Insights in the biology of extremely low-frequency magnetic fields exposure on human health

Abstract

The extremely low-frequency magnetic fields (ELF-EMF) are generated by electrical devices and power systems (1 to 300 Hz). In recent decades, exposure to ELF-EMF has emerged potential concerns on public health. Here, we discuss recent progress in the understanding of ELF-EMF biology with a focus on mechanisms of ELF-EMF-mediated disease and summarize the results of more recent experimental and epidemiological studies of ELF-EMF exposure effects on cancer, neurological, cardiovascular, and reproductive disorders. Current views on genomic instability effects, as well as scientific evidence about ELF-EMF therapy, are put forth. According to our literature review, exposure to ELF-EMF has an adverse biological effect depending on the current intensity, strength of the magnetic field, and duration of exposure. Accumulated epidemiologic evidence indicates a correlation between exposure to ELF-EMF and childhood cancer incidence, Alzheimer's disease (AD), and miscarriage. However, adult cancer does not show augmented risk caused by the ELF-EMF. Also, no consistent evidence exists in cardiovascular disease mortality due to ELF-EMF exposure. There is a lack of comprehensive mechanisms for explaining the biological effect of ELF-EMF. Eventually, more studies are needed to clarify the mechanisms of these magnetic fields.

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Molecular Biology Reports
https://doi.org/10.1007/s11033-020-05563-8
REVIEW
Insights inthebiology ofextremely low‑frequency magnetic elds
exposure onhuman health
AbbasKarimi1,2 · FarzanehGhadiriMoghaddam1,3· MasoumehValipour3
Received: 16 April 2020 / Accepted: 27 May 2020
© Springer Nature B.V. 2020
Abstract
The extremely low-frequency magnetic fields (ELF-EMF) are generated by electrical devices and power systems (1 to
300Hz). In recent decades, exposure to ELF-EMF has emerged potential concerns on public health. Here, we discuss
recent progress in the understanding of ELF-EMF biology with a focus on mechanisms of ELF-EMF-mediated disease and
summarize the results of more recent experimental and epidemiological studies of ELF-EMF exposure effects on cancer,
neurological, cardiovascular, and reproductive disorders. Current views on genomic instability effects, as well as scientific
evidence about ELF-EMF therapy, are put forth. According to our literature review, exposure to ELF-EMF has an adverse
biological effect depending on the current intensity, strength of the magnetic field, and duration of exposure. Accumulated
epidemiologic evidence indicates a correlation between exposure to ELF-EMF and childhood cancer incidence, Alzheimer’s
disease (AD), and miscarriage. However, adult cancer does not show augmented risk caused by the ELF-EMF. Also, no
consistent evidence exists in cardiovascular disease mortality due to ELF-EMF exposure. There is a lack of comprehensive
mechanisms for explaining the biological effect of ELF-EMF. Eventually, more studies are needed to clarify the mechanisms
of these magnetic fields.
Keywords Extremely low-frequency electromagnetic fields (ELF-EMFs)· Long-term exposure· Leukemia· Fertility·
Alzheimer disease
Introduction
Both natural and human-made sources produce magnetic
fields (MF) and Electromagnetic fields (EMF), and electric
magnetic current is flowing everywhere. Extremely-low-
frequency magnetic fields originating from human-made
sources generally have much higher intensities than the
naturally occurring atmospheric fields [1]. Electric and
magnetic fields, which we continuously expose in wherever
electricity is generated, transmitted, or distributed, have
three frequency ranges including the low-frequency (LF)
fields (1Hz–100kHz), high-frequency fields in the band of
radiofrequency (100kHz–3GHz) and microwaves (above
3GHz) [2, 3]. MFs, happen when there is electric current
flow, with varied frequencies are measured in Hertz (Hz),
and size of waves. The lowest rate (0Hz) is represented
by direct current or static fields. The higher frequency than
1016Hz, comprises ionizing radiations X-rays, Gama rays,
and ultraviolet light (UV). The extremely low-frequency
electromagnetic field (ELF-EMF) has a long wavelength
and occupies the range between 3 and 300Hz. The electric
power network results in extremely low-frequency fields,
ranging from 50Hz in Europe, 60Hz in North America
[4]. The ELF-EMF is non-ionizing radiation (NIR) and does
not carry enough energy per quantum to ionize atoms or
molecules [5]. The common sources of ELF-EMF in the
home appliances are refrigerators, vacuum cleaners, TV,
computer monitors. Anyone at home and work are exposed
to a combination of weak electrical and magnetic fields emit-
ted by power lines and electronic devices. Indeed, enhanced
demand for electricity-leading technologies and changes in
social behavior have increased the resource of these fields,
* Abbas Karimi
karimia@tbzmed.ac.ir
1 Biotechnology Research Center, Tabriz University
ofMedical Sciences, Tabriz, Iran
2 Department ofMolecular Medicine, Faculty ofAdvanced
Medical Sciences, Tabriz University ofMedical Sciences,
Tabriz, Iran
3 Department ofBiology, Faculty ofScience, Azarbaijan
Shahid Madani University, Tabriz, Iran

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so the human-made origin of these types of radiations is
prominent than the natural source. What extends the ELF-
EMF may affect biological condition is dependent on the
field strength, distance from the source, and the exposure
time. The highest rate is when a person is very close to a
high power source and long exposure time [6, 7].
