group). Group
I received sham ELF-MF exposure 4 hours/day. Sham-exposed
mice were placed in a similar, but non-energized apparatus.
Group II received 50 Hz, 1 mT ELF-MF exposure 4 hours/day.
Group III received 50 Hz, 0.1 mT ELF-MF exposure 4 hours/
day.
After the exposure period, all mice were evaluated in an open-
field test and with a water-maze learning and memory task.
Following these evaluations, the animals were slightly anesthetized
and sacrificed by decapitation. Their brains were rapidly removed,
and the hippocampus and striatum were carefully dissected out
according to a mouse brain atlas with a previously described
method [23].
Magnetic Field Exposure System
As previously described [9], the electromagnetic field was
generated by a single coil of four layers, each having 250 turns.
Each layer was wrapped horizontally above the previous layer
around a 70 cm640 cm643 cm plastic frame. The coil was
connected to a waveform generator for modulating the frequency
and intensity of the electromagnetic field. By varying the input
current to the coil, the flux density of electromagnetic fields in the
exposure area can be adjusted from ambient levels to the
maximum coil-designed electromagnetic field strength of 14 mT.
The exposure area (60 cm630 cm643 cm) was inside the coil.
During exposure,mice were
(50 cm625 cm, with 25 cm high walls) which was mechanically
isolated from the magnet and rested on a freestanding wood. The
mice were free to move about the box ad libitum. The variation of
the electromagnetic fields in the plastic box was 64.5% of the
mean and was determined by measurement with a Gaussmeter.
placed ina plastic box
Open Field Test
In order to determine whether ELF-MF exposure produced
ataxia or motor impairments in the mice, locomotor activity was
monitored in an open field enclosed in a black Plexiglas square box
(40640630 cm). The open field tests were conducted after the 12
weeks of ELF-MF exposure. On the test day, mice were placed in
the center of the black Plexiglas square box (40640630 cm) for
a 5 min. Mice activity was recorded with a video camera that was
connected to a computer.
Water Maze Test
The mice were submitted to two versions of the water maze task
after the open field test. The water maze consisted of a round tank,
110 cm in diameter and 30 cm deep, filled with water. The water
temperature was maintained at 25uC. Several visual cues were
placed on the walls of the laboratory. The latency to reach the
escape platform was recorded with a video camera that was
connected to a computer.
Thirty-six mice (n=12/group) were submitted to a spatial
reference memory version of the water maze. This consisted of 4
training days, four consecutive trials per day, during which the
animals were randomly left in the tank facing the wall, and allowed
to swim freely to a transparent escape platform (8 cm in diameter)
submersed 2 cm under the water surface, placed in the center of
one of the four imaginary quadrants of the tank. The escape
platform position was maintained constant throughout all 4
training days. After the animal escaped to the platform it was
allowed to remain on it for 30 s and was then removed from the
tank for 30 s before being placed in the next random initial
position. If the animal did not find the platform during a period of
60 s it was gently guided to it [20].
The other thirty-six mice (n=12/group) were submitted to a cue
version of the water maze similar to the previous experimental
procedure, except that the position of the escape platform was
cued by a yellow ping-pong ball attached to the top of the platform
and floating above the water. Additionally, the position of the
platform was always changed in this version of the water maze for
each trial of the day. This memory task was a model of habit
learning [20].
Determination of Oxidative Stress
Mouse hippocampus and striatum were homogenized in
10:1 (vol/wt) ice-cold PBS. A quantity of the homogenate was
used to determine the activities of catalase (CAT), glutathione
peroxidase (GSH-PX), total antioxidant capability (T-AOC) and
the concentration of malondialdehyde (MDA) in the hippocampus
and striatum samples according to the manufacturer’s protocol
(Nanjing Jiancheng Bioengineering Institute, Nanjing, China).
These methods are described briefly below.
CAT is responsible for the detoxification of H2O2, a precursor
for intracellular free radicals [24]. The activity of CAT in the
samples was measured by the decrease in the H2O2concentration.
