Effects of electromagnetic fields exposure on the antioxidant defense system

Abstract

Technological devices have become essential components of daily life. However, their deleterious effects on the body, particularly on the nervous system, are well known. Electromagnetic fields (EMF) have various chemical effects, including causing deterioration in large molecules in cells and imbalance in ionic equilibrium. Despite being essential for life, oxygen molecules can lead to the generation of hazardous by-products, known as reactive oxygen species (ROS), during biological reactions. These reactive oxygen species can damage cellular components such as proteins, lipids and DNA. Antioxidant defense systems exist in order to keep free radical formation under control and to prevent their harmful effects on the biological system. Free radical formation can take place in various ways, including ultraviolet light, drugs, lipid oxidation, immunological reactions, radiation, stress, smoking, alcohol and biochemical redox reactions. Oxidative stress occurs if the antioxidant defense system is unable to prevent the harmful effects of free radicals. Several studies have reported that exposure to EMF results in oxidative stress in many tissues of the body. Exposure to EMF is known to increase free radical concentrations and traceability and can affect the radical couple recombination. The purpose of this review was to highlight the impact of oxidative stress on antioxidant systems.
Abbreviations: EMF, electromagnetic fields; RF, radiofrequency; ROS, reactive oxygen species; GSH, glutathione; GPx, glutathione peroxidase; GR, glutathione reductase; GST, glutathione S-transferase; CAT, catalase; SOD, superoxide dismutase; HSP, heat shock protein; EMF/RFR, electromagnetic frequency and radiofrequency exposures; ELF-EMFs, exposure to extremely low frequency; MEL, melatonin; FA, folic acid; MDA, malondialdehyde.

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Please
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Kıvrak
EG,
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al.
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
ARTICLE IN PRESS
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JMAU-141;
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Contents lists available at ScienceDirect
Journal
of
Microscopy
and
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journal homepage: www.elsevier.com/locate/jmau
Review
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system
Elfide
Gizem
Kıvrak∗,
Kıymet
Kübra
Yurt,
Arife
Ahsen
Kaplan,
Is¸
ınsu
Alkan,
Gamze
Altun
Department
of
Histology
and
Embryology,
Faculty
of
Medicine,
Ondokuz
Mayıs
University,
Samsun,
Turkey
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
16
May
2017
Received
in
revised
form
19
July
2017
Accepted
26
July
2017
Available
online
xxx
Keywords:
EMF
Oxidative
stress
ROS
Antioxidants
a
b
s
t
r
a
c
t
Technological
devices
have
become
essential
components
of
daily
life.
However,
their
deleterious
effects
on
the
body,
particularly
on
the
nervous
system,
are
well
known.
Electromagnetic
fields
(EMF)
have
var-
ious
chemical
effects,
including
causing
deterioration
in
large
molecules
in
cells
and
imbalance
in
ionic
equilibrium.
Despite
being
essential
for
life,
oxygen
molecules
can
lead
to
the
generation
of
hazardous
by-products,
known
as
reactive
oxygen
species
(ROS),
during
biological
reactions.
These
reactive
oxygen
species
can
damage
cellular
components
such
as
proteins,
lipids
and
DNA.
Antioxidant
defense
systems
exist
in
order
to
keep
free
radical
formation
under
control
and
to
prevent
their
harmful
effects
on
the
biological
system.
Free
radical
formation
can
take
place
in
various
ways,
including
ultraviolet
light,
drugs,
lipid
oxidation,
immunological
reactions,
radiation,
stress,
smoking,
alcohol
and
biochemical
redox
reac-
tions.
Oxidative
stress
occurs
if
the
antioxidant
defense
system
is
unable
to
prevent
the
harmful
effects
of
free
radicals.
Several
studies
have
reported
that
exposure
to
EMF
results
in
oxidative
stress
in
many
tissues
of
the
body.
Exposure
to
EMF
is
known
to
increase
free
radical
concentrations
and
traceability
and
can
affect
the
radical
couple
recombination.
The
purpose
of
this
review
was
to
highlight
the
impact
of
oxidative
stress
on
antioxidant
systems.
©
2017
Saudi
Society
of
Microscopes.
Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
Electromagnetic
fields
(EMF)
are
emitted
by
many
natural
and
man-made
sources
that
play
important
roles
in
daily
life.
More
than
3
billion
people
across
the
world
are
exposed
to
EMF
every
day
[1].
Lifetime
exposure
to
EMF
is
becoming
the
subject
of
sig-
nificant
scientific
investigation
since
it
has
the
potential
to
cause
crucial
changes
and
deleterious
effects
in
biological
systems.
The
biological
impacts
of
EMF
can
be
classified
as
thermal
and
non-
thermal.
Thermal
effects
are
associated
with
the
heat
created
by
EMFs
in
a
certain
area.
This
mechanism
occurs
via
an
alteration
in
temperature
deriving
from
radiofrequency
(RF)
fields.
It
is
possible
that
every
interaction
between
RF
fields
and
living
tissues
causes
an
energy
transfer
resulting
in
a
rise
in
temperature.
The
skin
and
Abbreviations:
EMF,
electromagnetic
fields;
RF,
radiofrequency;
ROS,
reactive
oxygen
species;
GSH,
glutathione;
GPx,
glutathione
peroxidase;
GR,
glutathione
reductase;
GST,
glutathione
S-transferase;
CAT,
catalase;
SOD,
superoxide
dis-
mutase;
HSP,
heat
shock
protein;
EMF/RFR,
electromagnetic
frequency
and
radiofrequency
exposures;
ELF-EMFs,
exposure
to
extremely
low
frequency;
MEL,
melatonin;
FA,
folic
acid;
MDA,
malondialdehyde.
∗Corresponding
author
at:
Department
of
Histology
and
Embryology,
Faculty
of
Medicine,
Ondokuz
Mayis
University,
55139,
Samsun,
Turkey.
E-mail
address:
elfide.gzm@gmail.com
(E.G.
