Download Arsenic and selenium toxicity and their interactive effects in humans

Environment International 69 (2014) 148–158
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Environment International
journal homepage: www.elsevier.com/locate/envint
Review
Arsenic and selenium toxicity and their interactive effects in humans
Hong-Jie Sun a, Bala Rathinasabapathi b, Bing Wu a, Jun Luo a, Li-Ping Pu c, Lena Q. Ma a,d,⁎
a
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210046, China
Horticultural Sciences Department, University of Florida, Gainesville, FL 32611, United States
c
Suzhou Health College, Suzhou, Jiangsu 215000, China
d
Soil and Water Science Department, University of Florida, Gainesville, FL 32611, USA
b
a r t i c l e
i n f o
Article history:
Received 5 February 2014
Accepted 29 April 2014
Available online xxxx
Keywords:
Arsenic
Selenium
Glutathione
Arsenite methyltransferase
Synergistic
Antagonistic
a b s t r a c t
Arsenic (As) and selenium (Se) are unusual metalloids as they both induce and cure cancer. They both cause carcinogenesis, pathology, cytotoxicity, and genotoxicity in humans, with reactive oxygen species playing an important role. While As induces adverse effects by decreasing DNA methylation and affecting protein 53 expression,
Se induces adverse effects by modifying thioredoxin reductase. However, they can react with glutathione and
S-adenosylmethionine by forming an As–Se complex, which can be secreted extracellularly. We hypothesize
that there are two types of interactions between As and Se. At low concentration, Se can decrease As toxicity
via excretion of As–Se compound [(GS3)2AsSe]−, but at high concentration, excessive Se can enhance As toxicity
by reacting with S–adenosylmethionine and glutathione, and modifying the structure and activity of arsenite
methyltransferase. This review is to summarize their toxicity mechanisms and the interaction between As and
Se toxicity, and to provide suggestions for future investigations.
Published by Elsevier Ltd.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . .
As and Se uptake and metabolism . . . . . . . . . . . . . .
2.1.
Arsenic . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Selenium . . . . . . . . . . . . . . . . . . . . . .
3.
Arsenic and selenium toxicity . . . . . . . . . . . . . . . .
3.1.
Epidemiological studies . . . . . . . . . . . . . . .
3.2.
Cytotoxicity . . . . . . . . . . . . . . . . . . . . .
3.3.
Genotoxicity . . . . . . . . . . . . . . . . . . . .
4.
Antagonistic and synergistic relation between As and Se toxicity
4.1.
Antagonistic effect between As and Se toxicity . . . . .
4.2.
Synergistic effect between As and Se toxicity . . . . . .
5.
Concluding remarks . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Arsenic (As) is ubiquitous in the environment and it exists in four
oxidation states: arsenate (+5), arsenite (+3), elemental arsenic (0)
and arsine (−3). It is released to the environment through both natural
⁎ Corresponding author at: Soil and Water Science Department, University of Florida,
Gainesville, FL 32611, USA. Tel./fax: +86 25 8969 0631.
E-mail address: lqma@ufl.edu (L.Q. Ma).
http://dx.doi.org/10.1016/j.envint.2014.04.019
0160-4120/Published by Elsevier Ltd.
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148
149
149
150
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155
155
155
processes and anthropogenic activities. Arsenic is widely distributed in
the earth, ranking 20th in abundance in the earth’s crust. It has been
widely used in agriculture as pesticides and wood preservatives
(Sharma and Sohn, 2009). On the one hand, As has been used to cure
acute promyelocytic leukemia in humans (Miller et al., 2002). On the
other hand, As causes adverse health effects including cancers in
human. At present, millions of people worldwide suffer from chronic arsenic poisoning (Hughes et al., 2011; Rodríguez-Lado et al., 2013) mainly due to consumption of As-contaminated water and food.
H.-J. Sun et al. / Environment International 69 (2014) 148–158
Arsenic contamination in the environment is becoming a serious
public health problem in several regions. It is known that arsenite
(AsIII) is more toxic than arsenate (AsV), with inorganic As being more
toxic than organic As (Petrick et al., 2000). However, different organic
As species have different toxicity. For example, as final As metabolites,
monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV)
are less toxic than inorganic arsenic, whereas the toxicity of intermediate metabolites such as monomethylarsonous acid (MMAIII) and
dimethylarsinous acid (DMAIII) are much more toxic than inorganic arsenic (Petrick et al., 2000). The toxicity of various arsenic species increases in the order of AsV b MMAV b DMAV b AsIII b MMAIII ≈ DMAIII.
Selenium (Se) is a metalloid in group VIA and an analog of sulfur,
with four oxidation states in nature: selenate (+6), selenite (+4), elemental selenium (0), and selenide (−2) (Tinggi, 2003). Unlike As, Se is
an essential nutrient for humans, animals, and bacteria. It is important
for many cellular processes because it is a component of several
selenoproteins and selenoenzymes with essential biological functions
(Table 2) (Letavayová et al., 2008). Furthermore, many studies demonstrated that proper doses of Se can prevent cancers in animals and
humans (Clark et al., 1996; Ganther, 1999). However, it is toxic at levels
slightly above homeostatic requirement (Zhang et al., 2014). Similar to
As where AsV is less toxic than AsIII, SeVI is less toxic than SeIV in eukaryote
and prokaryote (Rosen and Liu, 2009). Abbreviations are listed in Table 1.
It is of considerable interest to examine their dual role as a toxicant
and nutrient. Se and As are both metalloids with similar chemical properties, playing dual roles regarding cancer. Arsenic is known for its carcinogenicity, yet it is also used in treating certain cancers. Similarly, Se is
a known anticarcinogen, but it also triggers cancer. Much research was
done to understand their carcinogenic mechanisms (Bansal et al., 1990;
Rossman, 2003), and the relation between cancer and their dual roles as
carcinogen and anticarcinogen (Bode and Dong, 2002; Chakraborti
et al., 2003). However, there still exist contradictory results as both synergistic and antagonistic toxicity between As and Se has been reported
(Biswas et al., 1999).