Since the first evidence published in 1979 and deter-
mined the relation between the ELF-EMF and leukemia
in children, [8] studies in this context increased until the
International Agency for Research on Cancer (IARC) clas-
sified the ELF-EMF in group 2B, a "possible carcinogen" to
humans in 2002. This classification remains up to now [9].
Two decades of the study confirmed the association between
ELF-EMF and childhood cancers, especially leukemia [10];
likewise, there are reports of a twofold increase in the risk of
childhood leukemia from pooled analyses of previous stud-
ies [11]. Recently published studies data did not show con-
sistent results to support the association between ELF-EMF
and some types of cancer, such as glioma risk [12]. How-
ever, several pieces of evidence report the harmful effects of
ELF-EMF on the brain (Table1). The ELF-EMF exposure
influence a wide variety of diseases; a meta-analysis indi-
cates that occupational exposure to ELF-EMF increases the
risk of AD [13].
Moreover, there are hypotheses that ELF-EMF exposure
can cause heartbeat disturbances and cardiovascular dis-
eases [37]. The invivo and invitro studies have reported
that exposure to residential and occupational EMF affect
endocrine system function, reproductive function (such
as sperm motility, male germ cell death, and reproductive
endocrine hormones) and fetal development of animals
[38] (Fig.1). Albeit, there is a clear consensus on the EMFs
adverse effect; however, some studies highlight the posi-
tive effects of magnetic field therapy, in particular, in the
rehabilitation of post-stroke patients and cancer treatment,
specially in combination with an anticancer drug [39, 40].
Table 1 Possible effects of occupational exposure to ELF and diseases in recent 10-year studies
Asterisk indicate the studies included in the meta-analysis
Only findings from the studies in the last ten years evaluated occupational exposure of ELF on various diseases, and conditions based on JEM
methods are listed here. The ELF-MF JEM reflects the intensity of timeweighted average exposure in micro-Tesla (μT) by job-based on available
measurement data. Bowman etal. have evaluated how magnetic field JEMs can be used in population-based epidemiologic studies [36]
a Interactions between ELF and any of the chemical exposures
b Moderately increased risk estimates for MND and AD studies with considerable heterogeneity due to the methodologic differences among the
studies. Conflicting results are due to the misclassification of disease and imprecise exposure assessment in these studies
Study Condition Positive
evidence
References No
Turner etal. (2017) MeningiomaaNo [14]
Carlberg etal. (2018) Meningioma No [12]
Carlberg etal. (2017) Astrocytoma grade IV Yes [15]
Turner etal. (2014) Glioma Yes [16]
Oraby etal. (2018) Brain tumors No [17]
Li etal. (2009) Childhood brain tumors Yes [18]
Huss etal. (2018) Acute myeloid leukemia yes [19]
Talibov etal. (2019) Childhood leukemia*No [20]
Su etal. (2016) Parental occupational ELF-MF exposure and childhood leukemia risk*No [21]
Koeman etal. (2014) Follicular lymphoma (FL) yes [22]
Li etal. (2013) Breast cancer No [23]
Zhou etal. (2012) ALS*No [24]
Parlett etal. 2011) ALS No [25]
Huss etal. (2015) ALS Yes [26]
Koeman etal. (2017) ALS Yes [27]
Peters etal. (2019) ALS Yes [28]
Pedersen etal. (2017) Dementia, motor neurone disease, multiple sclerosis and epilepsy, Ye s [29]
Vergara etal. (2013) Primarily Alzheimer disease (AD) and motor neuron diseases (MNDs)b,*– [30]
van der Mark etal. (2015) Parkinson’s disease (PD) No [31]
Brouwer etal. (2015) PD mortality (occupational exposure to pesticides and ELF-MF) Yes [32]
Koeman etal. (2013) Cardiovascular disease (CVD) No [33]
Migault etal. (2020) Prematurity or small for gestational age (SGA) No [34]
Migault etal. (2018) Moderate prematurity or small for gestational age No [35]

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Although epidemiological studies provide destructive and
beneficial effects of EMF, still there is no precise mechanism
for explaining these processes. There are various underlying
molecular mechanisms for ELF-EMF exposure; changes in
free radical activities, including reactive oxygen and nitro-
gen species (ROS)/(RNS) species and endogenous antioxi-
dant enzymes and compounds that maintain physiological
free radical concentrations in cells. These changes can affect
many physiological functions including DNA damage;
immune response; inflammatory response; cell proliferation
and differentiation; wound healing process; neural activities;
and behavior [41]. Here, we review the role of ELF–EMF-
mediated diseases, with a focus on the mechanism of action
from published investigations. The weakness of these studies
prevents any firm conclusion, and those effects are not that
impressive.