Kıvrak).
other
superficial
tissues
usually
absorb
the
non-thermal
radiations
emitted
by
mobile
phones;
this
causes
the
insignificant
increase
of
temperature
of
the
brain
or
other
organs
in
the
body
[2].
Nonther-
mal
mechanisms
are
those
that
are
not
directly
associated
with
this
temperature
change
but
rather
to
some
other
changes
in
the
tissues
in
association
with
the
amount
of
energy
absorbed
[3,4].
Studies
on
the
health
effects
of
RF
energy
from
communication
systems
have
revealed
that
non-thermal
effects
should
also
be
discussed.
The
fact
that
the
possible
biophysical
mechanisms
of
RF-EMF
interaction
with
living
cells
have
not
yet
been
fully
elucidated
is
one
of
the
reasons
for
these
discussions
[4].
A
significant
part
of
many
studies
concerning
EMF
have
investigated
the
“non-thermal”
effects
of
RF
on
biological
tissues
[5,6].
It
has
been
observed
that
this
effect
is
mediated
by
generation
of
reactive
oxygen
species
(ROS)
[7].
ROS
are
involved
in
various
cellular
functions.
They
can
be
essential
or
extremely
toxic
to
cellular
homeostasis
[8].
Their
cytotoxic
effects
derive
from
peroxidation
of
membrane
phospholipids.
This
creates
a
change
in
the
conductivity
of
the
membrane
and
loss
of
mem-
brane
integrity
[9].
Exposure
to
EMF
has
been
observed
to
cause
increased
free
radical
production
in
the
cellular
environment.
Liv-
ing
organisms
have
anti-oxidative
mechanisms,
such
as
glutathione
(GSH),
glutathione
peroxidase
(GPx),
catalase
(CAT),
and
superox-
ide
dismutase
(SOD),
in
order
to
alleviate
the
damage
caused
by
ROS
and
their
products
[10].
This
defense
mechanism
acts
by
sup-
http://dx.doi.org/10.1016/j.jmau.2017.07.003
2213-879X/©
2017
Saudi
Society
of
Microscopes.
Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/
licenses/by-nc-nd/4.0/).

Please
cite
this
article
in
press
as:
Kıvrak
EG,
et
al.
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
ARTICLE IN PRESS
G Model
JMAU-141;
No.
of
Pages
10
2
E.G.
Kıvrak
et
al.
/
Journal
of
Microscopy
and
Ultrastructure
xxx
(2017)
xxx–xxx
pressing
or
impairing
the
chain
reaction
triggered
by
ROS.
In
this
case,
antioxidant
defense
mechanisms
are
impaired
by
being
sub-
jected
to
an
agent
that
causes
overproduction
of
ROS,
including
EMF,
thus
resulting
in
oxidative
stress
[11,12].
Studies
in
recent
years
have
reported
that
free
radicals
play
a
major
role
in
the
mech-
anism
behind
many
diseases,
such
as
diabetes
and
cancer
[13–15].
However,
there
is
still
much
uncertainty
on
the
subject,
and
several
questions
remain
to
be
answered.
This
review
evaluated
the
effect
of
exposure
to
EMF
on
biolog-
ical
tissues
by
concentrating
on
alterations
in
several
antioxidant
enzyme
activities
and
different
parameters
of
oxidation.
2.
Electromagnetic
field
effects
A
wide
spectrum
of
electromagnetic
waves
are
today
emit-
ted
by
radar,
communication
equipment,
mobile
phone
base
stations,
high
voltage
lines,
radio
and
television
transmitters,
substations,
and
electrical
equipment
at
home
and
work,
in
addi-
tion
to
many
electrical
systems
in
the
environment
[16].
The
Global
System
for
Mobile
Communications
(GSM,
850–900
MHz
and
1850–1990
MHz)
is
currently
the
most
extensive
system
for
mobile
telecommunications
worldwide
[17,18].
The
mobile
phone
models
(1800
MHz
−2200
MHz),
laptops
(1000
MHz–3600
MHz)
and
wireless
networks
in
use
today
function
with
high
frequency
(2.45
GHz)
microwave
radiation
[19].
In
parallel
to
technological
developments
in
this
century,
technological
devices
are
becom-
ing
ever
more
important
in
daily
life.
However,
despite
making
life
easier,
they
may
also
cause
a
number
of
health
problems.
In
partic-
ular,
the
average
age
of
beginning
mobile
phone
use
has
decreased
rapidly
to
elementary
school
age,
and
durations
of
exposure
to
EMF
are
also
increasing.
One
study
reported
that
extremely
low
expo-
sure
to
EMF
from
mobile
phones
may
cause
health
problems
[20].
Several
studies
have
reported
findings
such
as
stress,
headache,
tiredness,
anxiety,
decreased
learning
potential,
impairment
in
cog-
nitive
functions
and
poor
concentration
in
case
of
exposure
to
microwave
radiation
emitted
from
mobile
phones
[2,21,22].
EMFs
influence
metabolic
processes
in
the
human
body
and
exert
vari-
ous
biological
effects
on
cells
through
a
range
of
mechanisms.
EMF
disrupts
the
chemical
structures
of
tissue
since
a
high
degree
elec-
tromagnetic
energy
absorption
can
change
the
electric
current
in
the
body
[23].
As
a
result
of
this
exposure,
the
functions
of
organs
are
affected.
Electric
fields
exert
an
oscillatory
force
on
every
free
ion
on
the
both
sides
of
the
plasma
membrane
and
cause
them
to
cross
it.
This
movement
of
ions
causes
deterioration
in
the
ion
chan-
nels
on
the
membrane,
biochemical
changes
in
the
membrane
and
consequently
impairment
of
all
cellular
functions
[24].
Exposure
to
EMFs
can
damage
biological
tissues
by
inducing
changes,
which
can
be
explained
in
terms
of
thermal
or
non-
thermal
mechanisms
[25].
Thermal
effects
can
occur
with
the
conversion
and
absorption
of
heat
by
the
body’s
electromagnetic
energy.
