Regulatory Toxicology and Pharmacology 99 (2018) 78–88

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Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

A review on arsenic carcinogenesis: Epidemiology, metabolism, genotoxicity T

and epigenetic changes
Qing Zhou, Shuhua Xi∗
Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public Health, China
Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China

A R T I C LE I N FO A B S T R A C T

Keywords: Long-term exposure to arsenic (inorganic arsenic) is a world-wide environmental health concern. Arsenic is
Arsenic classified as the Group 1 human carcinogen by the International Agency for Research on Cancer (IARC).
Inorganic arsenic Epidemiological studies have established a strong association between inorganic arsenic (iAs) exposure in
Carcinogenesis drinking water and an increased incidence of cancer including bladder, liver, lung, prostate, and skin cancer. iAs
Epidemiology
also increases the risk of other diseases such as cardiovascular disease, hypertension and diabetes. The molecular
Methylation
Signal transduction
mechanisms of carcinogenesis of iAs remain poorly defined, several mechanisms have been proposed, including
genotoxicity, altered cell proliferation, oxidative stress, changes to the epigenome, disturbances of signal
transduction pathways, cytotoxicity and regenerative proliferation. In this article, we will summarize current
knowledge on the mechanisms of arsenic carcinogenesis and focus on integrating all these issues to garner a
broader perspective.

1. Introduction increased risks manifesting 40 years after arsenic exposure reduction

Arsenic is an environmental contaminant found in soil, air, food,
and water. Chronic exposure to high levels of iAs is associated with a
wide range of adverse effects, such as skin lesions, peripheral vascular
diseases, reproductive toxicity, and neurological effects. In addition,
several epidemiological studies have linked arsenic exposure to a
variety of human malignancies in skin, lungs, bladder, liver (Sankpal
et al., 2012). Exposure occurs primarily via drinking water, but dietary
exposure can also be substantial. Inhalation is a main route of arsenic
exposure in occupational environment (Aylward et al., 2014). It is es-
timated that more than 100 million people worldwide are exposed to
carcinogenic levels of iAs, the majority of which are caused by drinking
arsenic contaminated groundwater. In some areas of the world, iAs in
drinking water is still at a very high level, such as Taiwan, Bangladesh,
India, China, Chile, Argentina and Mexico (Humans, 2012; Sankpal
et al., 2012; Cohen et al., 2013). Lung, bladder, and kidney cancer
mortality due to arsenic exposure have very long latencies, with
(Cohen et al., 2013).
The mechanisms by which arsenic induces carcinogenesis are un-
clear, in part due to lack of animal carcinogenicity studies for many
years. At presents, several mechanisms of tumorigenesis induced by
arsenic compounds have been proposed, including oxidative stress,
genotoxic damage, chromosomal abnormalities, modification of gene
expression, epigenetic mechanisms, cytotoxicity and regenerative pro-
liferation (Zhang et al., 2007a; b; Kitchin and Wallace, 2008; Cohen
et al., 2013). However, the main shortcomings in oxidative stress,
genotoxicity, and chromosomal abnormalities are that most the studies
supporting these modes of action being in vitro at lethal concentrations.
Furthermore, some of the genotoxicity data in vivo have several defi-
ciencies. Further understanding of the mechanisms of arsenic carcino-
genesis is needed. Therefore, in this paper, we provide and discuss
important information about the mechanisms of arsenic carcinogenesis.

Abbreviations: As3MT, arsenic-3-methyl transferase enzyme; BER, base excision repair; CA, chromosomal aberration; DAPK, death-associated protein kinase; DMA,
dimethylarsinous acid; DNMT, DNA methyltransferase; DSBs, DNA double strand breaks; EGF, epidermal growth factor; ERCC2, excision repair; ERK1/2, extra-
cellular signal-regulated kinase1/; GSH, glutathione; GSTO, glutathione-S-transferase omega; JNK, c-Jun N-terminal protein Kinase; MAPK, mitogen-activated
protein kinase; MMA, monomethylarsonous acid; MN, micronuclei; Nrf2, nuclear factor erythroid 2-related factor 2; NF-кB, nuclear factor-kappa B; PI3K, phos-
phoinositide 3-kinases; ROS, reactive oxygen species; RPA1, replication protein A1; SAM, s-adenosyl-l-methionine; SCE, sister chromatid exchange; VEGF, vascular
endothelial growth factor
∗
Corresponding author. Tel.: +86 13390587580.
E-mail address: Shxi@cmu.edu.cn (S. Xi).

https://doi.org/10.1016/j.yrtph.2018.09.010
Received 15 May 2018; Received in revised form 8 September 2018; Accepted 12 September 2018
Available online 15 September 2018
0273-2300/ © 2018 Elsevier Inc. All rights reserved.
Q. Zhou, S. Xi
2. Epidemiology of arsenic and cancer
To date, the International Agency for Research on Cancer (IARC)
has confirmed the association of arsenic exposure with cancer of the
skin, lung, and bladder, while reports on the relationship with the liver,
kidney, and prostate cancer are still limited. It is noteworthy that ar-
senic has been only related to kidney pelvis tumors rather than the
usual renal cell tumors, which are urothelial and an extension of the
urinary bladder (Ferreccio et al., 2013). Key epidemiological evidence
regarding the carcinogenicity of arsenic comes from studies of Taiwan,
Bangladesh, Chile, and Argentina, where drinking water contains high
concentrations of this metalloid (150 μg/L) (IARC, 2012). However,
there are few epidemiological studies to assess the carcinogenic effects
of arsenic at low to moderate levels of arsenic in drinking water and
food.
2.1. Skin cancer
According to the IARC, there is sufficient human evidence of skin
carcinogenicity of iAs (IARC, 2004). Skin cancer was the first docu-
mented carcinogenic effect from chronic exposure to iAs and has been
studied extensively (Hughes et al., 2011). Skin lesions, including skin
cancer, are characteristic of exposure to arsenic in drinking water
(Cohen et al., 2013). In skin, arsenic relates to increased risk for
squamous cell carcinoma (SCC) in situ, invasive SCC and basal cell
carcinoma (BCC) (Naujokas et al., 2013). Several studies have reported
the relationship between the chronic exposure of arsenic in drinking
water and the development of skin cancer. Arsenic induced skin cancer
due to high contamination of arsenic in drinking water has also been
observed in West Bengal, India (Haque et al., 2003). Most studies on
skin cancer have found an increased risk only at concentrations above
100 μg/L, but a case–control study by Leonardi et al. (2012) found a
positive association between BCC and exposure to iAs through drinking
water with concentrations < 100 μg/L. Overall, the risk of skin cancer
is increased in populations with high (> 100 μg/L) exposure to iAs in
drinking water.