ELF‑EMF andcancer
Cancer is one of the significant problems of global health;
it is believed that occupational and residential exposure to
ELF-EMF can be carcinogenic. It was assumed that peo-
ple living near power lines and who have the occupational
and residential exposure to ELF-EMF have the chance of
developing cancer, as described for the first time in 1979 for
childhood leukemia [8]. Published meta-analyses between
1998 and 2000 concluded that there is positive evidence of
elevated risk of childhood leukemia concerning residential
proximity to high-current power lines [42]. A pooled anal-
ysis has concluded that exposure to ELF-EMF with ≥ 0.4
μT intensity increase twofold the risk of childhood leu-
kemia; however, there is little evidence for linking child-
hood brain tumors and exposed to ELF-EMF with ≥ 0.4
μT intensity [11, 42]. Notwithstanding, some studies in
various countries have not found a significant association
between exposure to ELF-EMF and the risk of childhood
leukemia based on job-exposure matrix (JEM) method [20,
21], which is a tool for assessing exposures to power–fre-
quency (ELF-EMF) in retrospective epidemiologic studies
(Table1) [43, 44]. It may be due to the lack of appropriate
animal models recapitulating the natural history of leuke-
mia development. In childhood B‐cell acute lymphoblastic
leukemia (B‐ALL), the common chromosomal alteration is
the ETV6‐RUNX1 fusion gene. The B‐ALL mouse model
for the human ETV6‐RUNX1 + preleukemic state can pro-
vide an invivo tool to probe the epidemiologically observed
association of childhood leukemia with ELF‐MF exposure
[45]. Although some studies indicate associations between
parental occupational ELF-MF exposure and childhood
cancer [46]; however, there are inconsistent data regard-
ing parental occupational exposure to ELF-MF and risk of
ALL and acute myeloid leukemia (AML) in their offspring
[47]. Findings from the Childhood Leukemia International
Consortium (CLIC) did not find any associations between
parental occupational ELF-MF exposure and childhood
Fig. 1 Schematic illustration of ELF-EMF effects on human health.
The excessive exposure to extremely low-frequency magnetic fields
from power lines and electrical devices led to an increase in the risk
of neurodegenerative disorders, cancer, cardiovascular diseases. It
also has destructive effects on the reproductive system in which the
most common are Alzheimer disease, childhood leukemia, heartbeat
disturbances, and sperm motility, respectively

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leukemia [20]. Some studies have concluded occupational
ELF-EMF was not associated with increased risk of child-
hood brain cancer, including meningioma [12, 48, 49]. The
large-scale INTEROCC study using JEM to different levels
of ELF-EMFs indicated positive associations between ELF
and glioma [50]. A meta-analysis of breast cancer risk and
ELF-EMF exposure indicates ELF-EMF can increase the
risk of breast cancer in postmenopausal women [51]. At the
same time, other studies revealed no significant increased
risk of breast cancer [23, 52–54].