Increased
body
temperature
is
stabilized
and
alleviated
by
blood
circulation.
Although
non-thermal
effects
do
not
raise
the
body
temperature
sufficiently
to
impair
the
structure
of
tissues,
their
effects
can
still
be
seen
as
an
increase
in
free
radical
pro-
duction
in
tissues
[3].
EMFs,
no
matter
where
they
occur
in
the
frequency
spectrum,
are
reported
to
causes
a
rise
in
levels
of
oxygen
free
radicals
in
an
experimental
environment
in
plants
and
humans
[26].
3.
EMF-related
oxidative
stress
and
effects
on
tissue
Free
radicals
are
reactive
molecules
produced
during
the
con-
version
of
foods
into
energy
through
oxygen.
The
formation
of
free
radicals
is
an
oxidation
reaction
that
occurs
on
an
oxygen
basis.
[27].
Since
oxygen
is
essential
for
survival,
the
formation
of
free
radicals
cannot
be
avoided.
However,
factors
including
ionizing
and
non-
ionizing
radiation
alter
the
transcription
and
translation
of
genes
such
as
JUN,
HSP
70
and
MYC,
via
the
epidermal
growth
factor
receptor
EGFR-ras,
leading
to
the
generation
of
ROS
[28,29]
and
resulting
in
the
overproduction
of
ROS
in
tissues
[30].
The
Fenton
reaction
is
a
catalytic
process
that
converts
hydrogen
peroxide,
a
product
of
mitochondrial
oxidative
respiration,
into
a
highly
toxic
hydroxyl
free
radical.
Some
studies
have
suggested
that
EMF
is
another
mechanism
through
the
Fenton
reaction,
suggest-
ing
that
it
promotes
free
radical
activity
in
cells
[31,32].
Although
some
researchers
have
reported
that
ROS
perform
beneficial
func-
tion,
a
high
degree
of
ROS
production
may
cause
cellular
damage,
resulting
in
a
range
of
diseases.
These
radicals
react
with
vari-
ous
biomolecules,
including
DNA
(Fig.
1).
Namely,
the
energy
of
free
radicals
is
not
enough,
and
for
this
reason
they
behave
like
robbers
who
seize
energy
from
other
cells
and
rob
a
person
to
sat-
isfy
themselves
[33].
Many
studies
have
suggested
that
EMF
may
trigger
the
formation
of
reactive
oxygen
species
in
exposed
cells
in
vitro
[34–37]
and
in
vivo
[7,31,38].
The
initial
stage
of
the
ROS
production
in
the
presence
of
RF
is
controlled
by
the
NADPH
oxi-
dase
enzyme
located
in
the
plasma
membrane.
Consequently,
ROS
activate
matrix
metalloproteases,
thereby
initiating
intracellular
signaling
cascades
to
warn
the
nucleus
of
the
presence
of
external
stimulation.
These
changes
in
transcription
and
protein
expression
are
observed
after
RF
exposure
[39].
Kazemi
et
al.
investigated
the
effect
of
exposure
to
900-MHz
on
the
induction
of
oxidative
stress
and
the
level
of
intracellular
ROS
in
human
mononuclear
cells.
Excessive
elevation
in
ROS
levels
is
an
important
cause
of
oxidative
damage
in
lipids
and
proteins
and
nucleic
acids.
It
therefore
causes
changes
in
enzyme
activity
and
gene
expression,
eventually
leading
to
various
diseases,
including
sleep
disorder,
arthrosclerosis,
loss
of
appetite,
diabetes,
dizziness,
rheumatoid
arthritis,
cardiovascular
disease,
nausea
and
stroke
[40–42].
In
addition,
degradation
of
the
pro-oxidant-antioxidant
balance
due
to
an
uncontrolled
increase
in
ROS
may
also
result
in
lipid
peroxidation.
Lipid
peroxidation
is
the
process
in
which
cell
membranes
are
rapidly
destroyed
due
to
the
oxidation
of
components
of
phospholipids
containing
unsaturated
fatty
acids.
By
continuing
this
reaction,
lipid
peroxides
(-C0,
H)
accumulate
in
the
membrane,
and
transform
polyunsaturated
fatty
acids
into
biologically
active
substances
[43].
Consequently,
lipid
peroxidation
leads
to
significant
damage
in
the
cells,
such
as
distur-
bances
in
membrane
transport,
structural
changes,
cell
membrane
fluidity,
damage
to
protein
receptors
in
membrane
structures,
and
changes
in
the
activity
of
cell
membrane
enzymes
[44].
Hoyto
et
al.
demonstrated
significant
induction
of
lipid
peroxidation
after
exposure
to
EMF
in
the
mouse
SH-SY5Y
cell
and
L929
fibroblast
cells
[45].
Epidemiological
studies
have
also
suggested
that
oxida-
tive
damage
to
lipids
in
blood
vessel
walls
may
be
a
significant
contributor
to
the
development
of
atherosclerosis
[46–48].
Studies
generally
focus
on
the
brain,
since
cell
phones
are
held
close
to
the
head
during
use.
There
is
considerable
evidence
that
EMF
can
affect
neural
functions
in
the
human
brain
[50].
The
rela-
tion
between
EMF
and
neurological
disorders
can
be
explained
in
terms
of
the
heat
shock
response
[51].
The
heat
shock
protein
(HSP)
response
is
generally
concerned
with
heat
shock,
exposure
to
heavy
metals
and
environmental
insults
such
as
EMF.
Generally,
HSP
is
a
marker
in
cells
under
stress.
Living
organisms
generate
stress
pro-
teins
in
order
to
survive
environmental
stressors.
The
heat
shock
response
is
regarded
as
a
general
response
to
a
wide
variety
of
stresses,
such
as
oxidative
stress
[52].
In
humans
and
other
mam-
mals,
many
environmental
stimuli
causes
ultraviolet
radiation
[53],
ionizing
radiation
[54]
and
laser
radiation
[55]
are
caused
by
cellu-
lar
stresses
and
alter
Hsp90
and
70
levels.