Hence the relation between As and Se has attracted increasing attention. This review summarizes and compares their toxicity mechanisms
to better understand the relation between As and Se toxicity.
2. As and Se uptake and metabolism
2.1. Arsenic
In terrestrial environment, As is mainly present as inorganic As,
which exists as pentavalent (AsV) under aerobic condition and trivalent
(AsIII) under anaerobic environment (Matschullat, 2000). However, AsIII
and AsV exert toxicity differently.
149
AsIII is typically present as a neutral species (As(OH)3°, pKa = 9.2) in
aqueous solution at physiological pH (Gailer, 2007). Due to its structural
similarity to glycerol, AsIII can be transported into cells through
aquaglycerolporins, a pore protein for transporting small organic compounds such as glycerol and urea (Liu et al., 2002). However, AsV uses
a different pathway into animals and human cells. As a phosphate analog, they have similar dissociation constants (pKa of arsenic acid: 2.26,
6.76, and 11.3 and pKa of phosphoric acid: 2.16, 7.21, and 12.3) (VillaBellosta and Sorribas, 2008). Similar to phosphate, AsV is present as an
2−
at pH 5–7. As chemical
oxyanions in solution, i.e., H2AsO−
4 and HAsO4
analogs, they compete for entry through phosphate transporters
(Huang and Lee, 1996).
After entering the cells in animals and humans, AsV is rapidly reduced to AsIII. Then AsIII undergoes multistep in cells through arsenite
methyltransferase (AS3MT) using S-adenosylmethionine (SAM) as the
methyl donor, producing methylated As compounds including MMAIII,
DMAIII, MMAV, and DMAV (Kojima et al., 2009). A classical pathway of
arsenic methylation was first proposed by Challenger (1945) who suggested that arsenic methylation involves a series of reduction and oxidation steps (Fig. 1A). Thereafter, Zakharyan and Aposhian (1999)
reported that AsIII can be methylated non-enzymatically in the presence
of both methylcobalamin and glutathione (GSH) (Fig. 1B).
In subsequent studies, investigators further explored the mechanism
of arsenic methylation and found enzymes play an important role in arsenic methylation. A new enzymatic metabolic pathway for arsenic
methylation is proposed (Fig. 1C). The –OH groups of As(OH)3 are
substituted by glutathionyl moieties, forming GSH conjugates As(GS)2
–OH and As(GS)3 (Hayakawa et al., 2005). Subsequently, as the
major substrates for AS3MT, AsIII–glutathione complexes are further
methylated to monomethylarsonic diglutathione MMA(GS)2 and
dimethylarsinic glutathione DMA(GS). Since DMA(GS) is unstable, it is
immediately oxidized to pentavalent DMAV, which is the major metabolite and is excreted from cells (Rehman and Naranmandura, 2012). In
addition, during arsenic methylation and in the absence of GSH, endogenous reductants (e.g., thioredoxin/thioredoxin reductase/NADPH) play
an important role (Waters et al., 2004).
Recently, Naranmandura et al. (2006) demonstrated a different
pathway of arsenic metabolism via investigating the hepatic and renal
metabolites of arsenic after an intravenous injection of AsIII in rats
(Fig. 1D). They confirmed that AsIII bound to proteins (AsS3 protein) is
metabolized in the body during the successive reductive methylation
by AS3MT in the presence of GSH and SAM and the reduced products
are excreted externally. Consistent with the mechanisms, both trivalent
and pentavalent inorganic and organic arsenicals have been detected in
the urine of individuals after chronic exposure to arsenic and in cell medium following in vitro exposure to arsenic (Devesa et al., 2004).
Table 1
Abbreviations used.
Chemical
Abbreviations
Chemical
Abbreviations
Arsenic
Arsenite
Arsenate
Monomethylarsonic
Dimethylarsinic
Monomethylarsonous
Dimethylarsinous
Selenium
Selenite
Selenate
Arsenite methyltransferase
S-adenosylmethionine
Arsenite-glutathione complex
Monomethylarsonic diglutathione
Dimethylarsinic glutathione
Selenocysteine
Dimethylselenide
Glutathione
As
AsIII
AsV
MMAV
DMAV
MMAIII
DMAIII
Se
SeIV
SeVI
AS3MT
SAM
As(GS)2–OH, As(GS)3
MMA(GS)2
DMA(GS)
Se–Cys
DMSe
GSH
Selenide
Selenopersulfide
Hydrogen selenide
Methylselenol
Dimethyselenide
Trimethylselenonium
Reactive oxygen species
Selenomethionine
Poly ADP-ribose polymerase
Xerodermapigmentosum protein A
Cardiovascular disease
Mitogen-activated protein kinases
Damage-regulated autophagy modulator
Excision repair cross-complement
Seleno-bis (S-glutathionyl) arsinium ion
Tumor necrosis factor
Thioredoxin reductase
Thioredoxin
Se2−
GSSeH
H2Se
CH3SeH
(CH3)2–Se
[(CH3)3Se]+
ROS
Se–Met
PARP-1
XPA
CVD
MAPK
DRAM
ERCC1
[(GS)2AsSe]−
TNF
TR
Trx
150
H.-J. Sun et al. / Environment International 69 (2014) 148–158
Table 2
Overview of selenoproteins in mammals adapted from Papp et al. (2007).