While the toxicity of arsenic, in general, is well established, studies
on the association between exposure to low arsenic concentration and
the development of skin cancer are not enough. The association be-
tween the risk of skin cancer and concentrations of iAs in drinking
water needs further exploration.
2.2. Lung cancer
Lung is one of the major targets for tumorigenesis due to arsenic
exposure (Hubaux et al., 2013). Arsenic in drinking water has been
classified as a known cause for the lung cancer by IARC. Exposure to
inorganic arsenic in various mining occupations led to lung cancer also
could be discovered. Various epidemiological studies have shown the
link between ingestion of iAs through drinking water and development
of human lung cancer. In a case-control study, a clear trend in lung
cancer odds ratios (OR) and 95% confidence intervals with increasing
concentration of arsenic in drinking water was observed (Ferreccio
et al., 2000). Additionally, the associations between arsenic levels in
drinking water and mortality of lung cancer using village as unit were
assessed in ten townships in Taiwan, a significant increase in the
mortality of lung cancer in both genders with arsenic levels above
0.64 mg/L was found, but no significant effect was observed at lower
levels (Guo, 2004). Another study in northern Chile showed that lung
and bladder cancer incidence in adults was markedly increased fol-
lowing exposure to arsenic in early life, even up to 40 years after high
exposures ceased (Steinmaus et al., 2014). Smith et al. (2012) found
that a significant increase in lung cancer mortality in a region of Chile
where iAs concentrations in water ranged from 90 μg/L to nearly
1000 μg/L.
However, Ferdosi H (Ferdosi et al., 2016) did not demonstrate that
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Regulatory Toxicology and Pharmacology 99 (2018) 78–88
an increased risk of lung cancer was associated with median drinking
water arsenic levels in the range of 3–59 μg/L. A recent meta-regression
by Lamm et al. (2015) indicates negative slope at low exposure levels
(100–150 μg/L) with lung cancer. There is an increased risk of both
bladder cancer and lung cancer only at relatively high concentrations in
the drinking water (> 150 μg/L). In addition, tobacco smoking com-
bined with arsenic exposure increases the risk of lung cancer and de-
creasing arsenic exposure can also decrease the risk of lung cancer in
smokers (Chen et al., 2004a; b). Chen et al. (Chen et al., 2010a; b) found
no significant association between ingestion of well water containing
iAs at levels of 300 μg/L or less and lung cancer among never-smokers.
The OR was 2.25 for iAs concentrations in drinking water that are
greater than 300 μg/L (95% CI: 1.43–3.55). The threshold was found to
be modified by smoking. The relative contribution of iAs vs smoking
could not be assessed from the available data.
Until now, researches have focused on the association between lung
cancer and exposure to high levels of arsenic, but these studies are not
sufficient to evaluate the potential of iAs to induce lung cancer at low
exposures. In view of the potential relevance of low arsenic con-
centration to arsenic exposure, it needs further investigation.
2.3. Bladder cancer
The IARC considers there to be sufficient evidence for arsenic to
increase risk of urinary bladder cancer in humans, yet risks related to
exposure in the 10–100 μg/L range of arsenic remain uncertain
(Humans, 2004a; b; Meliker et al., 2010). An increased cancer mortality
among cohorts exposed to extremely high arsenic levels has also been
reported in Japan (Tsuda et al., 1995) and Chile (Marshall et al., 2007).
Studies confirm that the association between exposure to iAs in
drinking water and bladder cancer is found only after exposure to iAs
concentrations greater than 100 μg/L. A prospective cohort study in
northeastern Taiwan reported that the multivariate-adjusted relative
risk of urinary tract cancer was statistically significant for residents who
drank well water containing arsenic at levels > 100 μg/L (Chiou et al.,
2001). Schoen et al. (2004) concluded that an increase in bladder
cancer is observed only in humans who were exposed to iAs in drinking
water at high concentrations, usually several hundred μg/L. A cohort
study by Chen et al. (Chen et al., 2010a; b) found statistically significant
increase in urinary tract carcinomas in a Taiwanese population who
ingested iAs at concentrations greater than 100 μg/L. Wang et al. (Wang
et al., 2013a; b) found an increased risk of bladder or upper urinary
tract urothelial carcinoma only in non-smoking Taiwanese exposed to
iAs in drinking water at concentrations of ≥350 μg/L for 10 years or
more. Results from different geographical areas indicate a threshold for
association between iAs exposure and bladder cancer at concentrations
of 100 μg/L or higher (Mink et al., 2008; Chen et al., 2010a; b; Tsuji
et al., 2014).
These studies have only verified the correlation between bladder
cancer and high concentrations of arsenic, the studies at lower ex-
posures have shown inconsistent results. In a lower exposure study
conducted in the US, no increase in bladder cancer incidence was found
in population consuming drinking water containing iAs at concentra-
tions of 10–100 μg/L (Meliker et al., 2010). This finding was consistent
with results of an earlier ecological study in Michigan (Meliker et al.,
2007). In addition, an ecologic analysis in the United States found no
arsenic-related increase in bladder cancer mortality was found over the
exposure range of 3–60 μg/L (Lamm et al., 2004). However, an ecolo-
gical study conducted by Mendez et al. supports an association between
low arsenic concentrations in drinking water (1.5–15.4 μg/L) and
bladder cancer incidence in the United States (Mendez et al., 2017).
Mink et al. (2008) conducted a meta-analysis of data from eight studies
of low levels of iAs. The meta-analysis did not find significant asso-
ciations between exposures to low levels of iAs in drinking water (ty-
pically < 100–200 μg/L) and bladder cancer for never smokers. The
multiple epidemiologic studies support the conclusion that low
Q. Zhou, S. Xi
exposure to iAs does not increase the risk of bladder cancer (Tsuji et al.,
2014).