Non-ionizing
radiation
also
causes
HSP
changes
in
various
tissues,
including
the
brain
[56],
myocardium
[57],
testis
[5]
and
skin
[58].
Studies
have
described
these
findings
as
an
adaptation
or
readjustment
of
cellular
stress

Please
cite
this
article
in
press
as:
Kıvrak
EG,
et
al.
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
ARTICLE IN PRESS
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JMAU-141;
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Journal
of
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Ultrastructure
xxx
(2017)
xxx–xxx
3
Fig
1.
Reactive
oxygen
species
generated
by
the
effects
of
exposure
to
EMF
can
damage
various
cellular
structures
in
neurons
of
the
central
nervous
system
[49].
proteins
before
preparing
the
cellular
machinery
for
an
adequate
environmental
change.
Small,
transitory
readjustments
of
the
cir-
cuits
may
thus
decisively
influence
overall
stress
tolerance
[59,60].
Low
frequency
(0–300
Hz)
and
RF
(10
MHz–300
GHz)
EMF
has
also
been
reported
to
alter
the
permeability
of
the
blood–brain
bar-
rier
[61–63].
At
the
same
time,
these
changes
in
the
blood-brain
barrier
may
lead
to
excess
accumulation
of
heavy
metals
and
specif-
ically
of
iron
in
the
brain.
This
effect
may
trigger
several
neuronal
disorders
[64,65].
Some
studies
have
reported
that
DNA
damage
and
blood–brain
barrier
disruption
is
connected,
and
that
autism
spectrum
conditions
are
associated
with
EMF
exposure.
The
dis-
ruption
of
fertility
and
reproduction
associated
with
EMF/RFR
may
also
be
related
to
the
increasing
incidence
of
autism
spectrum
con-
ditions
[66–68].
Oxidative
stress
plays
an
important
role
in
DNA
damage
pro-
cess,
general
and
specific
gene
expression
and
cell
apoptosis.
The
brain
has
a
high
metabolic
rate,
making
it
more
prone
to
damage
by
ROS
and
oxidative
damage
compared
to
other
organs
[69].
Exces-
sive
amounts
of
ROS
in
tissues
may
lead
to
necrosis,
the
death
of
neurons
and
neuronal
damage
in
brain
tissue,
as
well
as
to
neu-
rological
disorders
such
as
Alzheimer’s
disease,
spinal
cord
injury,
multiple
sclerosis,
and
epilepsy
[70]
(Fig.
2).
Several
studies
have
observed
neuronal
damage
and
cellular
losses
caused
by
exposure
to
EMF
in
many
regions
of
the
brain,
including
the
cortex,
basal
ganglia,
hippocampus
and
cerebellum
[71–75].
One
epidemiologi-
cal
study
determined
an
association
between
amyotrophic
lateral
sclerosis
and
exposure
to
high
intensity
EMF,
but
no
correlation
was
observed
with
other
neurodegenerative
diseases
[76].
Rubin
et
al.
noted
that
the
pain
level
of
headache
may
increase
during
exposure
but
decreased
immediately
when
exposure
ceased
[77].
Haynal
and
Regli
suggested
that
exposure
to
extremely
low
fre-
quency
(ELF)-EMF
may
be
linked
to
amyotrophic
lateral
sclerosis,
a
fatal
neurodegenerative
disorder
[78].
Maskey
et
al.
investigated
the
effects
on
the
brain
of
835-MHz
over
different
exposure
times
and
observed
a
significant
loss
of
pyramidal
cells
in
the
CA1
region
of
the
hippocampus
[79].
Another
case
control
study
by
Villeneuve
et
al.
reported
a
5.3-fold
increased
risk
of
one
brain
cancer
type,
glioblastoma,
in
individuals
exposed
to
EMF,
but
no
increased
risk
for
other
brain
cancers
[80].
Some
studies
have
shown
that
microwave
exposure
failed
to
induce
a
detectable
genotoxic
effect
by
itself,
and
have
reported
interference
with
DNA-repair
mechanisms
[82–85].
Oxidative
damage
in
DNA
occurs
as
a
result
of
interaction
between
free
radi-
cals
and
DNA,
with
the
addition
of
bases
or
abstractions
of
hydrogen
atoms
from
sugar
moiety.
Modified
nucleotides
emerge
as
prod-
ucts
of
damage
(8-OH-dG)
when
DNA
is
modified
by
the
oxidative
damage
caused
by
reactive
oxygen
molecules
[86].
These
products
are
markers
of
oxidative
stress
measured
using
analytical
methods
[87,88].
Agarwal
and
Saleh
and
Aitken
et
al.
have
reported
that
ROS
may
have
harmful
effects
on
sperm
DNA
and
other
biomolecules,
proteins
and
lipids,
consequently
leading
to
male
infertility
[89,90].
At
the
same
time,
men
carrying
phones
in
their
pocket
or
on
their
belt
and
therefore,
most
of
adverse
effects
of
the
EMF
are
seen
in
reproductive
organs.
Sepehrimanesh
et
al.
showed
that
exposure
to
RF-EMF
produces
increases
in
testicular
proteins
in
adults
that
are
related
to
carcinogenic
risk
and
reproductive
damage
[6].
Neu-
roendocrine
changes
caused
by
EMFs
are
a
key
factor
in
changing
hormone
functions
[91].
Ero˘
glu
et
al.
stated
that
exposure
to
cell
phone
radiation
reduces
the
motility
and
changes
the
morphol-
ogy
of
isolated
sperm
cells.
They
also
discussed
the
effects
of
EMFs
on
female
infertility
[92].
Goldhaber
et
al.
reported
a
significant
increase
in
fetal
abnormalities
and
spontaneous
abortions
in
preg-
nant
women
exposed
to
EMF
[93].
Many
of
these
effects
may
occur
due
to
hormonal
changes
[94,95].
Studies
on
the
effects
of
EMF
on
tissues
discussed
here
are
set
out
in
Tables
1
and
2.
4.