Selenoprotein
Category
Function
Glutathione peroxidase (GPx)
GPX1,
GPX2
GPX3,
GPX4
SelK,
SelR,
SelW
TrxR1
TrxR2
TrxR3
Sep 15
SelN
SelM
SelS
DIO1
DIO2
DIO3
SPS 2
Sel P
Metabolize hydrogen peroxide hydroperoxides
Protect the gastrointestinal tract against inflammation and cancer
Eliminatehydrogen peroxide, fatty acid hydroperoxides and phospholipid hydroperoxides
Directly reduce phospholipid- and phosphatidyl choline hydroperoxides
Perform an antioxidant function in the heart
Required to repair oxidative damaged proteins
Protect cells against oxidative stress (in the cytoplasm)
Reduce lipid hydroperoxides and hydrogen peroxide in biological processes, control
selenoprotein synthesis, and required for apoptosis (precise function remains elusive)
Involved in disease of brain
Involved in type 2 diabetes, inflammation, and vascular disease
Selenoprotein
Thioredoxin reductase (TrxR)
Iodothyroninedeiodinase (DIO)
Selenophosphatesynthetase (SPS)
Selenoprotein P
2.2. Selenium
As an essential trace mineral, Se is indispensable for cells to function
properly. Two inorganic species, selenite (SeIV) and selenate (SeVI), are
important in biogeological and biochemical cycle of Se, but they exhibit
different biochemical properties. For example, their toxicity and energy
consumption during uptake and metabolism are different (Shen et al.,
1997; Weiller et al., 2004). Hence, their transport and metabolic pathways have attracted more attention than the study of other forms of
Se. Nickel et al. (2009) indicated that SeVI shares a sodium-dependent
transport system with sulfates. Bergeron et al. (2013) pointed out that
sodium-sulfate cotransporters are responsible for transporting SeVI
whereas SeIV is mainly absorbed into cells by passive diffusion (Park
and Whanger, 1995).
Play a role in T3 production and control T3 circulating levels
Functioned in the local deiodination processes
Sec synthesis
Transport and storage of Se
Studies demonstrated that inorganic and organic Se can exchange
roles via a series of reactions in intracellular environment (Fig. 2).
After entering cells in animals and humans, inorganic Se is metabolized
via different pathways to selenide (Se2−) (Spallholz, 1994). For example, SeIV is readily reduced to Se2− by GSH via a non-enzymatic process.
For SeVI, its redox potential is too high to be reduced by GSH, so it must
first undergo enzymatic reduction to SeIV, which then is reduced to Se2−
by GSH (Ogra and Anan, 2009).
Weiller et al. (2004) proposed that SeIV is reduced to Se2−intracellularly via a different pathway. SeIV first reacts with reduced GSH to form
seleno-diglutathione (GS–Se–SG). Seleno-diglutathione is then converted to seleno persulfide (GSSeH), which either decays spontaneously
to elementary Se and GSH or is enzymatically converted to hydrogen
selenide (H2Se) under anaerobic conditions. The common intermediate,
Fig. 1. Pathways of arsenic metabolism in cells: A): arsenic methylation in Scopulariopsis brevicaulis (Challenger, 1945); B): non-enzymatic As methylation in rat liver (Zakharyan and
Aposhian, 1999); C): arsenic metabolic pathway in rat liver (Hayakawa et al., 2005); and D): metabolic pathway in rat liver (Naranmandura et al., 2006) where SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine; CH3+ = methyl group; GSH: glutathione; (CH3)(OH)2AsO− = monomethyl arsonous acid; (CH3)2(OH)AsO− = dimethylarsinic acid;
(CH3)3As = trimethyl arsine oxide; As(GS)3 = arsenic triglutathione; MMA = monomethylarsonic acid; DMA = dimethylarsinic acid; MAsIII(GS)2 = monomethylarsonic diglutathione;
DMAsIII(GS) = dimethylarsinic glutathione; DMAsIII = trivalent monomethyl arsonous acid; DMAsV = pentavalent dimethylarsinic acid; MMAV = pentavalent monomethylarsonic acid.
H.-J. Sun et al. / Environment International 69 (2014) 148–158
SeVI
Se
Se2-
GSH
GSSG
l
thy
me
De
M
SA
CH3SeH
Methyl
Demethyl
Methyl
(CH3)2Se
Demethyl
+
(CH3)3Se
th
ea
Br
Ur
ine
SeIV
Reductant
Selen
opho
spha
te
Lyase
Reacti
ons
ROS
Extracellular
C3H7NO2Se
Trans-selenation
C5H11NO2Se
General Protein
Fig. 2. Pathways of selenium metabolism in human and rats where SeVI = selenate;
SeIV = selenite; Se2− = selenide; GSH = glutathione; GSSG = oxidized glutathione;
SAM = S-adenosylmethionine; CH3SeH = methylselenol; (CH3)2Se = dimethyselenide;
(CH 3 ) 3 Se + = trimethylselenonium cation; C 3 H 7 NO 2 Se = selenocysteine; and
C5H11NO2Se = selenomethionine.
Se2−, is then used either for selenoprotein biosynthesis or for biomethylation to methylselenol (CH3SeH), dimethyselenide [(CH3)2–Se] or the
trimethylselenonium cation [(CH3)3Se+]. The later two can be extruded
to extracellular space, with (CH3)2–Se being released in the breath and
[(CH3)3Se+] being excreted in urine (Gailer, 2002).
Different selenocompounds are metabolized into Se2− by different
pathways. The C–Se bond in seleno amino acid, a main organic Se
compound, can be cleaved and transformed into Se2 − by lyase
reactions (Schrauzer, 2000; Suzuki, 2005). Selenocysteine (Se–Cys)
and selenomethionine (Se–Met), typical organic Se, can be transformed
into Se2 −. Selenocysteine forms Se2 − via β-lyase reaction while
selenomethionine is transformed into Se2− either through β-lyase reaction after successive trans-selenation reaction to selenocysteine or directly through γ-lyase reaction (Suzuki et al., 2007). Methylselenide,
the product of Se methyl metabolism, can demethylate to form Se2−
(Ohta and Suzuki, 2008).
3. Arsenic and selenium toxicity
Several review articles documented arsenic toxicity in humans and
animals (Fig. 3). Arsenic is a carcinogen, causing skin, bladder, liver,
and lung cancers (Tapio and Grosche, 2006; Yoshida et al., 2004).