2.4. Liver cancer
The epidemiological data for the skin, lung and urinary bladder is
widely accepted, whereas the association of long-term iAs exposure
through drinking water with risk of liver cancer mortality remains
controversial (Liu and Waalkes, 2008). IARC listes the liver as a po-
tential organ for arsenic carcinogenesis (IARC, 2004). The increase of
liver cancer mortality in population drinking water with elevated ar-
senic was first reported in the southwestern population of Taiwan (Chen
et al., 1985). Moreover, increased liver cancer mortality associated with
drinking water arsenic levels have been reported in populations from
Inner Mongolia, China, Bangladesh, and Japan (Liu and Waalkes,
2008). A meta-analysis indicated that long-term iAs exposure through
drinking water increased the risk of liver cancer mortality (Wang et al.,
2014). In addition, an investigation in Chile revealed that exposure to
arsenic in drinking water during early childhood may result in an in-
creased in childhood liver cancer mortality (Liaw et al., 2008). Al-
though studies conducted in Argentina, Chile, and other regions have
reported a relationship of liver cancer with arsenic levels in drinking
water, no consensus has been made on this relationship mostly because
of a limited availability to representative data (Morales et al., 2000;
Baastrup et al., 2008).
2.5. Prostate cancer
Multiple studies in humans reveal an association between environ-
mental inorganic arsenic exposure and prostate cancer mortality or
incidence, prostate is considered to be a potential target for iAs carci-
nogenesis (Benbrahim-Tallaa and Waalkes, 2008). A US prospective
cohort study suggested that low to moderate exposure to inorganic
arsenic was prospectively associated with increased mortality of pros-
tate cancer (Garcia-Esquinas et al., 2013). Roh et al. conducted an
ecologic study in Iowa, which showed a significant dose-dependent
association between low-level (1.08–2.06 μg/L) arsenic exposure and
prostate cancer (Roh et al., 2017). Moreover, in a US based ecologic
study, counties with higher mean arsenic levels in community water
systems had significantly higher prostate cancer incidence. However, an
individual-level study of prostate cancer incidence and low-level ar-
senic exposure is needed (Bulka et al., 2016).
Overall, a reliable relationship between ingestion of iAs and cancers
including skin, lung, and bladder cancer was only found in drinking
water concentrations exceeding 100 μg/L (Mink et al., 2008; Tsuji et al.,
2014). Lack of significant associations may result from methodological
issues (e.g., inadequate statistical power and by potential mis-
classification of exposure) (National Research Council, 2001). In addi-
tion, exposure to inorganic and organic arsenicals via food supply,
which can confound epidemiology studies considerably, especially at
low exposures to arsenic in water (Aylward et al., 2014).
3. Metabolism of arsenic
The metabolism of arsenic is related to its toxicity. Inorganic arsenic
is absorbed in the gastrointestinal tract when ingested through food or
drinking water. Arsenic uptake is strongly dependent on its oxidation
state. iAsV enters cells through membrane transporters, such as the
sodium/phosphate co-transporters. The methylated pentavalent or-
ganic forms of arsenic are not transported, whereas the trivalent forms
(iAsIII) are readily transported (Rosen, 2002; Cohen et al., 2013). iAsIII
enters the cell via aquaglyceroporin channels and transporters (Yang
et al., 2012). The major transporters for the trivalent arsenicals include
P-glycoproteins, ATP-binding cassette transporters (multidrug-resistant
proteins), and glucose transporters (Cohen et al., 2013). The most of
circulating arsenic undergoes bio-transformation in hepatocytes where
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Regulatory Toxicology and Pharmacology 99 (2018) 78–88
arsenite undergoes a series of sequential oxidative-methylation and
reduction steps (Vahter, 2002). In the human arsenic metabolic
pathway, iAsV is converted to iAsIII, with subsequent methylation to
monomethylated and dimethylated arsenicals, respectively. Methyla-
tion is an important step in conversion of arsenic from inorganic to the
organic form, and the process consumes both S-adenosyl-l-methionine
(SAM) and glutathione (GSH) (Drobna et al., 2005). The arsenic-3-
methyl transferase enzyme (As3MT) metabolizes inorganic forms to
methylated forms (MMA and DMA), including both trivalent and pen-
tavalent forms, with SAM as the methyl-donating cofactor. (Suzuki
et al., 2002; Naranmandura et al., 2006). The dimethyl form also can be
further methylated to trimethyl arsenic oxide (TMAO) in rodents and
does not occur in humans except at extremely high exposures (Cohen
et al., 2013). In the biotransformation of inorganic arsenic, glutathione-
S-transferase omega (GSTO) catalyzes the reduction of arsenate, MMAV,
and DMAV to the +3 arsenic species which are more toxic. Chowdhury
et al. (2006). reported on the complete methylation of arsenate to
DMAIII in GSTO knockout mice. There appears to be other enzyme(s)
other than GSTO able to reduce arsenic(V) species but to a lesser extent.
While there is evidence that GSTO can reduce pentavalent arsenicals in
vitro, its in vivo relevance is lacking (Nemeti et al., 2015). The general
scheme of reactions is AsV + 2e→ AsIII + Me+→ MMAV + 2e →
MMAIII + Me+→DMAV + 2e→ DMAIII. Since arsenic metabolism in-
volves oxidative methylation with S-adenosyl methionine as the methyl
donor, some nutrients such as folate levels affecting one carbon meta-
bolism may influence the arsenic methylation patterns, leading diffi-
culties in exposure analysis (Gamble et al., 2005).
In the environment, the main forms of arsenic are iAsV and iAsIII
(National Research Council, 2001). The trivalent forms of arsenic,
especially organic trivalent arsenicals, are highly reactive and cyto-
toxic, with activity at low micromolar concentrations (Cohen et al.,
2013). It has been demonstrated that the trivalent forms of arsenic are
the toxic forms in a variety of cell systems. The trivalent forms of or-
ganic arsenic, MMAIII and DMAIII, have been also detected in the urine
of rodents and humans that were exposed to high concentrations of iAs
(Valenzuela et al., 2005). But the organic pentavalent forms of arsenic
are mostly much less reactive, with activity generally at millimolar
concentrations (Cohen et al., 2013).
Notably, arsenic methylation is considered to be a bioactivation and
detoxification pathways. The overall toxicity of arsenic is dependent on
the rate of methylation of the iAsIII. In vitro study has shown that
MMAIII and DMAIII are much more toxic than the pentavalent forms,
and trivalent methylated arsenicals are more toxic than trivalent in-
organic arsenic (Mass et al., 2001). Chen et al. suggested that a higher
ratio of MMA to DMA in urine is associated with an increased risk of
bladder cancer development (Chen et al., 2003; Chen et al., 2004a; b).
Recent studies showed that the higher percentage of methylated arsenic
in urine, the more evidence of increased risk of skin and bladder cancer
(Moe et al., 2016; Khairul et al., 2017). Moreover, it has been found
that MMAIII and DMAIII can inhibit the activities of many enzymes and
are more genotoxic than iAsIII (Dopp et al., 2010).