The
antioxidant
defense
system
and
EMF
Antioxidant
defense
systems
have
developed
in
organisms
to
control
the
formation
of
free
radicals
and
to
prevent
the
harm-
ful
effects
of
these
molecules
[122].
These
antioxidants
reduce
or
impair
the
damage
mechanism
of
ROS
via
their
free
radical
scaveng-
ing
activities
[123].
Two
major
mechanisms
have
been
identified
for
antioxidants
[124].
The
first
is
a
mechanism
of
chain
disrup-
tion
in
which
the
primary
antioxidant
releases
an
electron
to
the
free
radical
found
in
the
systems.
The
second
mechanism
includes
elimination
of
the
initiators
of
species
of
ROS/reactive
nitrogen
(secondary
antioxidants)
by
suppressing
chain-initiating
catalysts.
Antioxidants
may
also
impact
on
biological
systems
by
various
mechanisms
involving
electron
releasing,
metal
ion
chelation,
co-
antioxidants,
or
by
maintaining
the
expression
of
genes
[125].
If
these
antioxidant
defense
mechanisms
are
impaired
through
expo-
sure
to
an
agent
that
causes
the
overproduction
of
ROS,
including
EMF,
antioxidants
may
not
be
sufficient
or
free
radical
formation
may
increase
to
such
an
extent
that
it
overpowers
the
defense

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Kıvrak
EG,
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Effects
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electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
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/
Journal
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xxx
(2017)
xxx–xxx
Fig.
2.
The
role
of
EMF
emitted
from
several
devices,
depicting
an
increase
in
the
generation
of
ROS
and
consequent
oxidative
stress
in
the
central
nervous
system
resulting
from
the
inability
of
the
antioxidant
defense
system
to
cope
with
this
increase
in
ROS
[81].
capabilities
of
antioxidants
[10].
This
is
known
as
oxidative
stress.
EMFs
can
initiate
various
biochemical
and
physiological
changes,
including
oxidative
stress,
in
the
systems
of
various
species.
Several
studies
in
the
literature
show
that
plasma
membrane
receptors
are
possible
targets
for
field
interactions
[126,127].
Generally,
antioxidants
have
been
divided
into
exogenous
groups
(carotene,
C,
and
vitamin
E),
and
endogenous
groups
(mela-
tonin
(MEL)),
SOD,
GSH-Px,
CAT,
including;
protein
(MEL),
vitamins
(vitamin
C),
trace
elements
(Mg,
Se),
complexes
of
compound,
hydrophilic
(ascorbic
acid,
urate,
flavonoids)
and
hydrophobic
(␤-
carotene,
␣-tocopherol)
substances,
with
direct
impacts
(SOD,
CAT),
and
indirect
effects
(vitamin
E).
Substances
with
functions
concerning
the
membrane
(vitamin
A
and
E,
␤-
carotene),
circula-
tion
(vitamin
C,
amino
acids
and
polyphenols),
cytosol
(co-enzyme
Q10)
are
classified
as
antioxidants
[122,128].
4.1.
Glutathione
Glutathione
(GSH)
is
an
endogenous
antioxidant
and
an
impor-
tant
cellular
defense
agent
against
oxidative
damage.
GSH
reacts
with
the
free
radicals
in
the
cell
and
reduces
the
entry
of
hydrogen
peroxides
[129].
GSH
also
prevents
the
oxidization
of
sulfhydryl
groups
in
the
protein
structure.
GSH
levels
in
tissues
are
often
used
as
a
marker
for
measuring
radical
damage.
It
acts
as
a
substrate
for
antioxidant
enzymes
that
causes
resistance
to
radical-induced
damage,
behaving
like
a
radical
scavenger.
GSH
is
especially
impor-
tant
for
the
activity
of
glutathione
peroxidase
(GSH-Px),
glutathione
reductase
(GR)
and
glutathione-S-transferase
(GST).
In
the
oxida-
tive
stress
process,
levels
of
GSH
decrease,
while
glutathione
disulfide
increases.
In
this
case,
accumulation
of
hydrogen
perox-
ide
(H2O2)
is
scavenged
by
the
effects
of
reductase
and
glutathione
peroxidase
(GSH-Px).
GSH-Px
is
also
an
important
enzyme,
which
prevents
damage
to
phagocytic
cells
caused
by
free
radicals.
A
decrease
in
GSH-Px
activity
leads
to
the
accumulation
of
hydrogen
peroxide
and
to
cell
damage.
GSH-Px
also
prevents
the
initiation
of
lipid
peroxidation
[65].
EMF
emitted
by
cellular
phones
is
known
to
be
related
to
a
decreased
level
of
GSH
in
brain
tissue
and
blood
[97].
However,
a
decreased
level
of
blood
GSH
may
possibly
be
explained
by
an
elevated
oxidation
rate
and
use
of
GSH
during
the
elimination
of
lipid
and
other
peroxides
[130].
Awad
and
Hassan
investigated
the
brains
of
rats
exposed
to
900-MHz
EMF
from
mobile
phones
for
1
h/day
for
one
week.
They
observed
an
increase
in
lipid
per-
oxidation
after
exposure
to
mobile
phones
[131].
Aydın
and
Akar
studied
the
effect
of
900-MHz
EMF
for
2
h/day
for
45
days
on
lym-
phoid
organs
in
immature
and
mature
rats.
They
reported
that
CAT
and
GPx
activities
decreased
significantly
compared
to
a
control
group.
Similarly,
an
increase
in
lipid
peroxidation
and
a
concomi-
tant
demolition
in
GSH
levels
were
seen
in
all
lymphoid
organs
after
EMF
exposure,
suggesting
that
increased
levels
of
lipid
peroxida-
tion
may
have
been
a
consequence
of
depleted
GSH
stores
[32].
Luo
et
al.
investigated
that
the
whether
the
protective
effects
of
LSPCs
performed
by
oral
gavage
on
oxidative
stress
injury
induced
by
ELF-
EMF
exposure.