The H2O2 decomposition reaction catalysed by catalase was
stopped by adding ammonium molybdate. The remaining H2O2
combined with ammonium molybdate to form a yellow com-
pound, which absorbed maximally at 405 nm. One unit of
catalase activity was defined as 1 mmol of decomposed H2O2in
one milligram of tissue for one minute and expressed as units per
mg protein.
The T-AOC is a useful index for the capacity of tissue samples
to modulate the damage associated with enhanced production of
free radicals [25]. A spectrometric method was applied to evaluate
the T-AOC. In the reaction mixture, ferric ions were reduced by
antioxidant reducing agents and a blue complex Fe2+–TPTZ
(2,4,6-tri(2-pyridyl)-s-triazine) was produced. One unit of T-AOC
was equal to 0.01 increases in absorbance of the reaction mixture
at 520 nm per milligram protein per minute under 37uC
incubation. The T-AOC activities were expressed as units per
mg protein.
GSH-PX is responsible for breaking down peroxides [24]. The
activity of GSH-PX was measured by measuring the rate of
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glutathione
(2GSH+H2O2RGSSG+2H2O) as catalyzed by GSH-PX present
in the sample. The activity was measured with the addition of
glutathione reductase and NADPH. Glutathione reductase con-
verts oxidized glutathione (GSSG) to the reduced form, while
oxidizing NADPH to NADP. The rate of GSSG formation was
subsequently measured by following the decrease in absorbance of
the reaction mixture at 340 nm as NADPH was converted to
NADP. A GSH-PX unit was defined as the enzyme activity
required to convert 1 nmol of NADPH to NADP per mg tissue
protein. The GSH-PX activity was expressed as units per mg
protein.
MDA is one of the most frequently used indicators of lipid
peroxidation [26]. The thiobarbituric acid reaction (TBAR)
method was used to determine the MDA. The method was used
to obtain a spectrophotometric measurement of the color
produced during the reaction of TBA with MDA at 535 nm.
MDA content was expressed as nmol/mg protein.
Protein concentrations were determined according to the Lowry
method [27].
oxidationbyhydrogenperoxide
Statistical Analysis
Statistical analysis was performed using SPSS software. All
results were expressed as mean 6 standard error of the mean.
Differences between groups in body weight, oxidative stress levels
and the distance in open field were analyzed by one-way repeated
measures analysis of variance (ANOVA) followed by a post hoc
LSD test. Escape latencies in water maze were analyzed by two-
way repeated measures ANOVA using treatment as the between-
subjects factor and session day as the repeated measure.
Differences were considered to be statistically significant when
p,0.05.
Results
Body Weight and Locomotion
During the treatment, animals were all in the growth state.
There was no significant difference in weight gain across the three
groups [F(2,33)=0.271, p=0.764]. The effect of ELF-MF
exposure on general locomotor activity of the mice was examined
in an open field test and the ELF-MF exposure did not cause
significant differences in horizontal locomotion [F(2,33)=0.767,
p=0.516]. This finding suggests that magnetic field exposure did
not produce ataxia or motor impairments in the mice.
ELF-MF Exposure Induced Oxidative Stress in the
Hippocampus and Striatum
The levels of CAT, GSH-PX, T-AOC and MDA in mice
hippocampus and striatum were determined in this study. ELF-
MF exposure (0.1 mT) for 12 weeks did not result in the
development of oxidative stress in mice hippocampus or striatum.
However, ELF-MF exposure for 12 weeks (1 mT) resulted in the
development of oxidative stress in mice hippocampus and
striatum. The levels of MDA in mice hippocampus and striatum,
parameters of oxidative stress, were significantly increased in the
1 mT ELF-MF exposure group compared with the other two
groups[Hippocampus:F(2,33)=40.62,
F(2,33)=23.148, p,0.001]. The levels of CAT, GSH-PX, and
T-AOC in hippocampus [CAT: F(2,33)=7.765, p=0.002; GSH-
PX: F(2,33)=9.151,p=0.001;
p,0.001] and striatum [CAT: F(2,33)=16.31, p,0.001; GSH-
PX: F(2,33)=11.89, p,0.001; T-AOC: F(2,33)=4.37, p=0.021]
were significantly declined in 1 mT ELF-MF exposure group
compared with the other two groups (Fig 1, Table 1).