Mechanism ofaction
Despite many studies, the carcinogenic mechanisms related
to ELF-EMF are still unclear. Ramazzini Institute in Italy
has conducted the two large systematic and integrated pro-
jects of long‐term bioassays on over 7000 Sprague Dawley
rats to show the carcinogenic potential of non‐ionizing radia-
tion focusing on sinusoidal‐50Hz magnetic field (S‐50Hz
MF) from electric power. According to this report, sinusoi-
dal-50Hz Magnetic Field (S-50Hz MF) combined with
acute exposure to gamma radiation for 104weeks induces
a significantly increased incidence of malignant tumors in
male and female mice [55]. The exposure to ELF-EMF may
result in various changes at the cellular level that may lead
to cancer. To find out the mechanism of ELF-EMF related
childhood leukemia in transgenic animals exposed to ELF-
EMF, T-cells reduction, especially CD8 + cells has been
observed [56]. Male C57BL/6J mice exposed to 7.5kHz MF
at 12 or 120 μT for continuously 5weeks, and rat primary
astrocytes exposed to a 7.5kHz MF at 30 or 300 μT for 24h
emerged the same results and proposed that magnetic field
may increase cell proliferation or suppression of cell death
[57]. In male Wistar rats, exposure to 5.5 mT ELF-EMF for
7days induced an increased level of lipid peroxidation and
superoxide anion production at the brain [58]. Exposure of
human HaCaT cells for 144h by 60Hz ELF-EMF at 1.5 mT
activates the ATM/ChK2 signaling pathway and increases
the expression of p21 protein [59].
The mitogen-activated protein kinases (MAPKs), regu-
late essentially all stimulated cellular processes, include the
extracellular signal-regulated kinases 1/2 (ERK1/2) that are
responsive to extracellular cues. Single or repetitive expo-
sure of HeLa and primary IMR-90 fibroblast for 168h to
a 60Hz ELF-EMF at 6 mT neither induced DNA damage
nor affected cell viability. However, continuous exposure
increased the cell proliferation and phosphorylation of AKT
and ErK1/2 and decreased the intracellular reactive oxygen
species [60]. These results demonstrate that EMF uniformity
at an extremely low frequency (ELF) is an important fac-
tor in the cellular effects of ELF-EMF. Kapri-Pardes etal.
showed that the application of various field strengths ELF-
MF and time periods to eight different cell types increase
ERK1/2 phosphorylation. In this study, 0.15 µT ELF-MF
had the lowest and ∼10 µT hadmaximal effect on ERK1/2.
However, the phosphorylation of ERK1/2 is likely too low
to induce ELF-MF-dependent proliferation or oncogenic
transformation [61].
In another study MCF10A, MCF7, Jurkat, and NIH3T3
cell line exposed for 4 or 16h to a 60Hz at 1mT; Jurkat and
NIH3T3 cells showed no change, but MCF7 and MCF10A
had a significant decrease in cell count and DNA synthesis
followed by upregulation of PMA/P1 gene in MCF7 cells
[62]. Exposure of five tumor-derived cell line (HL-606K562,
MCF-7, A375, HH4) to 50 and 60Hz of ELF-EMF at a 2,
20, 100, and 500 μT density for 3days has demonstrated
that this electromagnetic field does not affect cell growth
or initial response of cell proliferation [63]. Exposure of
human umbilical vein endothelial cells (HUVECs) to sinu-
soidal 50Hz EMF at 1 mT for up to 12h of EMF can cause
an increase in cell proliferation and the phosphorylation and
overall expression of VEGF receptor 2 (KDR/FIK-1) [64].
In myelogenous leukemia cell line K562 exposed to 50Hz
ELF-EMF at 1 mT, significant modulation of INOS, CAT,
and Cytochrome P450 expression has been reported [65].
Despite the numerous studies, up to now, there is no
specific and unique biological mechanism for the potential
carcinogenesis of ELF-EMF. Anyway, as mentioned above,
ELF-EMF can induce cancer through stimulatory and
inhibitory effects on the immune system by affecting cell
cycle regulators and signaling pathways, which potentially
can affect cell proliferation and death. ELF-EMF can also
interfere with angiogenesis activity by effecting the VEGF-
related signaling pathway. Also, the ELF-EMF can modulate
cell cycle, apoptosis, angiogenesis, invasion, and metastasis
that lead to cancer by impacting the free radical production.