4. Genotoxicity
Genotoxicity can be produced either by direct interaction with DNA
or by indirect effects that produce errors in DNA. These indirect effects
can involve micronucleus (MN) formation, Sister chromatid exchange
(SCE) or chromosomal aberrations (CAs). In addition, inhibition of DNA
repair enzymes could also lead to an indirect genotoxic process.
4.1. Direct damage to DNA
The chromosomal effects and DNA damage were postulated to be
critical events in the initiation and progression of human cancer.
Nesnow et al. (2002) demonstrated that DNA reaction did not occur
with arsenicals. A direct interaction of arsenicals with DNA would lead
Q. Zhou, S. Xi
to formation of DNA adduct, and no arsenic containing DNA adduct has
been reported.
4.2. Indirect damage to DNA
The iAs-mediated chromosomal instability occurs frequently at
centromeres, leading to the formation of acentric chromosomes or the
fusion of centromeres between two chromosomes (Kesari et al., 2012).
Fusion of two chromosomes at their centromeres can cause improper
chromosome segregation, which results in aneuploidy or micronuclei
formation (Xie et al., 2014). However, a fusion occurring at chromo-
somal ends may result in the formation of ring-like structures and/or
participate in abnormal SCE (Kesari et al., 2012). At low doses, iAs does
not cause DNA base pair mutations; instead, generate double-stranded
breaks (Xie et al., 2014), which results in large-scale CAs (Klein et al.,
2007).
Increased incidences of CAs, SCE and MN have been reported from
the human populations exposed to arsenic through drinking water
(Ostrosky-Wegman et al., 1991; Lerda, 1994; Dulout et al., 1996;
Gonsebatt et al., 1997; Maki-Paakkanen et al., 1998; Mahata et al.,
2003). MN are detected in exfoliated bladder cells, buccal cells, sputum
cells, and lymphocytes from arsenic-exposed humans (Tian et al., 2001;
Basu et al., 2002). In vitro studies, concentrations of arsenite are
usually extremely high, frequently greater than 10 μmol/L, which
would be lethal to most cell lines (Kligerman et al., 2003; Gentry et al.,
2010). Such high concentrations of trivalent arsenicals usually used in
vitro could not be reached in vivo at environmentally relevant con-
centrations of iAs. In animal studies, the positive results appear at ex-
tremely high doses of arsenic, which would be expected to produce
cytotoxicity and cell death.
However, there are numerous difficulties in interpretation of these
studies. To begin with, most of these studies have not shown a dose
response in relation to arsenic exposure as assessing either drinking
water levels or urinary arsenic. Exposure to tobacco and tobacco pro-
ducts affect MN formation (Reali et al., 1987; Humans, 2004a; b; Roy
et al., 2016). This is particularly likely as a confounding factor given the
extensive use of betel quid in some populations and the relatively high
smoking rates (Humans, 2004a; b). Another possible variety among
populations could be folate levels, which vary between populations and
affect arsenic metabolism and toxicity (Gamble et al., 2006, 2007;
Peters et al., 2015). Folate is also associated with variability in micro-
nucleus formation (Lindberg et al., 2007; Bull et al., 2012).
4.3. Inhibition of DNA repair
Interaction with a variety of DNA repair proteins could potentially
lead to an increased risk of genotoxicity (Banerjee et al., 2008; Chen
et al., 2010a; b; Cohen et al., 2013). Inhibition of DNA repair has been
implicated as a mechanism of arsenic contaminated drinking water
induced carcinogenesis. Gentry et al. (2010) highlighted inhibition of
DNA repair is a mode of action of arsenic carcinogenic effect. Arsenic
can inhibit nucleotide excision repair (NER), base excision repair (BER),
and mismatch repair (Hossain et al., 2012). Arsenic interfering with
DNA repair is expected to promote mutation of key tumor suppressor
genes such as tumor protein P53 (TP53) in patients exposed to arsenic,
leading to increased risk of bladder cancer (Kelsey et al., 2005). Ar-
senic-mediated oxidative damage in enzymes is also reported to inter-
fere with the DNA repair mechanisms by either inhibiting ligation or
down-regulating the gene expression of DNA repair enzymes such as
DNA polymerase β (Sinha and Roy, 2011). Additionally, arsenic induces
formation of DNA adducts and leaves unreplicated stretches in re-
plicating DNA followed by DNA double strand breaks (DSBs) when the
adduct is excised. As arsenic impairs DNA repair mechanisms, the un-
repaired DSBs can lead to chromosome or chromatid type aberrations
(Wang et al., 2001).
In summary, arsenic negatively impacts DNA repair capability.
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Regulatory Toxicology and Pharmacology 99 (2018) 78–88
Arsenite interferes with the DNA damage response at multiple levels,
these effects of arsenic exposure likely contribute to its roles as a car-
cinogen.
5. Epigenetic changes
Recent a large body of studies on the mechanism of arsenic carci-
nogenesis have shown the potential involvement of altered epigenetic
regulation in gene expression changes induced by arsenic exposure
(Bjorklund et al., 2017). Epigenetics refers to the reversible regulation
of gene expression, independent of DNA sequences. Epigenetic me-
chanisms allow cells to rapidly alter long-term transcriptional activity,
thereby permitting coordinated changes in gene expression without
permanently altering the sequence of DNA. Epigenetic alteration, which
is not a genotoxic effect, leads to heritable phenomena that regulate
gene expression and thus could be considered a form of potentially
reversible DNA modification. Epigenetic alterations are also believed to
play an important role in the complex mode of action of iAs. The main
epigenetic mechanisms are DNA methylation in gene promoter regions
that regulate gene expression, covalent posttranslational histone mod-
ifications, and microRNAs (miRNAs) expression changes associated
with iAs exposure.
5.1. DNA methylation
DNA methylation is one of the several epigenetic mechanisms which
cells use to control gene expression. DNA methylation provides suffi-
cient control over genes regulating cell differentiation, proliferation
and organism development, and these changes can be passed to
daughter cells during replication (Herceg, 2007). Global genomic DNA
methylation is a sign of many types of cancer. DNA methylation is the
covalent addition of a methyl group to the 5th carbon (C5) position of
cytosine-rich region, known as CpG islands (Bjorklund et al., 2017). In
normal pathologically cells, promoter CpG islands regions are typically
unmethylated.