According
the
results,
GST
activity
was
significantly
decreased
in
the
ELF-EMF
group
when
compared
with
the
control
group.
They
found
that
LSPCs
could
effectively
prohibit
oxidative
stress
damage
induced
by
ELF-EMF
exposure,
it
may
be
related
to
the
ability
to
remove
free
radicals
and
induce
antioxidant
enzyme
activity
[132].
Singh
et
al.
investigated
the
biochemical
mechanism
of
the
interaction
of
900-MHz
mobile
phone
EMF
with
root
for-
mation
in
mung
bean
hypocotyls.
The
obtained
results
showed
up
regulation
of
the
activities
of
antioxidant
enzymes
such
as
CAT
and
GR,
which
protect
against
oxidative
damage
induced
by
EMF
[133].
Sepehrimanesh
et
al.
studied
that
effect
of
900-MHz
electro-
magnetic
field
(EMF)
exposure
on
rat
serum
and
testes
antioxidant
enzyme
levels.
They
observed
that
after
30
days
exposure
both
SOD
and
GPx
activities
decreased
in
the
long-time
EMF
exposure
group
[134].
In
the
other
study
RF-EMF
exposure
caused
increase
antiox-
idant
stress
response
via
increase
of
CAT
and
GR
activity
it
lead
to
the
generation
of
lipid
and
protein
oxidative
damage
[135].
4.2.
Catalase
CAT
is
a
common
enzyme
present
in
organisms
exposed
to
oxy-
gen,
such
as
vegetables,
fruits
and
animals.
It
catalyzes
the
reaction
that
degrades
hydrogen
peroxide
to
water
and
oxygen.
It
is
a
cru-
cial
enzyme
in
the
protection
of
the
cell
against
oxidative
damage
caused
by
ROS.
CAT
exerts
its
peroxidase
activity
in
vivo.
It
can
also
catalyze
the
reaction
of
oxidation,
by
hydrogen
peroxide,
of
numerous
metabolites
and
toxins,
not
excluding
formaldehyde,
formic
acid,
phenols,
acetaldehyde
and
alcohols.
Its
basic
function
is
to
remove
hydrogen
peroxide
and
peroxide
ROOH
in
molecular
oxygen
in
order
to
prevent
irreversible
damage
to
the
membranes

Please
cite
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as:
Kıvrak
EG,
et
al.
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
ARTICLE IN PRESS
G Model
JMAU-141;
No.
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Pages
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E.G.
Kıvrak
et
al.
/
Journal
of
Microscopy
and
Ultrastructure
xxx
(2017)
xxx–xxx
5
Table
1
Some
experimental
studies
on
the
oxidative
effects
of
EMF.
Reference
Biological
endpoint
Results
Ghodbane
et
al.
[96]
Kidney
In
the
study
investigated
that
whether
Static
magnetic
fields
induces
oxidative
stress
and
apoptosis
in
rat
tissues
and
to
evaluate
the
possible
protector
effect
of
selenium
(Se)
and
vitamin
E
(vit
E)
supplementation.
In
the
results
have
been
shown
exposure
to
SMF
induced
oxidative
stress
in
kidney
that
will
be
able
prevented
by
treatment
with
Se
or
vit
E.
Meral
et
al.
[97]
Brain
890-915-MHz
EMF
emitted
by
cellular
phones
may
generate
oxidative
stress.
MDA
levels
increased
and
GSH
level
and
CAT
enzyme
activity
decreased,
while
vitamin
A,
E
and
D3
levels
remained
unchanged
in
the
brain
tissue
of
guinea
pigs
Misa-Agusti˜
no
et
al.
[98]
Thymus
The
thymus
tissue
exhibited
several
morphological
changes,
including
increased
distribution
of
blood
vessels
along
with
the
appearance
of
red
blood
cells
and
hemorrhagic
reticuloepithelial
cells
Balcı
et
al.
[99]
Cornea
and
lens
To
investigate
the
adverse
effects
of
mobile-phone
on
the
antioxidant
balance
in
corneal
and
lens
tissues
and
to
observe
any
protective
effects
of
vitamin
C
in
this
setting.
The
results
of
this
study
suggest
that
mobile
telephone
radiation
leads
to
oxidative
stress
in
corneal
and
lens
tissues
and
that
antioxidants
such
as
vitamin
C
can
help
to
prevent
these
effects.
Bodera
et
al.
[100] Antioxidant
capacity
of
blood EMF
exposure
at
1800
MHz
significantly
reduced
antioxidant
capacity
in
both
healthy
animals
and
those
with
paw
inflammation
Ozorak
et
al.
[101]
Kidney
and
testis
In
the
present
study
was
investigated
that
the
effects
of
both
Wi-Fi
and
900
and
1800
MHz
EMF
on
oxidative
stress
and
trace
element
levels
in
the
kidney
and
testis
of
growing
rats
from
pregnancy
to
6
weeks
of
age.
It
has
been
observed
Wi-Fi
and
mobile
phone-induced
EMR
may
cause
precocious
puberty
and
oxidative
kidney
and
testis
injury
in
growing
rats.
Ozgur
et
al.
[102] Liver
and
kidney
RF
exposure
is
reported
to
induce
lipid
peroxidation,
accompanied
by
decreased
activity
of
superoxide
dismutase
(SOD),
myeloperoxidase
(MPO)
and
glutathione
peroxidase
(GSH-Px),
in
various
organs,
such
as
guinea
pig
liver
and
rat
kidney
˙
Ikinci
et
al.
[103]
Spinal
cord
The
aim
of
this
study
was
therefore
to
investigate
changes
in
the
spinal
cords
of
male
rat
pups
exposed
to
the
effect
of
900
MHz
EMF.
The
study
results
showed
that
MDA
and
GSH
levels
in
EMFG
increased
significantly
while
CAT
and
SOD
levels
decreased
following
application
of
900-MHz
EMF
pathological
changes
may
occur
in
the
spinal
cords
of
male
rats
following
exposure
to
900
MHz.
Gurler
et
al.