ELF‑EMF andneurodegenerative diseases
Evidence from the studies in the last 10years on ELF-EMF
exposure on neurodegenerative diseases are inconsistent and
conflicting [30, 31] (Table1). The effect of ELF magnetic
fields on neurodegenerative diseases was first described in
1996 by Eugene Sobel and colleagues. In this study, occu-
pational exposure from moderate to high EMF was signifi-
cantly associated with an increased risk of Alzheimer’s dis-
ease (AD) [66]. The results of other studies were in line with
this study and confirmed the impact of occupational expo-
sure of ELF-EMF on AD development [13, 67]. A report
from Switzerland indicates that residential magnetic field
exposure from power lines has considerable effects on AD,
senile dementia, amyotrophic lateral sclerosis (ALS), multi-
ple sclerosis, and Parkinson’s disease occurrence [68]. How-
ever, some studies report no association between occupa-
tional exposure to the ELF-EMF and Parkinson’s condition

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[31, 69]. In the Netherlands, a potential association between
ALS-related mortality among men and occupational expo-
sure to ELF-EMF has been reported [27].
Mechanism ofaction
Epidemiological and animal studies from research focusing
on a possible contribution of ELF-EMF and the development
of neurodegenerative disorders show conflicting data. Find-
ings from primary mouse neuronal cultures indicate that pro-
longed exposure to the ELF-MFs changes the intracellular
biochemical and epigenetic balance that might progressively
boost neurons toward a degenerative phenotype. In neuronal-
like SH-SY5Y neuroblastoma cells exposed to ELF-EMF
(50Hz/1 mT) the balance between generation and elimina-
tion of reactive oxygen species, and the balance between
pro- and anti-inflammatory cytokines linked to oxidative
stress, is maintained indicating that cells respond correctly
to ELF-EMF exposure. Although in this study following 1
mT ELF exposure, 5-hydroxyindoleacetic acid/5-hydroxy-
tryptamine ratio reflecting the rate of transmitter synthesis,
catabolism and release are increased while matrix metal-
loproteinases that play critical roles in neuronal cell death
were not significantly altered that did not provide a positive
link between ELF-EMFs and neurodegeneration [70]. Also,
ELF-MFs exposure (50-Hz (1 mT)) on SH-SY5Y cells and
mouse primary cortical neurons reduce the expression of
miR-34a that regulates neural stem cell differentiation [71].
One of the proposed mechanisms for AD is the decline of
melatonin (MLT) function. As reported by Kolbabová etal.
the secretion of salivary MLT is decreased following expo-
sure of 1–2months old cattle calves to 50Hz-MF. Accord-
ing to this study, ELF exposure decrease and increase MLT
secretion in winter and summer, respectively [72]. Overnight
exposure of H4 neuroglioma cells to 50Hz ELF-EMF at 3.1
mT intensity induces a significant increase of amyloid-beta
peptide secretion that is in keeping with beta-amyloid effects
on the risk of AD development [73]. Also, a recent study has
shown that above 50 μT ELF-MF may induce chromosome
instabilities as those found in AD patients [74]. In familial
Amyotrophic Lateral Sclerosis (fALS) mouse model that
carrying two mutant variants of the superoxide dismutase
1 (SOD1) gene, prolonged ELF stimulation (50Hz, 1 mT)
does not affect the viability and redox homeostasis, but sig-
nificantly impairs the expression of iron-regulating genes
(i.e., TfR1, MNFR1, and IRP1) [75]. There is growing evi-
dence regarding ELF-EMF and neurodegenerative diseases;
the sensible discrepancy is observed in the result of such
studies. Most of them report a direct relationship between
ELF-EMF and AD and ALS; however, there is little evi-
dence that is negligible for connecting the ELF-EMF expo-
sure and Parkinson’s disease needing further evaluation.
Cardiovascular diseases andELF‑EMF
Epidemiological studies report that exposure to ELF-EMF
alters heart rate variability (HRV) as predictive of spe-
cific cardiovascular pathologies [76]. Heart rate variability
(HRV) is the physiologic phenomenon of variation in the
time interval between heartbeat and results from the action
of neuronal and cardiovascular reflexes, including those
involved in the control of temperature, blood pressure, and
respiration. Laboratory research into the cardiovascular
effects of ELF showed that HRV is reduced after nocturnal
exposure to intermittent 60-Hz magnetic fields, and long-
term exposure to ELF-MF may be associated with acute
myocardial infarction and arrhythmia-related deaths [77].
However, a pooled analysis of laboratory studies did not
show a consistent impact on cardiovascular effects in par-
ticular on microcirculatory indicators such as heart rate,
HRV, and blood pressure [76].
