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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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.

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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

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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).

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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.

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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

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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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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.

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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

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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. References Abhyankar LN, Jones MR, Guallar E, Navas-Acien A. Arsenic exposure and hypertension: a systematic review. Environ Health Perspect 2012;120:494–500. Abul-Hassan KS, Lehnert BE, Guant L, Walmsley R. Abnormal DNA repair in seleniumtreated human cells. Mutat Res 2004;565:45–51. Akay C, Thomas III C. Arsenic trioxide and paclitaxel induce apoptosis by different mechanism. Cell Cycle 2004;3:322–32. Amundson SA, Myers TG. Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene 1998;17:3287–300. Andrew AS, Karagas MR, Hamilton JW. Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. Int J Cancer 2003;104: 263–8. Andrew AS, Burgess JL, Meza MM, Demidenko E, Waugh MG, Hamilton JW, et al. Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic. Environ Health Perspect 2006;114:1193. Apel K, Hirt H. Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol 2004;55:373–99. Aro A, Alfthan G, Soimakallio S, Voutilainen E. Se concentrations in serum and angiographically defined coronary artery disease are uncorrelated. Clin Chem 1986;32: 911–2. Bansal MF, Mukhopadhyay T, Scott J, Cook RG, Mukhopadhyay R, Medina D. DNA sequencing of a mouse liver protein that binds selenium: implications for selenium's mechanism of action in cancer prevention. Carcinogenesis 1990;11:2071–3. Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol 2002;14:86–91. Becker D, Reul B, Ozcelikay A, Buchet JP, Henquin JC, Brichard S. Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats. Diabetologia 1996;39:3–11. Benbrahim-Tallaa L, Waterland RA, Styblo M, Achanzar WE, Webber MM, Waalkes MP. Molecular events associated with arsenic-induced malignant transformation of

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