151
Arsenic induces epidemiological toxicity, damaging organisms by producing excess ROS (Shi et al., 2004b; Wang et al., 2001). Arsenic is
also cytotoxic (Suzuki et al., 2007; Zhang et al., 2003) and genotoxic
(Benbrahim-Tallaa et al., 2005; Gentry et al., 2010). In addition, it is
well known that chronic exposure to arsenic can lead to arsenicosis, including skin lesions, blackfoot disease, peripheral vascular disease and
cancers. However, many studies have reported arsenicosis, see Jomova
et al. (2010) for example.
With respect to Se, many report its detoxification property, while its
toxicity has also been tracked for several decades. Several studies demonstrated that low Se is an efficacious anticarcinogen whereas high Se
can induce carcinogenesis, cytotoxicity and genotoxicity (Fig. 4)
(Selvaraj, 2012; Selvaraj et al., 2013). Some studies reported that As
and Se can induce similar toxicity via different pathways. So for this review, we focus on the common toxicity of As and Se, and compare the
mechanisms of their toxicity.
3.1. Epidemiological studies
As a well-known human carcinogen, extensive studies have explored As-induced mechanisms of carcinogenesis. Since cancer is a complex process, arsenic induces carcinogenesis by multiple mechanisms.
Mounting evidences have shown that arsenic interferences with a series
of gene proliferation process (e.g., DNA damage and repair, and cell
cycle and differentiation) and alter signal transduction pathways (e.g.,
protein 53 signaling pathway, Nrf2-mediated redox signaling pathway
and MAPK pathway) (Sinha et al., 2013; Wang et al., 2012). ROS induced
by As also play a crucial role in triggering cancer (Shi et al., 2004a). Furthermore, investigations found that methylation metabolites of arsenic
are also potential carcinogens. Wei et al. (2002) demonstrated that
DMA is a carcinogen for urinary bladder cancer in rat.
Besides being a carcinogen, arsenic also causes a number of noncancerous multi–systemic diseases including dermal disease, cardiovascular disease, hypertension and diabetes mellitus (Centeno et al., 2002;
Jomova et al., 2011). Researchers pointed out that trivalent arsenicals
(AsIII, MMAIII and DMAIII) can induce diabetes via disrupting glucose
metabolism based on intact pancreatic islets from mice (Douillet et al.,
2013; Paul et al., 2007). In addition, AsIII–induced inhibition of pyruvate
and α-ketoglutarate dehydrogenases is a main cause for diabetes
(Navas-Acien et al., 2006). Cardiovascular disease is closely associated
with hypertension (Chiou et al., 1997). There are several pathways for
arsenic-induced hypertension, including promoting inflammation activity and endothelial dysfunction, altering vascular tone in blood vessels, and affecting kidney function (Abhyankar et al., 2012). Besides,
Fig. 3. Arsenic toxicity in humans and rats.
152
H.-J. Sun et al. / Environment International 69 (2014) 148–158
Fig. 4. Selenium toxicity in humans and rats.
many researchers agreed that ROS’s role in As-induced non-carcinogenic effects should not be neglected (Halliwell, 2007; Nesnow et al., 2002).
Arsenic-induced ROS has been linked to alteration in cell signaling, apoptosis, and increase in cytokine production, leading to inflammation,
which in turn leads to more ROS and mutagenesis, contributing to pathogenesis of arsenic-induced diseases (Eblin et al., 2006).
As an essential nutrient, Se affects the functions of several specific intracellular selenoproteins as an essential constituent of selenocysteine
(Se–Cys). Epidemiological studies indicate that Se deficiency can induce
several diseases in humans. Se plays a vital role as an antioxidant in
humans. Considering its importance for humans, the recommended
dietary intake for Se is 55 and 30 μg/d for healthy adults in the US and
Europe and 50–250 μg/d for adults in China by Chinese Nutrition
Society.
The anticarcinogenic nature of Se has been investigated for several
decades. However, researchers found that there is an inverse relationship between Se content and cancer risk. For example, Whanger
(2004) reported that Se doses at 100–200 μg/d inhibit genetic damage
and cancer development in human subjects; however, at ≥ 400 μg/d,
Se probably induces cancer (Zeng and Combs, 2008). Although excessive Se can induce cancer in humans, the relation between Se and cancer
is still unclear. Several mechanisms are summarized in Tables 3 and 4.
It is well accepted that excess Se generates ROS (Shen et al., 2000;
Stewart et al., 1999), which is closely related to carcinogenesis
(Klaunig and Kamendulis, 2004; Valko et al., 2006). Therefore, ROS induced by excessive Se is a pathway for Se carcinogenesis, which is similar to arsenic. Kim et al. (2003) demonstrated that Se compounds
(selenite, selenocystine and selenodioxide) induce mitochondrial permeability transition (MPT)-mediated oxidative stress in HepG2 cells,
triggering cancer. Stewart et al. (1999) also found that Se compounds
(selenite and selenocystamine) generate 8-hydroxydeoxyguanosine
DNA adducts and induce apoptosis by generating ROS. In addition,
some studies also indicate adequate Se in the diet may drive tumorigenesis by elevating TR1 expression (Hatfield et al., 2009; Yoo et al., 2007).
Besides a close relation with carcinogenesis, Se is associated with development of chronic degenerative diseases such as amyotrophic lateral
sclerosis and cardiovascular disease (Bleys et al., 2007a; Vinceti et al.,
2009). High Se levels are positively associated with diabetes in humans
(Bleys et al., 2007a, 2007b). This is because Se can activate some important metabolic enzymes, which are originally controlled through the insulin signal transduction pathway, hence regulating metabolic
processes such as glycolysis, gluconeogenesis, fatty acid synthesis and
the pentose phosphate pathway (Becker et al., 1996; Stapleton, 2000).
In addition, Se can trigger neurodegenerative effect through killing
motor neurons and activating protein 38–53, which induces amyotrophic lateral sclerosis (Chen et al., 2010; Vinceti et al., 2013).