Methylation is a major and important step in arsenic bio-
transformation. These methylation steps facilitate arsenic excretion but
consume SAM at the same time. SAM, as the methyl donor for the
majority of methyltransferases, modifies DNA, RNA, histones and other
proteins, dictating replicational, transcriptional and translational fide-
lity, mismatch repair, chromatin modeling, epigenetic modifications
and imprinting, and thus plays an important role in cancer research
(Loenen, 2006). In humans, DNA methylation is initiated by the denovo
DNA methyltransferase 3 (DNMT3A and B) and maintained by DNA
methyltransferase 1 (DNMT1) (Bestor, 2000). Following low-dose iAs
exposure, the expression of the DNMTs is reduced, which results in less
methylation at target sites (Reichard et al., 2007; Cheng et al., 2012).
When cells metabolize arsenic, the arsenic methyltransferase, AS3MT,
transfers a methyl group from SAM to the arsenite, depleting the
available methyl groups needed to the DNMTs for DNA methylation
(Reichard et al., 2007).
Hypo- and hypermethylation of DNA in promoter regions are known
to mediate gene expression and to suppress gene expression, respec-
tively. Both global DNA hypomethylation and hypermethylation in the
promoter region of tumor suppressor genes are often associated with
carcinogenesis and cancer outcomes. Population studies have shown
that individuals having relatively lower capacity to methylate arsenic to
DMAV are at greater risk for skin cancers, bladder cancer, and periph-
eral vascular disease (Chen et al., 2003; Tseng et al., 2005). A hospital-
based case-control study performed in northern Mexico found that
women with higher %MMA and/or primary methylation index (PMI)
had an increased bladder cancer risk (Wei et al., 2017). Additionally,
human skin exposure to iAs also led to global hypomethylation of tumor
tissues (Zhang et al., 2007a; b). Arsenic exposure has been reported to
induce DNA hypomethylation in vitro and in animal studies. For ex-
ample, rats (Uthus and Davis, 2005) and mice (Okoji et al., 2002; Chen
Q. Zhou, S. Xi
et al., 2004a; b; Xie et al., 2004) exposed to iAsIII for several weeks
displayed global DNA hypomethylation and aberrant gene expression.
Studies in cell lines in vitro yielded similar results, with a reduction in
global genomic DNA methylation resulting from iAsIII exposure
(Reichard et al., 2007). Urothelial carcinoma patients with high arsenic
exposure show death-associated protein kinase (DAPK) promoter hy-
permethylation with low expression of the DAPK gene (Chen et al.,
2007). Hypermethylation and lower protein expression of DAPK were
also detected in iAs treated SV40-immortalized human uroepithelial
cells (Chai et al., 2007).
Conversely, some research indicates that iAs exposure leads to hy-
permethylation at the promoters of specific tumor-suppressor genes
(Miao et al., 2015). In iAs-exposed human hepatocytes, significant hy-
permethylation of the promoters of genes involved in DNA repair such
as excision repair cross-complementation group 2 (ERCC2) and re-
plication protein A1 (RPA1), and of genes associated with the Wnt
pathway like c-MYC (MYC) and Wnt family member 2B (WNT2B), was
observed (Miao et al., 2015). Dose-dependent hypermethylation at the
promoter region of several tumor suppressor genes was induced by
arsenic exposure in vitro and in vivo (Stabile et al., 2005; Zhang et al.,
2007a; b). Significant hypermethylation of the promoters of the tumor
suppressor p16, and the DNA repair gene, mutl homolog 1 (MLH1)
(Hossain et al., 2012; Lu et al., 2014), was observed in whole blood
obtained from humans chronically exposed to iAs. Additionally, the
promoter region of the p53 tumor suppressor gene was also found hyper
methylated in arsenic-induced skin cancer patients (Chanda et al.,
2006). In a population-based study of bladder cancer, a significant in-
crease in methylation at the RASSF1A and PRSS3 promoters was found
(Chai et al., 2007). This outcome was recapitulated in arsenic-induced
lung cancer in A/J mice, in which the arsenic exposure reduced the
expression of RASSF1A resulting from hypermethylation of its promoter
region (Chai et al., 2007).
Methylation of ingested iAs to MMAs and DMAs relies on folate-
dependent one-carbon metabolism. Most studies have not taken into
account controlling for this confounding factor, particularly for studies
from Asia, including India, Bangladesh, and China, where folate defi-
ciency can be quite common. This can greatly influence the result of
studies. In a cross-sectional study, Gamble ascertained that folate con-
ditions are associated with lower arsenic methylation (Gamble et al.,
2005). Subsequent study provides compelling evidence that folic acid
supplementation to adults with low plasma concentrations of folate
would result in increased arsenic methylation (Gamble et al., 2006,
2007).
Clearly, the results of various studies demonstrate that iAs can in-
duce global levels of DNA hypomethylation and promoter specific hy-
permethylation of tumor suppressor genes and suggest that iAs-induced
disruption of DNA methylation may be important in carcinogenesis. But
the current available studies are essentially descriptive and difficult to
interpret because of the complexity of the study populations and limited
information provided in the reports. Studies systematically in-
vestigating DNA methylation on a genome wide level in arsenic-ex-
posed cell lines and in target tissues are needed. Such studies would
help to clarify potential effects of arsenic exposure on DNA methylation
and carcinogenesis.
5.2. Histone modifications
In addition to DNA methylation, histone modifications could be
potential biomarkers for the assessment of arsenic exposure and pre-
diction of adverse health effects (Ma et al., 2016). Covalent post-
translational modifications of histone proteins are known to play an
important role in chromatin remodeling and thereby in regulation of
gene expression, causing various cellular responses to environmental
influences (Liu et al., 2015). To date, published studies on histone
modifications and arsenic toxicity have focused on acetylation, me-
thylation, and phosphorylation. These modifications modulate
82
Regulatory Toxicology and Pharmacology 99 (2018) 78–88
chromatin structure and regulate gene expression (Kouzarides, 2007).
Chromatin is structured within the cell nucleus in units called nucleo-
somes, in which DNA is packaged within the cell. The nucleosome core
particle consists of stretches of DNA wrapped in left-handed super he-
lical turns around a histone octamer consisting of two copies each of the
core histones H2A, H2B, H3, and H4 (Kouzarides, 2007).