In a community-based prospective cohort study, Koe-
man etal. reported no association between occupational
ELF-MF exposure and CVD mortality, including ischae-
mic heart disease (IHD), acute myocardial infarction
(AMI), subacute and chronic IHDs, arrhythmias, athero-
sclerosis and cerebrovascular diseases mortality [33]. In
the study of Johansen etal. on the impact of occupational
exposure to ELF-EMF on severe cardiac arrhythmia in
employees, no increased risk of severe cardiac arrhythmia
at 50 and 60Hz of ELF-EMF was reported [78]. Another
study report that occupational exposure to ELF-EMF
could slightly increase the risk of acute myocardial infarc-
tion [79]. Similarly, the 60-Hz magnetic field at 1800-µT
intensity did not affect desired cardiovascular parameters
[80].
Mechanism ofaction
The cell membrane is the first-line and as a primary site of
interaction with the low-frequency fields that interact with
moving charges in cells and change their velocities. There-
fore, the alterations in these charges and molecules affect the
production of biological effects as the magnetic field inter-
act with moving charges and change enzymatic activity and
the distribution of ions and dipoles [81, 82]. Such change
may pave molecular alterations in the cardiac function. EMF
exposure can affect the structure and function of the car-
diovascular system in rates and may facilitate myocardial
infarction by the nuclear changing of cardiomyocytes. ELE
exposure also induces increases in the activities of serum
creatinine phosphokinase, lactate dehydrogenase and aspar-
tate aminotransferase enzymes. Besides, it causes oxidative
stress and impaired antioxidant system [81].

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Exposure of cardiomyocytes isolated from neonatal
Sprague–Dawley rats to 15, 50, 75, and 100Hz ELF-EMF
at 2 mT density indicated that ELF-EMF could regulate
calcium-associated activities in cardiomyocytes [83].
Furthermore, exposure of the adult male Wistar rats to
60Hz ELF-EMF at 2 mT for 2h showed the possible
decrease in the Glutathione (GSH) content in the heart
[84] (Fig.2). In guinea pigs exposed to 50Hz MFs of 1, 2,
and 3 mT for 4h/day and 8h/day for 5day-duration, EMF
affected the formation of free radicals and the activity of
the antioxidant enzymes in the heart in proportion to inten-
sity and duration of exposure [85]. Inducing apoptotis,
dark brown stain muscle fiber nuclei, hyperemia muscle
fiber degeneration, distortion of some cardiac myocytes,
Fig. 2 The molecular mechanisms of ELF-EMF effects on cell func-
tion. The ELF-EMF decreases antioxidants concentration, which
antioxidants have a defense mechanism against free radicals. The
ELF-EMF could also induce the production of O2− in the cellular
environment, that play a major role in oxidative damage by two path-
way which includes excessive MDA production and Fenton pathway
that is subsequently lead to biomolecular damage, DNA double-
strand breaks, DNA/RNA damage, and cell death

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mononuclear cellular infiltration and histological struc-
ture of the myocytes spaces are serious histopathological
changes following ELE exposure in animal modesl [81,
82]. Despite extensive research efforts to date, there is no
evidence to conclude that exposure to ELF-EMF can cause
cardiovascular disease or cardiovascular-related mortality.
It is believed that ELF-EMF may harm the heart function
through free radical production and antioxidant enzymes
reduction.
Reproductive system andELF‑EMF
The adverse effects of ELF-MF on reproductive health
are controversial. Recent studies indicate that exposure to
ELF-EMF is a negative factor that contributes to its role in
miscarriage [86–88]. Women exposed to ELF-EMF during
pregnancy may have a high risk of spontaneous abortion
[89]. Fetal development may be affected by electric blankets
and heated waterbeds usage among pregnant women as a
consequence of the heat or electromagnetic field [90]. Nev-
ertheless, ELF-EMF effects on fetal growth and development
during human pregnancy have not yet been reported [34, 35,
91]. Also, exposure to ELF-EMF can increase sperm motil-
ity, depending on the field characteristics [92]. However, a
recent study demonstrated that laptop computers potentially
decrease sperm motility and increase DNA fragmentation
in sperms [93]. In addition to that, no association has been
reported for distance to residential exposure to ELF power
transmission lines and stillbirth mortality; however, more
efforts are needed for closer distances [94].