p,0.001;striatum
T-AOC:F(2,33)=22.35,
ELF-MF Exposure Induced Learning Deficit in the Water
Maze
The effect of ELF-MF exposure on the scores of the mice in the
spatial reference memory version of the water maze is presented in
Fig. 2. Two-way repeated measures ANOVA indicated a signifi-
cant effect of group [F(2, 33)=9.43, P=0.014], a significant effect
of training day [F(3, 99)=70.6, P,0.001] and a significant
interaction between group and training day [F(6, 99)=20.8,
P,0.001]. The effect of ELF-MF exposure on the scores of the
mice in the cue memory version of the water maze is presented in
Fig. 2. Two-way repeated measures ANOVA indicated a signifi-
cant effect of group [F(2, 33)=16.08, P=0.004], a significant
effect of training day [F(3, 99)=268, P,0.001] and a significant
interaction between group and training day [F(6, 99)=2.923,
P=0.01]. The mean escape latency of the mice improved
throughout the training days indicating that the mice were able
to learn the two versions of the task. However, the ELF-MF
exposure (1 mT) group took longer to find the platform compared
with the other two groups (p,0.001). Where as, no significant
deficit was observed in the ELF-MF exposure (0.1 mT) mice
(p.0.05).
Figure 1. The Antioxidatant Status in Mice Hippocampus and
Striatum. After extremely low frequency magnetic field (ELF-MF)
exposure for consecutive 12 weeks, the antioxidatant status in mice
hippocampus and striatum was impaired by ELF-MF exposure (1 mT)
but not by ELF-MF exposure (0.1 mT). Values represent means6SEM.
N=12. * indicates p,0.05.
doi:10.1371/journal.pone.0032196.g001
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Discussion
There are many factors that increase ROS concentration in
cells, animals and humans. A magnetic field can alter the energy
levels and spin orientation of electrons and, as a consequence,
increase the activity, concentration and lifetime of free radicals
[12,13,14]. Oxidative stress results from an imbalance between the
generation of free radicals and endogenous protective mechan-
isms. These protective mechanisms include enzymes that specif-
ically degrade potential ROS precursors, such as CAT that
degrades hydrogen-peroxide, and GSH-PX that degrades hydro-
gen-peroxide in a reaction where reduced glutathione is converted
to oxidized glutathione [24].
The present study demonstrated that, in general, exposure to an
ELF-MF decreased the activity of antioxidant enzymes and
increased the MDA level in two neuronal tissues; the hippocampus
and striatum, respectively. The decrease in antioxidant enzyme
activity levels might be interpreted as a decrease in protein
expression levels in response to the ELF-MF exposure or
potentially as the indirect inhibition of the enzymes by their
binding with oxidative molecules produced during the ELF-MF
exposure. Nonetheless, the GPX and CAT activity decreases may
lead to hydrogen-peroxide accumulation, which is favorable to the
peroxidation of lipids in tissues [26].
Additionally, the findings of this study show that ELF-MF
exposure (50 Hz, 1 mT) impaired the learning of mice in the two
versions of the water maze: the spatial reference memory version
of the water maze was a declarative memory model which was
dependent on the hippocampus [20,21], and the cue version of the
water maze task was a habit learning model which was dependent
on the striatum [20,22]. This study provided direct evidence for
the association between the impairment of learning induced by
ELF-MF exposure (50 Hz, 1 mT) and oxidative stress in these two
brain regions associated with learning and memory.
ROS can activate signal transduction pathways, cause DNA
damage, and result in the modification of gene expression.
Moreover, the overproduction of oxygen free radicals can give
rise to functional and morphological disturbances in the cell
through oxidative stress [12,18,19]. We speculate that the
oxidative stress induced by ELF-MF exposure (50 Hz, 1 mT)
may damage the structure and function of hippocampus and
striatum in the mice, and therefore impair their ability to generate
declarative memory and habit learning.