In addition, the role of Se in cardiovascular disease has been the
focus of major scientific debate and intensive investigation. In 1980s,
scientists failed to realize there is relation between serum Se and cardiovascular disease (Aro et al., 1986; Kok et al., 1987). However, recent
observations suggest a possible U-shaped association between Se concentration and cardiovascular disease (Bleys et al., 2009; Stranges
et al., 2010). Considering the inconsistent results, more research is
needed to provide insights into these elusive questions. In addition,
studies have also indicated that oxidative stress can be a factor in Seinduced toxicity (Letavayová et al., 2006; Maritim et al., 2003). Other
related toxic effects of Se (e.g., disruption of endocrine function, and
synthesis of thyroid hormones and growth hormones) are also related
to Se-induced oxidative stress (Valdiglesias et al., 2010).
In short, ROS plays an important role in epidemiological studies of As
and Se toxicity. Although the role of ROS in mammals exposed to As and
Se have been well documented, their mechanisms in inducing cancer,
cardiovascular disorders, and other diseases are not well characterized.
To better understand their epidemiological studies, further research is
necessary. Besides, ROS also plays an important role in arsenic cytotoxicity and genotoxicity (Nesnow et al., 2002; Pei et al., 2012).
3.2. Cytotoxicity
Cytotoxicity occurs when cell shows abnormal properties caused by
toxic contaminants. Many researchers explored the cytotoxicity of As
and Se, both causing cytotoxicity in cells via several pathways
(McKenzie et al., 2002; Selvaraj et al., 2013). They both induce cytotoxicity by generating ROS (Sies and de Groot, 1992). ROS levels can increase dramatically during cell exposure to As and Se. Arsenic causes
ROS production by inducing NADPH oxidase (Chou et al., 2004) whereas
Table 3
Role of Se as a carcinogen.
Exposure
Test material
Function
Reference
selenocystine phenylseleninic acid,
and ebselen for 30 min
XPA protein in recombinant mouse
Blessing et al., 2004
Sodium selenite and sodium
selenate for 24 h
Se for 1 h
Human peripheral lymphocytes
Human epithelial osteosarcoma cell
High Se diet for 7 months
Elder beagle dogs with and without prostate
Increase genetic instability, interfere with XPA–DNA
binding and Zn release from Zn finger motif, affect
gene expression and affect DNA repair
Damage chromosome
Induce carcinogenicity
Inhibit capacity of DNA repair
Induce carcinogeneity
Induce DNA damage
Induce cancer
Biswas et al., 2000
Abul-Hassan et al., 2004
Chiang et al., 2010;
Waters et al., 2005
H.-J. Sun et al. / Environment International 69 (2014) 148–158
153
Table 4
Role of Se as an anticarcinogen.
Exposure
Test material
Function
Reference
Methylseleninic acid and
Methylselenocysteine for 10 weeks
Molecular changes with Se
Selenite
Selenite
Selenite for 1 or 14 d
mice
Delay lesion progression, increase apoptosis,
and decrease proliferation
Prevent oxidative stress via selenopretion
Induce apoptosis
Regulate thioredoxin reductase 1
Modulate DNA and histones, and activate
methylation-silenced genes
Inhibited DNA methyltransferase
Wang et al., 2009
Prostate cancer cells Pr111, 117, 14, 14C1 and 14C2
Human hepatoma cell line (HepG2)
Lung cancer cell lines
Human prostate cancer cell
Phenylenebis(methylene)
selenocyanate for 24 h
Selenomethionine for 15 h
Se diet for 1 year
Human colon carcinoma HCT116 cells
Human lung cancer cells H1299
Female human (20–60) BRCA1 mutation carriers
High levels Se
Blood of inuit human (22–70 years)
Activate protein 53 tumor suppressor
Increased chromosome breakage in BRCA1
carriers and decrease breast cancers
Inhibited DNA adduct
Se diet for 3 months
7,12-dimethylbenz[a] anthracene
Single nucleotide polymorphisms
Blood of patients with chronic kidney disease
Mice
Blood of patients with colorectal cancer
Decrease DNA oxidative damage
Increase selenoprotein expression
Selenoprotein genes
Se induces ROS production from Se2 − reaction with thiols (Kitahara
et al., 1993). Excess ROS causes damage not only in lipids and proteins,
but also in mitochondria. ROS can trigger mitochondrial damage and
mitochondrial dysfunction (Kim et al., 2002, 2007). Shen et al. (2001)
found that ROS-induced oxidative stress results from a mitochondriadependent apoptotic pathway. It has been well established that ROS
generates cytotoxicity through activation of c-Jun N-terminal kinases
(JNK), an important subgroup of the mitogen-activated protein kinases,
which mediates diverse cellular functions such as cell proliferation, differentiation, and apoptosis (Shen and Liu, 2006). ROS can stimulate JNK
potentiated tumor necrosis factor (Ventura et al., 2004). In addition,
ROS can also serve as modulators of signal transduction pathways, subsequently affecting various biological processes including cell growth,
apoptosis, cell adhesion, and HIV activation (Apel and Hirt, 2004;
Suzuki et al., 1997).
Apart from ROS-induced cytotoxicity by As and Se, there exist different pathways of cytotoxicity between As and Se. Arsenic generates cytotoxicity by affecting the status of tumor-suppressor protein 53 (Huang
et al., 1999; Yih and Lee, 2000). Protein 53 has a crucial role in a wide
range of cellular functions by modulating transformation and regulation
of cell growth and cycle control, and DNA synthesis, repair, and differentiation, and apoptosis (Amundson and Myers, 1998; Ryan et al., 2001).
Yih and Lee (2000) reported that arsenic may induce protein 53
accumulation in human fibroblasts, which subsequently causes cell apoptosis by facilitating Bax translocation from the cytosol to the mitochondria, releasing cytochrome c and activating caspase-9 through
Apaf-1 and the apoptosome (Bargonetti and Manfredi, 2002; Kircelli
et al., 2007). In addition, protein 53 can also induce cell cycle arrest at
G2/M of the cell cycle by transcriptionally activating protein 21, the inhibitor of cyclin-dependent kinases (Akay and Thomas, 2004; Vogelstein
et al., 2000) and inducing autophagy in a DRAM (damage-regulated autophagy modulator)-dependent manner (Crighton et al., 2006).