[104]
Brain
In
the
study
has
been
investigated
that
the
oxidative
damage
and
protective
effect
of
garlic
on
rats
exposed
to
low
level
of
EMF
at
2.45
GHz
MWR.
It
may
be
concluded
that
EMF
increases
the
DNA
damage
in
both
brain
tissues
and
plasma
of
the
rats
whereas
it
increases
protein
oxidation
only
in
plasma.
It
may
also
be
argued
that
the
use
of
garlic
decreases
these
effects.
Türedi
et
al.
[105]
Bladder
In
the
study
investigated
the
effect
on
male
rat
bladder
tissues
of
exposure
to
900
MHz
EMF
applied
on
postnatal
days
22-59,
inclusive.
In
bladder
tissue,
degeneration
in
the
transitional
epithelium
and
stromal
irregularity
and
an
increase
in
cells
tending
to
apoptosis
were
observed
in
EMFG.
Yan
et
al.
[106]
Sperm
Rats
exposed
to
6
hours
of
daily
cellular
phone
emissions
for
18
weeks
exhibited
a
significantly
higher
incidence
of
sperm
cell
death
than
control
group
rats.
Rajkovic
et
al.
[107]
Thyroid
gland
After
significant
morphophysiological
changes
caused
by
ELF-EMF
exposure,
the
thyroid
gland
recovered
morphologically,
but
not
physiologically,
during
the
investigated
repair
period.
Deniz
et
al.
[108]
Kidney
In
the
results
was
observed
the
900-MHz
EMR
cause
to
kidney
damage
and
FA
may
exhibit
a
protective
effect
against
the
adverse
effects
of
EMR
exposure
in
terms
of
the
total
number
of
glomeruli.
Wang
et
al.
[109]
Blood-testicle
Barrier
In
the
study
investigated
the
effect
of
electromagnetic
pulse
(EMP)
exposure
on
cerebral
micro
vascular
permeability
in
rats.
It
has
been
shown
that
exposure
to
200
and
400
pulses
(1
Hz)
of
EMP
at
200
kV/m
can
increase
the
permeability
of
the
blood-testicle
barrier
in
mice
Avenda˜
no
et
al.
[110]
Sperm
Four-hour
EMF
exposure
ex
vivo
to
a
wireless
internet-connected
laptop
caused
a
significant
decrease
in
progressive
sperm
motility
and
an
increase
in
sperm
DNA
fragmentation
Narayanan
et
al.
[111]
Human
semen
RF
exposure
for
one
month
induced
oxidative
stress
in
the
rat
brain,
but
the
magnitude
differed
in
the
various
regions
studied,
and
RF-induced
oxidative
stress
may
be
one
underlying
causes
of
the
behavioral
deficits
seen
in
rats
after
RF
exposure
Hancı
[112]
Spleen
and
thymus
900
MHz
EMF
applied
to
spleen
and
thymus
tissue
caused
significant
histopathological
changes
at
the
TEM
and
LM
levels
[136].
EMF
is
known
to
impact
on
biological
systems
by
increas-
ing
ROS,
which
causes
oxidative
stress
by
altering
the
CAT
levels
of
tissues
[137–139].
Odaci
et
al.
observed
a
decrease
in
CAT
lev-
els
in
an
EMF-exposed
group.
Exposure
to
EMF
during
the
prenatal
period
also
caused
oxidative
stress
in
developing
rat
embryos.
This
oxidative
stress
persisted
through
postnatal
day
21
[140].
Vuokko
et
al.
reported
that
EMF
exposure
led
to
depression
of
antioxidant
systems
because
of
raised
lipid
peroxidation
and
generation
of
free
radicals
[141].
Mobile
phones
triggered
oxidative
damage
in
the
liv-
ing
cell
by
increasing
the
levels
of
xanthine
oxidase
and
carbonyl
group
activity
and
reducing
CAT
activity.
Treatment
with
MEL
sig-
nificantly
prevents
oxidative
damage
in
the
brain
[142].
Özgüner
et
al.
reported
that
EMF
exposure
leads
to
renal
tissue
damage
by
raising
nitric
oxide
and
malondialdehyde
(MDA)
levels
[143].

Please
cite
this
article
in
press
as:
Kıvrak
EG,
et
al.
Effects
of
electromagnetic
fields
exposure
on
the
antioxidant
defense
system.
J
Microsc
Ultrastruct
(2017),
http://dx.doi.org/10.1016/j.jmau.2017.07.003
ARTICLE IN PRESS
G Model
JMAU-141;
No.
of
Pages
10
6
E.G.
Kıvrak
et
al.
/
Journal
of
Microscopy
and
Ultrastructure
xxx
(2017)
xxx–xxx
Table
2
Some
clinical
studies
of
the
oxidative
effects
of
EMF.
Reference
Biological
endpoint
Results
Lantow
et
al.
[113]
Monocytes
and
lymphocytes
No
significant
ROS
generation
was
measured
in
human
cell
lines
exposed
to
1800
MHz.
Baohong
et
al.
[114]
Human
blood
lymphocytes
RF
exposure
for
1.5
and
4
h
did
not
significantly
exacerbate
human
lymphocyte
DNA
damage,
but
may
reduce
and
increase
DNA
damage
in
human
lymphocytes
induced
by
ultraviolet
C
at
1.5
and
4
h
incubation.
Ansarihadipour
et
al.
[115]
Human
blood
proteins
EMF
exacerbated
oxidative
damage
to
plasma
proteins
as
well
as
conformational
changes
in
Hb.
Wu
et
al.
[35] Human
epithelial
lens
cells RF
at
4W/kg
for
24
h
significantly
increased
intracellular
ROS
and
DNA
damage.
Belyaev
et
al.
[116] Human
blood
lymphocytes Decreased
background
levels
of
p53
binding
protein
1
foci
and
may
indicate
a
reduced
accessibility
of
53BP1
to
antibodies
because
of
stress-induced
chromatin
condensation.
Agarwal
et
al.