Yet, the relationship between ELF-MF exposure, oxidative
stress and learning impairments is not clearly defined, despite
many studies attempting to investigate ELF-MF. For example,
Mostafa et al. reported that exposure to ELF-MF (50 Hz,
0.2 mT, 24 per day for 1, 2 or 4 weeks) was associated with
impairment in discrimination between familiar and novel objects,
where as Sienkiewicz et al. found no effect of ELF-MF exposure
(50 Hz, 75 mT, 45 min, once only) on object discrimination
[28,29]. Lee et al. reported that ELF-MF exposure (60 Hz, 1 mT)
had no influence on the transformation activities of stress factors
such as reactive oxygen species [30]. Our previous results also
complicate the issue. We have shown that exposure to ELF-MF
(50 Hz,1 mT, 50 min per day) had no effect on response latency
Table 1. The activities of CAT, GSH-PX, T-AOC and the concentration of MDA.
GroupCAT(U/mg protein)GSH-PX(U/mg protein) T-AOC(U/mg protein)MDA(nmol/mg protein)
Hippocampus control 21.2161.2631.2260.931.6560.083.8360.19
Hippocampus 1 mT 14.2860.84* 20.1564.65*0.5960.22* 9.5760.26*
Hippocampus 0.1 mT19.3261.89 30.0761.241.2960.16 4.3760.32
Striatum control23.7260.94 39.8161.99 1.8260.105.1060.21
Striatum 1 mT14.4561.89*22.6861.99* 1.3560.19*9.3860.31*
Striatum 0.1 mT21.0961.18 32.6363.581.7460.055.9160.51
*p,0.05.
doi:10.1371/journal.pone.0032196.t001
Figure 2. Effect of Electromagnetic Fields Exposure on Two
Versions of Water Maze Task. The data represent the latency time
to escape to a submersed platform during 4 training days, with four
consecutive trials per day. Mice exposed to extremely low frequency
magnetic fields (1 mT) took longer to find the platform in the two
versions of the water maze compared with the other two groups
(p,0.001). No significant deficit in the two versions of the task was
observed in the ELF-MF (0.1 mT) exposed mice (p.0.05). Values
represent means6SEM. N=12. * indicates p,0.05.
doi:10.1371/journal.pone.0032196.g002
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of detour learning, but that exposure to ELF-MF (50 Hz, 1 mT,
20 hours per day) significantly delayed detour learning [8].
Nonetheless, the inconsistencies found in the results of these
studies may have been due to the differences in the duration of
ELF-MF exposure between these studies. Furthermore, the
present study showed that the mice of the ELF-MF exposure
(1 mT, 4 hours per day) group needed more time to learn the
water maze task than the mice of the other two groups and that
the development of learning and memory was delayed by ELF-
MF (1 mT, 4 hours per day) chronic exposure, where as ELF-
MF (0.1 mT, 4 hours per day) chronic exposure did not have an
effect on learning or on oxidative stress. All told, the present
results, along with the listed previous studies, suggest that the
biological effects of ELF-MF exposure depend on the dosage and
duration of ELF-MF exposure.
It is also interesting to note that despite the growing body of
evidence that links ELF-MF to neurological disfunction and the
worrying reports these deleterious effects might have, a small
number of studies have suggested beneficial effects of low magnetic
or ELF-MF on human health under certain circumstances
[31,32,33].
Nonethelss, our results do suggest that there may be a negative
effect of chronic exposure to ELF-MF (50 Hz, 1 mT, 4 hours per
day) on learning and memory, and that this negative effect is
associated with oxidative stress. Although, a detailed inquiry into
the factors that gave rise to the learning impairment observed here
was beyond the scope of the data collected, we believe that the
effects of ELF-MF exposure may be complex and subtle and that
precise relationship between ELF-MF strength and biological
response needs further study.
Author Contributions
Conceived and designed the experiments: Y. Che ZG CZ ZZ SG Y. Cui.
Performed the experiments: Y. Cui CZ ZZ SG. Analyzed the data: Y. Che
ZG Y. Cui. Contributed reagents/materials/analysis tools: Y. Cui ZG CZ
ZZ SG Y. Che. Wrote the paper: Y. Che ZG Y. Cui JR.
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PLoS ONE | www.plosone.org5 May 2012 | Volume 7 | Issue 5 | e32196