Studies have shown that Se, a component of selenoprotein, has close
relation with redox, which can trigger cytotoxicity by modifying
thioredoxin reductase (TrxR), together with thioredoxin (Trx) forming
a powerful dithiol-disulphide oxidoreductase system (McKenzie et al.,
2002). The system can regulate cell growth by binding to signaling molecules (such as apoptosis signal-regulating kinase-1 and thioredoxininteractin protein), which is responsible for cell growth and survival
(Yoshioka et al., 2006). Wallenberg et al. (2010) also pointed out that
glutaredoxin proteins, as redox-active proteins, might also contribute
to Se cytotoxicity by reducing intracellular cystine. In addition, Se can
also modulate cell signaling pathways through a thiol redox mechanism
(Park et al., 2000). In short, As and Se induce cytotoxicity not only
through ROS generation but also by affecting corresponding genes and
proteins.
Calvo et al., 2002
Shen et al., 1999
Selenius et al., 2008
Xiang et al., 2008
Fiala et al., 1998
Seo et al., 2002
Kotsopoulos et al., 2010;
Kowalska et al., 2005
El-Bayoumy, 2001;
Ravoori et al., 2010
Zachara et al., 2011
Hudson et al., 2012
Méplan et al., 2010
3.3. Genotoxicity
Genotoxicity results from cell damages of genetic information,
which causes mutations. To date, there are numerous studies about
the genotoxicity of As and Se (Lu et al., 1995; Valdiglesias et al., 2010).
Similar to cytotoxicity, both As and Se induce genotoxicity by generating
ROS (Hei and Filipic, 2004; Yamanaka and Okada, 1994). When excess
ROS are present in cells, they react with cellular components, causing
genotoxicity. This is because they react with both deoxyribose and
bases in DNA, causing base lesions and strand breaks. In addition, ROS
also oxidize DNA, affect DNA repair and gene regulation, and threaten
gene stability (Ramana et al., 1998). Besides, both As and Se interact
with DNA repair proteins containing functional zinc finger motifs,
which is involved in transcription factors, DNA repair proteins, and
DNA–protein and protein–protein binding (Hartwig, 2001; Zhou et al.,
2011). Zhou et al. (2011) reported that AsIII impacts zinc fingers through
binding with its target molecule PARP-1, subsequently leading to breaks
of single-strand and double-strand of DNA and oxidative DNA damage
(Ho, 2004). Further, Se can react with metallothionein and release Zn,
affecting DNA-binding capacity and genomic stability (Blessing et al.,
2004; Larabee et al., 2009).
Apart from ROS-induced genotoxicity, researchers also explore
other pathways of genotoxicity induced by As and Se. Studies found
that arsenic can directly impact DNA repair capacity by decreasing repair and expression of the nucleotide excision repair pathway member
ERCC1 (Andrew et al., 2003, 2006). Chronic exposure of cells to arsenic
can also induce SAM depletion in cells, causing a global loss of DNA
methylation, and then DNA hypomethylation in turn affects genomic
instability (Sciandrello et al., 2004; Zhao et al., 1997). Moreover, arsenic
and trivalent methylated arsenic can interact with enzymes of SAM
synthesis pathways (Lin et al., 1999; Stýblo and Thomas, 1995).
This is consistent with Zhong and Mass (2001) who confirmed
that AsIII or its metabolites can alter the activities of DNA methyltransferases, and then inhibit or stimulate the enzymes of SAM synthesis
pathways. Similar to cytotoxicity, arsenic can also generate genotoxicity
by affecting the status of protein 53 (Jiang et al., 2001; Mass and Wang,
1997).
Regarding Se, some authors proposed that Se induces genotoxicity
via ROS generation by interacting with thiol groups (Letavayová et al.,
2006; Ramoutar and Brumaghim, 2007). However, Abul-Hassan et al.
(2004) found that dicentric chromosomes are approximately 2 times
greater in Se-plus irradiation treatment than Se-minus irradiation control. The result demonstrated that Se can directly inhibit cellular DNA
repair ability. Furthermore, Se generates genotoxicity by affecting ataxia
telangiectasia mutation and protein 53 (Wei et al., 2001; Zhou et al.,
2003). In short, the mechanisms of genotoxicity induced by As and Se
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H.-J. Sun et al. / Environment International 69 (2014) 148–158
have not been clarified though most researchers have attributed to their
ability to induce oxidative stress.
4. Antagonistic and synergistic relation between As and Se toxicity
Although they are both trace elements, As and Se possess different
uptake pathways by cells. While the uptake of AsV into cells is by the
phosphate transporter, SeVI uptake is via the sulfate transporter. SeIV
and AsIII do not compete through aquaglyceroprins (Rosen and Liu,
2009). Although they won’t compete to cross into the cells, they can
be toxic to each other. Some reported that Se alleviates As toxicity
(Biswas et al., 1999; Selvaraj, 2012) whereas others found that Se enhances As toxicity (Huang et al., 2008; Spallholz, 2004; Styblo and
Thomas, 2001). So there exists a pronounced synergistic and antagonistic toxicity relation between As and Se. To address this question, subsequent research traced the toxicity relationships between As and Se.
4.1. Antagonistic effect between As and Se toxicity
ð3Þ
In addition, another pathway was proposed by Rossman and Uddin
(2004). They pointed that SeIV can protect against AsIII-induced oxidative DNA damage via upregulation of the selenoproteins GSH peroxidase and thioredoxin reductase. There are also numerous in vivo
studies to support the antagonistic effect between As and Se toxicity.
When As and Se are taken up by humans, most As and Se are
transported to liver and reduced there, which is an important detoxification location. Due to high intracellular concentrations of GSH in hepatocyte, the –OH groups of As(OH)3 can be substituted by glutathionyl
moieties to form (GS)2AsOH (Gailer and Lindner, 1998). In the meanwhile, SeIV undergoes a spontaneous reaction with abundantly present
reduced GSH to form hydrogen selenide (H2Se) (Weiller et al., 2004).