5.3. Histone methylation
Histone methylation is also a reversible process, which occurs in
both lysine and arginine residues (Wysocka et al., 2006). In mammals,
histone methylation is usually found on histone H3 and H4, although it
also occurs on H2A or H2B. AsIII treatment can lead to differential ef-
fects on the methylation of H3 lysine residues, including increased H3
lysine 9 dimethylation (H3K9me2) and H3 lysine 4 trimethylation
(H3K4me3) and decreased H3 lysine 27 trimethylation (H3K27me3)
(Zhou et al., 2008). Elevated H3K9me2, mediated by increased levels of
histone methyltransferase G9a protein, correlates with transcriptional
repression (Peterson and Laniel, 2004; Zhou et al., 2008); and elevated
H3K9me2 was involved in the silencing of tumor suppressors in the
cancer cell lines (Esteve et al., 2007). Arsenite induces global and gene
specific changes in DNA methylation and alteration in global histone
methylation levels, suggesting that epigenetic mechanisms contribute
to arsenite-induced aberrant gene expression. However, data on the
patterns of histone methylation induced by arsenic exposure are lim-
ited, and further studies are required to decipher the relationship be-
tween altered histone methylation and gene expression, as well as its
effect on arsenic-induced carcinogenesis.
5.4. Histone acetylation
Histone acetylation is a dynamic and reversible event (Glozak and
Seto, 2007), which stimulates the nucleotide excision repair pathway in
vivo by increasing the chromatin accessibility (Escargueil et al., 2008).
More recently, changes in histone H3 acetylation have been observed in
AsIII and MMAIII - induced malignant transformation of human ur-
othelial cells in vitro. These modifications are arsenic specific, sug-
gesting that arsenicals may participate in tumorigenesis by altering the
epigenetic terrain of select genes (Jensen et al., 2008). Genome-wide
analysis suggests that iAs exposure during embryonic development
causes global hypo-acetylation at H3K9 (Jensen et al., 2008). Recently,
study showed that the global level of H4K16 acetylation in human
bladder epithelial cells was reduced in a dose- and time-dependent
manner by both AsIII and MMAIII treatment (Liu et al., 2015). A re-
duction in H4K16 acetylation caused by chronic arsenic exposure could
contribute to bladder carcinogenesis in bladder epithelial cells. More-
over, knockdown of MYST1, the gene responsible for H4K16 acetyla-
tion, resulted in increased cytotoxicity from arsenical exposure in
human bladder epithelial cells, suggesting that H4K16 acetylation may
be important for resistance to arsenic-induced toxicity (Jo et al., 2009).
These studies clearly support an association of iAs/MMAIII exposure
and altered histone acetylation, but further work is needed to under-
stand the underlying mechanisms and to clarify the effect of altered
histone acetylation on arsenic-induced toxicity and carcinogenesis.
5.5. Histone phosphorylation
Besides, phosphorylation of core histone proteins may be deeply
involved in arsenic-induced carcinogenicity (Ren et al., 2011). All four
core histone proteins, H2A, H2B, H3, and H4 can be post-translationally
modified by phosphorylation, and are targets of protein kinases
(Peterson and Laniel, 2004). Cyclin-dependent kinases are believed to
be responsible for H1 phosphorylation. Several kinases can phosphor-
ylate H2A and H2B. Phosphorylation of H3 has been specifically im-
plicated in cell cycle progression and regulation of gene expression
(Houben et al., 2007). Similarly, phosphorylation of histone H4 (serine
Q. Zhou, S. Xi
1) increases during the cell cycle, which is believed to be regulated by
casein kinase 2 (Barber et al., 2004). Only a few studies have demon-
strated a connection between histone phosphorylation and arsenic-in-
duced carcinogenicity. Studies have suggested that arsenic induced H3
phosphorylation might be responsible for the up-regulation of the on-
cogenes c-fos and c-jun (Li et al., 2003). Because arsenite exposure is
known to activate JNK and p38/Mpk2 kinase by inhibition of the cor-
responding protein phosphatases, phosphorylation of histone H3 via the
JNK/SAPK pathway might be a common mechanism of metal-induced
histone modification. In addition, Ray et al. reported that iAs induces a
coordinated regulation of Nrf2 and histone H3S10 phosphorylation,
which activates the human heme oxygenase-1gene (HMOX1) (Ray
et al., 2015). These studies suggest that H3 phosphorylation may also
contribute to As-induced carcinogenesis.
5.6. MicroRNAs
Several studies have shown that differential miRNA expression can
be a hallmark of cancer and miRNAs can function as potential onco-
genes or tumor suppressor genes influencing tumor development, pro-
gression and response to therapy (Gonzalez et al., 2015; States, 2015).
miRNAs constitute another epigenetic mechanism of gene regulation
affecting development, growth, and the response to stress. miRNAs are
single strand small non-coding RNAs that function as negative reg-
ulators of target mRNA expression at the post-transcriptional level,
which participate in diverse biological regulatory events and are tran-
scribed mainly from non-protein-coding regions of the genome (He and
Hannon, 2004). Each miRNA is thought to target several hundred
genes, and as many as 30% of mammalian genes are regulated by
miRNA (Lewis et al., 2005). miRNAs can modify essential cellular
functions such as proliferation, differentiation and programmed death
(He et al., 2005). The exact mechanisms by which expression of target
mRNA is repressed are still under investigation but may include the
inhibition of protein synthesis, the degradation of target mRNAs, and
the translocation of target mRNAs into cytoplasmic processing bodies
(Suarez et al., 2007). miRNAs bind to the 3′-UTR (untranslated regions)
of target mRNAs through base pairing, stimulating mRNA degradation
or inhibiting protein translation (Hei and Filipic, 2004; Flora et al.,
2007).