Mechanism ofaction
The isolated trophoblasts from first-trimester human chori-
onic villi exposed to a 50-Hz MF of 0.4 mT for 72h suggest
that MF inhibits the secretion of Human chorionic gonado-
tropin (hCG) and progesterone by trophoblast. However, to
what extent apoptosis affected in trophoblasts is unknown
[95]. In the study of Aydin etal. the adult Wistar female
rats were kept with 7.5m vertical distance to a power line
and exposed for 1, 2 and 3months continuously to ELF-
EMF; significant changes in plasma catalase activities,
without any effects on the morphological structure, weight
of uterus and ovaries was reported [96]. Infemale Wistar
albino rats exposed to 50-Hz 1 mT ELF-MF for 3h/day for
50 and 100days, the alterations in malondialdehyde (MDA)
concentrations and ultrastructural changes or irregularity in
nucleus and nucleolus in germinal epithelial cells of the rat
ovaries and uterushas been reported [97] (Fig.2). In the
study of Liu etal. the mouse spermatocyte-derived GC-2
cells intermittent exposed to a 50-Hz ELF-EMF at 1, 2, and
3 mT intensities for 72h. The ELF-EMF at 1 mT intensity
reduced the expression of DNMT1 and DNMT3b and
decreased genome-wide methylation, while 3 mT intensity
induced DNMT1 expression and increased the genome-wide
methylation [98]. In the study of Al-Akhras etal. the adult
female Sprague–Dawley rats were exposed to a 50-Hz sinu-
soidal MF at 25 µT for 18weeks, depending on the duration
of exposure, alteration in LH, FSH, estrogen, and progester-
one levels but no effect on ovary weight was reported [99].
In the study of Elbetieha etal. the adult male and female
mice were exposed to a 50-Hz sinusoidal MF at 25 µT for
90days, no effect on fertility and reproduction was found
[100]. Also, in another study by Al‐Akhras etal. exposure
to 50-Hz ELF-EMF at 25 μT for 18weeks on male rats
showed no effect on the weight of the body and the testes.
Nevertheless, an increase in the level of LH and a decrease
in the sperm count, testosterone level, and the weights of
seminal vesicles and preputial glands was observed [101].
In the zebrafish fertilized embryos exposed to 50-Hz sinusoi-
dal MF at 30, 100, 200, 400, and 800 μT intensity for 96h,
adverse effect on the embryonic development by affecting
the hatching, decreasing the heart rate, and inducing apop-
tosis were revealed [102]. In the study of Koziorowska etal.
the porcine uterus tissues were exposed to 50 and 120Hz
EMF at 8 mT for 2, and 4h in the presence or absence of
progesterone, according to frequencyand duration of expo-
sure to ELF-EMF, alteration in the synthesis and release of
oestradiol-17β (E2) in uterine tissues was observed [103]. In
Mouse spermatocyte-derived GC-2 cells exposed to a 50-Hz
ELF-EMF at 1, 2, and 3 mT intensities for 72h, no effect
on the growth, apoptosis or cell cycle was revelaed but in
differenet intensities an altration on the miRNAs expression
was reported [104]. El-Hussein etal. showed that exposure
to 125-Hz PMF at 1.0 μT for 48h induces developmental
abnormalities [105]. According to the studies mentioned
above, there are relevant evidence concerning-EMF-medi-
ate embryonic developmental abnormalities. On the other
hand, the invivo and invitro studies report that these fields
can disrupt the balance of the synthesis and secretion of
hormones in animals. Furthermore, ELF-EMF exposure can
affect reproduction and fertility in animals. Further studies
are needed to find out ELF-EMF effects on human reproduc-
tion and fertility.
ELF‑EMF andgenome instability
Numerous invivo and invitro studies have been carried
out to investigate ELF-EMF influences on DNA damage
[106–109] and DNA repair [110–112]. DNA damage can
be one of the sources of genome instability. DNA damage
can lead to cell death, aging, and cancer [113]. The most
apparent ELF-EMF influence on DNA is strand breaks
that include single-strand breaks (SSB), and double-strand

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breaks (DSB) [114, 115]. Some studies show an associa-
tion between ELF-EMF exposure and chromosomal dam-
age [116], and oxidative DNA damage [117]. DNA strands
breaks are produced as a result of endogenous agent effects;
for instance, free radicals and exposure to exogenous agents
such as ionizing and none-ionizing radiation and chemi-
cal. Exposure to ELF-EMF can cause DNA strand breaks
and cell death through an increase in free radical formation
[118–120] (Fig.2). Findings from a cross-sectional study
from Iran on power plant workers indicated occupational
exposure to ELF-MF is associated with SSBs in DNA of the
peripheral blood cells of power line workers [121].