In this case, nucleophilic attack of HSe− on (GS)2AsOH in aqueous
solution to form (GS)2AsSe− (Eq. (1)), which is transformed into
[(CH3)2As(Se)2]− (Eq. (3)) and subsequently excreted out of cells. So
during antagonistic effects between As and Se toxicity, the contents of
both As and Se in mice and rat decrease (Fig. 5) (Biswas et al., 1999;
Messarah et al., 2012).
4.2. Synergistic effect between As and Se toxicity
Many have investigated the toxicological and metabolic interactions
between As and Se, most of which focus on their antagonistic
effects. However, Levander (1977) pointed out that Se metabolites
(trimethylselenium ion and dimethyl selenide) can enhance arsenic
toxicity. Kraus and Ganther (1989) also reported that AsIII adversely affects Se metabolism, which enhances the toxicity of its partially methylated forms by blocking its metabolism in male rats. Recently, some
investigators reported that there is synergistic effects between As and
A
Selenide
GSH
B
Selenide
As
As
H2Se
GSSG
(GS)2As-OH
CH3SeH
(CH3)2Se
GSH
(GS)2AsSe-
H2Se
GSH
MMA
GSH
During the reaction, by virtue of nucleophilic capacity, HSe− attacks
the arsenic atom and displaces its − OH group (Eq. (1)). Eventually
[(GS)2AsSe]− is excreted out of the cell. Manley et al. (2006)
obtained similar conclusion, they indicated [(GS)2AsSe]− is formed in
−
−
ðGSÞ2 AsSe þ SAM→ ðCH3 Þ2 AsðSeÞ2 þ H2 O
GSH
ð1Þ
ð2Þ
Considering As–C bond is more stable than As–S, another
pathway is that SAM may have provided the methyl groups to transform [(GS)2AsSe]− into [(CH3)2As(Se)2]− and a methyltransferase
using [(GS)2AsSe]− as a substrate (Eq. (3)). However, more
studies are needed to elucidate the relation between [(GS)2AsSe]−
and [(CH3)2As(Se)2]−.
S-adenosylmethionine
−
−
ðGSÞ2 AsOH þ HSe → ðGSÞ2 AsSe þ H2 O
−
−
ðCH3 Þ2 AsOH þ HSe → ðCH3 Þ2 AsðSeÞ2 þ H2 O
S-adenosylmethionine
When As and Se are taken up by animals and humans, most of the
AsV and SeVI are transported to liver where they are reduced to AsIII
and SeIV, so it is important to discuss the relation between AsIII toxicity
and SeIV toxicity. Arsenic, a well-known carcinogen, was found to prevent selenite toxicity in the 30s, and the amazing finding has attracted
attentions from many scientists. For example, Moxon and DuBois
(1939) indicated that AsIII at 5 mg kg−1 completely prevents Se-induced
liver damage at 5 mg kg−1 through oral administration of water to rat.
In order to confirm this finding, more follow up research was conducted. Palmer and Bonhorst (1957) indicated that AsIII at 2 mg kg− 1
lowered SeIV toxicity at 5 mg kg−1 after intravenous injection to rats.
On the other hand, Holmberg and Ferm (1969) found SeIV decreased
AsV toxicity via an intravenous injection experiment. Rotruck et al.
(1973) first proposed that Se has biological function, indirectly proving
that Se can help organism to deal with arsenic toxicity. The antagonistic
effect of Se on arsenic toxicity has been gradually accepted by the public.
In recent years, more in vitro research showed that Se can alleviate arsenic toxicity by modifying cytotoxicity, genotoxicity and oxidative
stress (Chitta et al., 2013; Selvaraj, 2012). This conclusion was verified
via in vivo experiment by Sah and Smits (2012) who reported that dietary Se at 0.6 mg kg− 1 improved rats’ antioxidant capacity and
counteracted chronic arsenic toxicity in rats. Besides, Sah et al. (2013)
also demonstrated that high Se at 0.3 mg kg−1 diets can improve immunity to counter As-induced immunotoxicity.
By further comparing their metabolism, researchers found that As
and Se share similar methylation pathways (Figs. 1 and 2). Moreover
some have found that As and Se can mutually inhibit the excretion of
their methylation metabolite (Kenyon et al., 1997; Levander and
Argrett, 1969). Based on these results, they hypothesize that an As–Se
compound is probably formed, which generates less damage on cells
than As or Se alone.
Much effort has been devoted to understand the formation
of the As–Se compound. Based on X-ray absorption spectroscopy,
Gailer et al. (2000) first revealed the new As–Se compound as selenobis (S-glutathionyl) arsinium ion [(GS)2AsSe]−, which can be excreted
from hepatocytes to bile. The report is important to understand the toxicology induced by As and Se. Further research found that (GS)2As–OH
forms first when As and Se enter cell simultaneously, which then reacts
with hydrogen selenide HSe− to form [(GS)2AsSe]− (Gailer et al.
(2002b) (Eq. (1)).
erythrocytes and excreted into blood. However, there is another As–Se
compound [(CH3)2As(Se)2]− being detected (Gailer et al., 2002a,
2003). It was speculated that DMAV was first reduced by GSH to DMAIII,
then HSe− attacks the arsenic atom and displaces the − OH group,
yielding [(CH3)2As(Se)2]− (Gailer et al., 2002a) (Eq. (2)).
respire
excretion
(CH3)3Se+urine excretion
(CH3)2AsSe-
excretion
Fig. 5. Synergistic and antagonistic relation between As and Se toxicity: A): antagonistic
effect between As and Se toxicity; B): synergistic effects between As and Se toxicity.
H.-J. Sun et al. / Environment International 69 (2014) 148–158
Se toxicity through mutually inhibiting each other’s metabolites (Styblo
and Thomas, 2001; Walton et al., 2003). Based on these reports, we
hypothesize that As and Se can mutually inhibit the formation of
their methylated metabolites, resulting in more retention of inorganic
and/or monomethyl As and/or Se in tissues (Fig. 5).