Several in vitro and human studies demonstrate that arsenic-in-
duced alterations in miRNA gene expression. A recently study provide
strong evidence that the differential expression of miRNAs and target
genes at early stage of arsenite exposure may contribute to arsenic in-
duced carcinogenesis (Al-Eryani et al., 2018). In prostate cancer, miR-
150 is upregulated, and is additionally correlated with tumor recur-
rence and metastasis, as well as poor overall survival; and miR-150
could serve as a novel and reliable prognostic biomarker for prostate
cancer patients (Dezhong et al., 2015). miR-21 is a key oncogene, which
is highly overexpressed in a wide range of cancers. miR-21 plays an
important role in the initiation and progression of cancer and is im-
plicated in multiple malignancy-related processes such as cell pro-
liferation, apoptosis, invasion, and metastasis. Knockdown of miR-21
can reduce proliferation and tumor growth in MCF- 7 cells, and reduce
invasion and metastasis in MDAMB-231 cells (Pratheeshkumar et al.,
2016). Upregulation of miR-21 can enhance the transformation po-
tential of cell by targeting programmed cell-death 4 (PDCD4) (Luo
et al., 2015). Gao founded that iAs-mediated autophagy was supported
by miR-21-induced PTEN-ERK signaling, and iAs-induced angiogenesis
occurred through a microRNA 425-5p-regulated CCM3 (Gao et al.,
2016). Furthermore, miR-155, an oncogenic miRNA, has been found to
be increased in many types of cancer (Xue et al., 2016). Chen C et al.
demonstrated for the first time that inhibition of miR-155 by its specific
inhibitor could remarkably attenuate the malignant phenotypes and
promote apoptotic cell death in arsenite-transformed cells (Chen et al.,
2017). Results from clinical trials showed that overexpressed miR-155
in the serum results in low survival rate and poor prognosis of patients
83
Regulatory Toxicology and Pharmacology 99 (2018) 78–88
with lung cancer (Xue et al., 2016). Moreover, inhibition of miR-155
also decreased the cell proliferation, and triggered the apoptotic cell
death in lung adenocarcinoma cells (Lv et al., 2016). These findings
indicate miR-155 may be served as the specific biomarker for diagnosis
and prognostic prediction of lung cancer. ROS generation resulting
from arsenic exposure is thought to play a large role in arsenic-induced
carcinogenesis and toxicity (Flora et al., 2007; Suarez et al., 2007) and
could potentially alter these miRNAs in a similar manner (Marsit et al.,
2006). The induced changes in miRNA expression were not stable,
suggesting that chronic exposure may be necessary to permanently alter
expression of miRNAs (Marsit et al., 2006).
Further studies are necessary to clarify whether chronic exposure to
arsenic can alter miRNA expression and what biological effects are re-
lated to the altered miRNA expression. All these epigenetic marks are
associated with iAs-induced carcinogenesis, additional research is re-
quired to clarify the mechanisms driving each system. More studies
comparing epigenetic alterations mediated by different arsenicals are
crucial, considering that toxicities and potential to cause cancer of ar-
senicals vary considerably. Expanded research in this area will de-
lineate the role of iAs exposure in the initiation and development of
cancer.
6. Signal transduction pathways
Signal transduction pathways transmit extracellular signals, via an
intracellular series of signaling molecules into gene. Cellular processes
such as proliferation, differentiation, and apoptosis are directed and
managed by these pathways or cascades. Arsenic can alter signal
transduction, which leads to activation or inhibition of transcription
factors, regulatory proteins which bind to DNA and regulates gene
transcription (Huang et al., 2004; Kumagai and Sumi, 2007; Platanias,
2009).
NF-κB is an inducible transcription factor involved in diverse sides
of cellular processes, NF-κB activation in cancers has been linked to
tumor cell resistance to apoptosis and necrosis, increasing proliferation,
angiogenesis, and metastasis (Chen et al., 2016). NF-κB is transiently
activated by a variety of signals, including cytokines, chemokines,
bacterial and viral products, and free radicals. Chen et al. recently
found that arsenite caused the oxidative damage by activation of Nrf2
and NF-κB-mediated pathways in cultured 16 E6/E7 transformed
normal human bronchial epithelial (16-HBE) cells (Chen et al., 2017). A
recently study showed that the transformation of HBE cells induced by
chronic exposure to sodium arsenite is mediated by decreased Nrf2
level and its downstream NQO1 and HO-1 protein, which subsequently
promote the malignant proliferation (Gu et al., 2016).
Epidermal growth factor (EGF) binds to EGF receptor (EGFR) and
ultimately activates mitogen-activated protein kinase (MAPK) path-
ways, which plays an important role in cellular stress response, in-
flammation, and growth. Arsenic can stimulate c-Src activity, which can
then activate EGFR by physical interaction resulting in two unique
tyrosine phosphorylation events, leading to ligand-independent EGFR
phosphorylation and constitutive activation (Simeonova and Luster,
2002). Arsenic can also induce activation of components of the EGFR
pathway in lung epithelial cells, such as Ras, Raf, MEK and ERK through
ROS (Zhang et al., 2007a; b; Miao et al., 2015). EGFR, an upstream
effector of MAPK signaling, is normally inhibited by protein tyrosine
phosphatases (PTPs) such as MAPK phosphatase 1. MAPK pathways
include the extracellular signal-regulated kinase1/2 (ERK1/2), p38
MAPK, and stress-activated protein kinase/Jun N-terminal protein ki-
nase (SAPK/JNK) pathways. Erk1/2 is involved in growth and differ-
entiation while p38 MAPK and SAPK/JNK are important in stress-in-
duced inflammation and mitochondrial-dependent apoptosis. Our
previous studies found that arsenic activated p-ERK, p-P38 and p-JNK
in SV-HUC-1 cells (Wang et al., 2013a; b). Arsenic-exposed hepatocel-
lular carcinoma cells display overexpression of EGFR (Sung et al.,
2012), while in leukemia cell lines, iAsIII is capable of activating Rac1
Q. Zhou, S. Xi Regulatory Toxicology and Pharmacology 99 (2018) 78–88

GTPases resulting in downstream engagement of the JNK pathway and immune system to some extent, the tumors related to arsenic, particu-
increasing cell survival and proliferation (Herbert and Snow, 2012). larly skin, lung, and bladder, are not increased in individuals who are
Furthermore, acute exposure to arsenite can stimulate the PI3K/ immunosuppressed (National Research Council, 1999). Essentially,
AKT phosphorylation cascade, leading to cellular transformation char- immunosuppression is only related to virally associated malignancies
acterized by increased proliferation and anchorage-independent growth such as lymphoma, Kaposi's sarcoma, various squamous cell carcinomas
(Liu et al., 2012). In human bronchial epithelial cells (HBECs), iAsIII can of mucous membranes, such as the cervix and oral cavity, and to a
stimulate AKT and the consequent release of vascular endothelial limited extent, liver cancer. (Cohen et al., 1991, 2004).
growth factor (VEGF), inducing cell migration through different me-
chanisms (Wang et al., 2012). During malignant transformation of stem
8. Cytotoxicity and regeneration
cells, arsenite has also been shown to suppress expression of PTEN, an
important inhibitor of PI3K/AKT signaling (Stueckle et al., 2012).