[117]
Human
ejaculated
semen
900
MHz
EMF
emitted
by
mobile
phones
may
cause
oxidative
stress
in
human
semen.
Lewicka
et
al.
[118]
Human
blood
platelets
(in
vivo)
The
largest
increase
in
ROS
concentration
vs.
a
control
sample
was
observed
after
exposure
to
EMF
of
220
V/m
intensity
for
60
min.
The
enzymatic
activity
of
SOD-1
also
decreased.
Lu
et
al.
[119]
Human
peripheral
blood
mononuclear
cells
Cell
apoptosis
can
be
induced
in
human
peripheral
blood
mononuclear
cells
by
900-MHz
GSM
radiofrequency
electromagnetic
field
at
a
specific
absorption
rate
of
0.4W/kg
when
exposure
exceed
2
h.
De
Iuliis
et
al.
[120]
Human
spermatozoa
(in
vitro)
Highly
significant
relationships
were
observed
between
SAR,
the
oxidative
DNA
damage
bio-marker,
8-OH-dG,
and
DNA
fragmentation
after
RF
exposure.
Yao
et
al.
[37]
Human
lens
epithelial
cells
DNA
damage
was
significantly
increased
by
comet
assay
at
3
and
4
W/kg,
whereas
double
strand
breaks
by
histone
variant
foci
were
significantly
increased
only
at
4
W/kg,
while
increased
ROS
levels
were
detected
in
the
3
and
4
W/kg
groups.
Sefidbakht
et
al.
[121]
Human
embryonic
kidney
cells
Results
showed
that
an
increase
in
the
activity
of
luciferase
after
60
min
of
continuous
exposure
may
be
associated
with
a
decrease
in
ROS
levels
caused
by
activation
of
the
oxidative
response.
4.3.
Superoxide
dismutase
SOD
is
an
enzyme
that
catalyzes
the
reaction
in
which
the
toxic
superoxide
(O2−)
radical
is
partitioned
into
molecular
oxygen
(O2)
or
hydrogen
peroxide
(H2O2).
Superoxide
is
generated
as
a
by-
product
as
a
result
of
the
oxygen
metabolism,
leading
to
several
types
of
damage
to
cells.
Three
forms
of
SOD
can
be
encountered
in
humans;
SOD1is
present
in
the
cytoplasm,
SOD2in
the
mitochon-
dria,
and
SOD3in
the
extracellular
compartment.
SOD
is
present
in
the
cytosol
and
mitochondria
and
inactivates
the
existing
super-
oxide
radicals,
as
well
as
protecting
cells
from
the
harmful
effects
of
the
superoxide
radicals
[144].
Research
has
shown
that
the
rat
brain
is
susceptible
to
the
effects
of
exposure
to
ELF-EMF.
Decreased
CAT
and
SOD
activity
results
in
after
exposure
suggested
that
EMF
might
change
the
antioxidant
levels
of
the
brain
[145].
Gambari
et
al.
reported
that
50-day
exposure
to
EMF
causes
oxidative
stress
by
increasing
MDA
levels
and
reducing
SOD
activity,
and
observed
that
treatment
with
vitamin
E
prevented
oxidative
stress
and
lipid
peroxidation
in
the
substantia
nigra
[146].
Another
study
reported
decreased
antioxidant
enzyme
levels
and
increased
levels
of
ROS
in
the
kidneys
of
rats
exposed
to
900-MHz
EMF
for
30
min/day
for
1
month
[143].
5.
Antioxidants
alleviate
the
potential
risks
of
EMF
exposure
When
applied
antioxidant
supplemented
with
EMF
exposure,
improved
the
hydrophilic,
lipophilic
and
enzymatic
antioxidant
blood
capacity
and
partially
compensated
for
these
changes
[147,148].
Vitamin
E
(tocopherol)
is
one
of
the
most
important
such
antioxidants.
Compounds
of
vitamin
E,
including
alpha,
beta,
gamma
and
delta
tocopherols,
are
soluble
in
lipid.
Vitamin
E
is
stored
in
the
liver
and
has
many
functions.
Its
main
antioxidant
function
is
to
prevent
lipid
peroxidation
[149].
Several
studies
have
shown
the
beneficial
effects
of
vitamin
E
observed
by
reducing
alteration
in
antioxidant
capacity
against
the
harmful
effects
of
EMF
[150,151].
Ghambari
et
al.
observed
that
exposure
to
3-MT
EMF
led
to
oxidative
stress
by
reducing
SOD
activity
and
reported
that
treatment
with
vitamin
E
prevents
the
lipid
peroxidation
in
the
substantia
nigra
[146].
Mohammadnejad
et
al.
studied
ultrastruc-
tural
changes
in
the
thymus
after
exposure
to
EMF
and
investigated
the
protective
effects
of
vitamin
E
in
preventing
these
change.
Their
results
demonstrated
that
exposure
to
EMF
caused
damage
to
the
immune
system
and
that
vitamin
E
consumption
can
prevent
ultra-
structural
alteration
in
tissue
[152].
Vitamin
B9
(folic
acid
and
folate)
is
crucial
for
several
functions
in
the
human
body,
ranging
from
the
production
of
nucleotides
to
homocysteine
remethylation.
In
humans,
folate
is
required
for
the
body
to
make
or
repair
DNA,
and
to
methylate
DNA,
in
addition
to
its
function
as
a
cofactor
in
various
biological
reactions.
Moreover,
this
vitamin
possesses
antioxidant
features
[153].
It
is
especifically
crucial
during
periods
involving
quick
cell
division
and
cellular
growth.
Folic
acid
(FA)
is
particularly
required
in
pregnancy
and
for
infant
brain
development.
It
is
also
necessary
for
the
formation
of
new
cells
[154].
Our
previous
study
revealed
that
FA
prevented
the
adverse
effect
of
exposure
to
EMF
by
preventing
reductions
in
cell
numbers
in
the
cerebellum
and
brain.
Kıvrak
observed
that
EMF
triggered
oxidative
damage
by
increasing