A recent study by Wilson etal. reports that highly unsta-
ble expanded simple tandem repeat (ESTR) loci that have
high rates of spontaneous mutation in mouse genome can
provide new insights for the mutation induction—that is a
hallmark of genomic instability—in the germline of mice
exposed to ELF-EMF [122]. Albeit c-Myc activation is asso-
ciated with transformation and genomic instability; however,
invitro exposure to 1 mT of 60Hz magnetic field does not
affect DNA double-strand breaks genomic instability medi-
ated by c-Myc [123]. Monitoring of mutation rate in male
mice exposed to 10, 100, or 300 µT of 50Hz magnetic fields
for 2 or 15h did not show significant increases in the fre-
quency ESTR mutation rate than germline, which indicates
a controversy on ELF and genomic instability [122].
Another genome instability factor is mobile genetic
elements, which can be affected by environmental factors
[124, 125]. The human neuroblastoma BE(2) cells exposed
to 50-Hz PMF at 1 mT for 48h caused a decrease in retro-
transposition events [126]. The mechanism of this effect is
still unknown. Up to 45% of the human genome is made up
of transposable elements (TEs), the extent to which TEs (in
particular HERVs elements) may be affected upon exposure
to ELF-EMF, and PMF are remained to be explored.
ELF‑EMF therapy
Recent studies have provided some evidence in favor of
ELF-EMF beneficial effects in treating some medical con-
ditions such as tissue reconstruction [127–130]. A recent
comprehensive study represents that in the wound healing
process, ELF-EMF can drive the transition from a chronic
pro-inflammatory state to an anti-inflammatory by modula-
tion of cytokine profiles [131]. Another study showed sim-
ilar results of the potential therapeutic role of ELF-EMF
in wound healing processes by an increase in cell prolif-
eration, volatility, and change in expression or activity in
the mediators of inflammation, such as nitric oxide syn-
thase (NOS) and other nitrogen intermediates and COX-9
(cyclooxygenase-2) [132]. A recent study found that ELF-
EMF improves functional recovery in stroke patients by the
effect on generation and metabolism of nitric oxide (NO)
[39]. Exposed to ELF-PMF for six weeks and 8h in a day in
adult male diabetic rats caused the improvement of diabetic
nephropathy (DN) symptoms [133]. IAD rat model exposed
to 50-Hz ELF-EMF for 14days showed an improvement in
learning and memory impairments [134]. In a study of the
diabetic wounded mice exposed to pulsed EMF, a positive
effect resulted, including wound healing through increased
expression of FGF2 and the prevention of tissue necrosis
[135]. The Pulsed electromagnetic fields (PEMF) can cause
healing tissues through increased angiogenesis by stimulat-
ing the endothelial release of FGF-2 [136]. A systematic
review by Elmas represents evidence that exposure to EMF
can treat myocardial ischemia [137].
Conclusion
This review suggest that exposure to ELF-EMF has an
adverse biological effect, which depends on the current
intensity, strength of the magnetic field, and duration of
exposure. Accumulated epidemiologic evidence indicates a
correlation between exposure to ELF-EMF and childhood
cancer incidence, AD, and miscarriage. However, adult can-
cer does not show augmented risk caused by the ELF-EMF.
Besides, no consistent evidence exists on the mortality of
cardiovascular disease due to ELF-EMF exposure. Addi-
tional epidemiological studies in large study populations
with improved exposure assessments are needed to clarify
current inconclusive relationships. The invivo and invitro
evidence confirms the association between DNA strands
breaks and exposure to ELF-EMF. On the other hand, some
studies show the therapeutic effect of these fields. There is
a lack of a comprehensive mechanism for explaining the
biological effect of ELF-EMF on human health. Eventually,
more studies are needed to clarify the mechanisms of these
magnetic fields.
Acknowledgements The authors thank the Faculty of Advanced Medi-
cal Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. This
project was financially supported by Biotechnology Research Center,
Tabriz University of Medical Sciences, Tabriz, Iran (Grant/Award
Number: 61741)
Compliance with ethical standards
Conflicts of interest The authors declare no conflict of interest.
Ethical approval This study was approved by the Tabriz University of
Medical Sciences Human Research Ethics Committee in Iran (Ref no:
IR.TBZMED.REC.1397.973).
Research involving human participants and/or animals In this review
research paper, we had not any experiments on human and animal
samples.

Molecular Biology Reports
1 3
Informed consent In this study, we did not deal with the research par-
ticipants, and we did not need for informed consent.
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