The mechanisms of cancer induced by arsenicals appear to involve
Evidence also suggests that this metalloid works through AKT to pro-
cytotoxicity with consequent regeneration (Cohen et al., 2006, 2013;
mote epithelial to mesenchymal transition (EMT), invasion, and mi-
Dodmane et al., 2013). Most commonly hyperplasia involves not only
gration of arsenic-transformed bronchial epithelial cells (Wang et al.,
an increase in the cell number but an increase in the replication rate
2012).
(Cohen et al., 2016). The evidence is strong and accumulating that
Endocrine disruptors (EDs) can mimic or antagonize the effects of
arsenic induced carcinogenesis of urinary bladder, skin and lung in-
estrogens in target tissue (Casals-Casas and Desvergne, 2011). Evidence
volves cytotoxicity and regeneration (Cohen et al., 2013; Dodmane
has accumulated that estrogen receptors α and β (ERα and ERβ) are
et al., 2013; Efremenko et al., 2015). Trivalent arsenicals (iAsIII,
expressed in lung tumors, acting both in membrane-initiated and nu-
MMAIII, and DMAIII) are highly toxic to cells at concentrations ranging
clear signaling (Siegfried and Stabile, 2014). Arsenic are EDs that ac-
from 0.1 μmol/L to less than 10 μmol/L. Concentrations less than
tivate genomic ERα, through interaction with the zinc fingers of the
0.1 μmol/L are adaptive, and concentrations ≥10 μmol/L are lethal to
DNA binding domain and/or activation of protein kinase C and/or di-
all cell types (Cohen et al., 2002, 2013; Gentry et al., 2010). High doses
rect interaction with the ligand binding domain (Fechner et al., 2011).
of DMAV orally administered for 10 weeks to rats increase urothelial
Several studies demonstrate that environmentally relevant concentra-
cell proliferation and cytotoxic changes, including cellular necrosis,
tions of NaAsO2 induces rapid activation of MAPK and cellular pro-
suggesting that administration of DMAV results in cytotoxicity with
liferation in human lung adenocarcinoma cells. Further, this activation
necrosis, followed by regenerative hyperplasia of the bladder epithe-
is mediated through ER, Src, EGFR, and GPER, and arsenite is de-
lium. Cohen et al. (2006) suggested that the toxic effects observed in
monstrated as EDs in lung adenocarcinoma (Stabile et al., 2005;
the rat urinary bladder induced by DMAV may be caused by DMAIII
Marquez-Garban et al., 2007; Pietras and Marquez-Garban, 2007).
formation in vivo.
Moreover, intense expression of ERα is observed in liver tumors and
Cytotoxicity has also been proposed as a nonlinear mode of action
tumor-surrounding normal tissues after gestational arsenic exposure in
for the bladder carcinogenicity of arsenic (Wei et al., 2005; Cohen et al.,
mice (Waalkes et al., 2004, 2006). ERα overexpression also occurs in
2006). Epidemiologic studies also support this conclusion. For the
uterine tumors, urinary bladder carcinoma (Waalkes et al., 2006).
cancer endpoint, it is not cancer that is induced by the arsenic but a
Overexpression of ERα and ER-linked cyclin D1 was also evident in
variety of toxicities, such as arseniasis skin changes, bronchitis, or ur-
liver biopsy samples of arsenicosis patients in Guizhou, China
othelial toxicity, which lead to regenerative proliferation and ulti-
(Marquez-Garban et al., 2007). Although aberrant ER signaling path-
mately an indirect induction of cancer.
ways may be important in carcinogenesis induced by arsenic, it may not
apply to all targets of arsenic carcinogenesis.
9. Conclusion
7. Immunosuppression
Inorganic arsenic is a human carcinogen targeting mainly urinary
The multiple effects of As on immune system tend to decrease the bladder, lung and skin. Genetic changes, inhibition of DNA repair,
immune surveillance system and increase the rate of infection, auto- changes to the epigenome and signal transduction are involved in ar-
immune disease, cancer and other immune mediated problems (Haque senic carcinogenesis. The metabolism of arsenic may also play a role in
et al., 2017). Recent studies found that arsenic disrupts macrophage this process. The biotransformation of iAsV into iAsIII and its methylated
function and exacerbate lipopolysaccharide-induced inflammation that conjugates play a crucial role in arsenic carcinogenicity at both genetic
is mediated by macrophages and monocytes (Srivastava et al., 2013). and epigenetic levels. Compared with iAs, MMAIII and DMAIII exert
Inflammation is a well-known hallmark event for cancer progression, several unique biological effects and are more cytotoxic and genotoxic.
which plays a key role in protecting the damaged tissues after injury, The methylation of iAs is considered a mechanism of activation of its
but also leads to several diseases, including various cancers (Rao et al., toxicity and carcinogenicity. In addition, the difference in susceptibility
2017). Increased secretion of inflammatory biomarkers like IL-8, TNF- to arsenic is related to arsenic carcinogenesis. The individual suscept-
α, and TGF-β is related with iAs exposure in urothelial cells (Liu et al., ibility may result from differences in metabolism genes, DNA repair,
2014). Chronic low-level iAs exposure (11–50 μg/L) evoke systemic cell transport, immune response, antioxidant defenses and cell cycle
inflammation by upregulating pro-inflammatory mediators like TNF-α, control. Evidence supporting arsenic carcinogenesis comes from in vitro
IL-6, IL-8, IL-12, and CRP (Prasad and Sinha, 2017). Dutta has reported investigations on human cells and epidemiological studies. Further
induction of various pro inflammatory and inflammatory markers in studies are still necessary for arsenic carcinogenesis.
chronic low level iAs exposed population (Dutta et al., 2015). These
results show that prolonged arsenic exposure can impair immune re-
Author contributions
sponses against inflammation. However, there are few in-depth and
systematic studies to determine whether arsenic causes cancer through
Qing Zhou conceived and drafted this manuscript. Shuhua Xi re-
inflammatory diseases. It is not clear whether arsenic changes the signal
vised and approved the final manuscript.
of inflammation first, and then causes chronic disease. Extensive la-
boratory studies (both in vitro and in vivo) are warranted to elucidate
the direct effects of arsenic on inflammation and cancer (Dangleben Conflicts of interest
et al., 2013).
Although there is evidence that inorganic arsenic can suppress the The authors declare no conflict of interest.

84
Q. Zhou, S. Xi
Acknowledgments
This work was supported by the gs1:National Natural Science
Foundation of China (81673207 and 81373023).
Transparency document
Transparency document related to this article can be found online at
https://doi.org/10.1016/j.yrtph.2018.09.010.
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