This is because that it is generally accepted that As and Se undergo
similar metabolic conversions and are linked by requirements for GSH
and SAM. GSH, as a fundamental reductant in organisms, can donate
electrons for reduction reactions during metabolism of As and Se. Limited GSH limits their detoxification ability, increasing the retention of inorganic species in body (Hayakawa et al., 2005; Yang et al., 1999). SAM,
as a versatile molecule used in many biological reactions, serves as a
methyl donor for detoxification process of As and Se. Limited SAM is
also a limiting factor for their detoxication. When organisms coexposed
to high dose of As and Se, they will mutually inhibit the formation of
their methylated metabolites by competing for the limited SAM.
Styblo and Thomas (2001) supported this conclusion via an in vitro
study. They revealed that SeIV significantly increased the content of inorganic arsenic and decreased contents of DMA after hepatocytes of
rat exposed concurrently to AsIII and SeIV at 2 μM for 12 h. To better understand the relation between the two in vivo, some researchers further
explored their interactive mechanisms in rats. Csanaky and Gregus
(2003) found that SeIV compromised monomethylation of arsenic. Subsequently Pilsner et al. (2011) verified the conclusion in humans. They
reported that Se can reduce the methylation capacity in humans, increasing As-induced health risk in humans.
In addition, AS3MT, as the main catalyst for arsenic methylation, is
another critical limiting element for arsenic detoxification. Some researchers focused on the importance of AS3MT, and found that SeIV
can interfere with arsenic methylation via AS3MT (Styblo et al., 1996).
Walton et al. (2003) also showed that SeIV at 2 or 10 μM inhibited AsIII
methylation via inhibiting AS3MT, resulting in ~2-fold increase in retention of inorganic As (iAs) in hepatocytes of rat and human. Later on,
Song et al. (2010) provided new evidence to support the opinion that
Se can accelerate arsenic toxicity. They indicated that Se can modify
the structure and activity of AS3MT through the formation of RS–Se–
SR adducts with protein thiols or disulfide, subsequently inhibiting
AsIII methylation.
More studies supported that the synergistic effect between As and Se
toxicity. For example, Spallholz (2004) found that high levels of chronic
ingestion of arsenic cause Se being more toxic and carcinogenic over
time. Huang et al. (2008) reported that long-term exposure to arsenic
enhances Se toxicity even at low arsenic exposure levels. Based on
their results, we hypothesize that the mechanism of synergistic effects
between As and Se toxicity is that Se can interact with one or several
cysteines in the structural residues of AS3MT, inhibiting its activity
through modifying its structure. Residual AS3MT is prone to combine
with iAs, because of the conversion of MMA to MDA is more sensitive
than the conversion of iAs to MMA, resulting in more iAs and/or MMA
being retained in body. In short, Se addition interferes with the normal
metabolism of arsenic via several pathways, including decreasing contents of GSH and SAM for arsenic methylation and inhibiting the activity
of AS3MT for arsenic methylation.
According to worldwide survey of arsenic pollution, millions of people are threatened by arsenic exposure, primarily via drinking water.
Chronic exposure to iAs can result in diseases associated with arsenic,
including cancer and skin lesions. Se, as an important component for
selenoproteins, is recommended as an antagonist for As-induced diseases, so it plays a protecting role in reducing arsenic-induced adverse
health effect in humans. However, this view has been questioned by
some scientists (Duffield-Lillico et al., 2003; Spallholz, 2004). Huang
et al. (2008) reported that Se supplement significantly increases skin lesions when blood Se concentrations are increased from 130 to 186 μg/L.
Long-term low Se status may enhance arsenic toxicity even at low arsenic levels (Huang et al., 2008). Kolachi et al. (2011) pointed out that low
blood Se was associated with a greater risk for skin lesions at all levels of
155
arsenic exposure. Due to the complexity of human internal environment, the process of how Se interferes with arsenic metabolism is susceptible to multi-factors (nutritional status, health status and dietary
habits), which may result in different effect. Further research is needed
to better understand the synergistic effects between As and Se toxicity
in humans.
5. Concluding remarks
This review summarized the toxicity mechanisms and the relation
between As toxicity and Se toxicity in animals and humans and provided suggestions for future research. According to literature, ROS play a
fundamental role in As- and Se- induced toxicity in humans. Furthermore, As also induces adverse effects by decreasing DNA methylation
and affecting protein 53 expression. Se exerts adverse effects by modifying thioredoxin reductase. Meanwhile, much research has focused on
the interactions between As and Se in cells. Cells use different uptake
pathways for As and Se. The uptake of AsV into cells is by the phosphate
transporter while SeVI uptake is via the sulfate transporter. SeIV and AsIII
do not compete through aquaglyceroporins but they are toxic to each
other. This is because their metabolism is linked to GSH and SAM.
Their toxicity can be reduced when [(GS3)2AsSe]− complex is formed,
which is secreted outside of cells.
Based on recent studies, there are two views regarding relations between Se toxicity and As toxicity: 1) Se can decrease As toxicity via excretion of As–Se compound [(GS3)2AsSe]−, which can be formed via
HSe− substitution of −OH group of (GS)2As–OH, and 2) Se can enhance
As toxicity via modifying the structure and activity of AS3MT. We hypothesize that the interaction between As and Se is concentration-dependent in cells. At lower concentration, Se forms [(GS3)2AsSe]− with
As, leaving inadequate Se to interfere with AsIII methyltransferase. Excess As can be excreted extracellularly as MMAV and/or DMAV. At high
concentration, excess Se inhibits AsIII methyltransferase and subsequently suppresses As methylation and [(GS3)2AsSe]− formation,
resulting in more retention of As and/or MMA in body and causing
more toxicity in humans.
Acknowledgements
This research was supported in part by Jiangsu Provincial Innovation
Project.
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