Introduction

Inorganic arsenic (iAs) is a potent environmental toxic element, and people are exposed over the world, mainly through contaminated drinking water (Wang et al. 2016; Yu et al. 2016; Yoon et al. 2016). Epidemiological studies have illustrated that long-term arsenic exposure favors development of different health hazard, viz. cardiovascular diseases, atherosclerosis with induction of cancer of skin, bladder, lung, and vital internal organs (Haines and Fox 2014; Lin et al. 2015; Liu et al. 2015). Arsenic is accumulated in paddy soil resulting in direct contamination of rice grain. JECFA ( 2010) reported that people are exposed to elevated levels of inorganic arsenic through drinking contaminated water, using contaminated water in food preparation and irrigation of food crops, industrial processes, eating contaminated food, and smoking tobacco. Consequently, the average daily human intake of arsenic is approximately 300 μg, virtually all of this ingested with food and water (Klaassen 1996; Kwong and Todd 1997). In 2010, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) re-evaluated the effects of arsenic on human health, taking new data into account. JECFA concluded that for certain regions of the world where concentrations of inorganic arsenic in drinking water exceed 50–100 μg/L, there is some evidence of adverse effects. In other areas, where arsenic concentrations in water are elevated (10–50 μg/L), JECFA concluded that while there is a possibility of adverse effects, these would be at a low incidence that would be difficult to detect in epidemiological studies. Rice contributes to an estimated 30–60% of the dietary intake of arsenic in polluted regions (Rahman et al. 2009). WHO recommends safe groundwater arsenic concentration up to 50 μg/L but proposes a provisional arsenic standard at 10 μg/L (Rahman et al. 2009). Cells continuously produce free radicals and reactive oxygen species (ROS) as part of metabolic processes. Arsenic exposure is assessed based on the concentrations of the sum of inorganic arsenic and its methylated metabolites (monomethylarsonic acid and dimethylarsinic acid) (Zhang et al. 2016). Arsenic exposure is a major public health concern because of its association with various types of cancers and other non-cancer adverse health effects. India and Bangladesh are most severely affected countries, due to the natural occurring arsenic contamination in groundwater that is used as drinking water (Rahman et al. 2015). Epidemiological studies have focused on investigating arsenic carcinogenicity with alteration of the immune system. It has been postulated that these carcinogenic effects are related to arsenic’s ability to act as a cocarcinogen with UV light exposure and its potential as a genotoxin (Ngalame et al. 2015; Son et al. 2015; Hsu et al. 2015). Arsenic is capable of oxidation through cellular stress mechanism by binding with sulfhydryl-containing proteins. Continued ingestion of arsenic for a long period leads to inflammatory and neoplastic and degenerative changes of skin, respiratory, nervous, cardiovascular, and reproductive system (Islam et al. 2012; Jovanović et al. 2012; Ma et al. 2012). Skin manifestations are the major negative health effect of chronic arsenic poisoning (Chakraborti et al. 2016; Yamaguchi et al. 2016). Respiratory complications are also found with lung cancer as a critical endpoint of chronic arsenic toxicity. Numerous epidemiological studies reported chronic cough, chronic obstructive pulmonary disease, and interstitial lung disease as common respiratory complications among the affected population (Smith et al. 2013; Chen et al. 2013a,b; Argos et al. 2014). Inorganic arsenic is clearly a human carcinogen causing tumors of the skin, lung, urinary bladder, and possibly liver. Impairment in the ratio of oxidants and antioxidants initiates the pathophysiological events that culminate in molecular and cellular damage to macromolecules and vital organs (Dávila-Esqueda et al. 2011; Majhi et al. 2014). The cellular system may be at great risk of oxidant-mediated cellular injury by direct tissue oxidation because it exists in oxygen-rich environment (Wnek et al. 2011; Flora et al. 2012). An increase in the generation of free radicals or suppression of antioxidant defense mechanism leads to the alteration of cellular dysfunction (Muenyi et al. 2011; Flora 2011). The mechanism of arsenic carcinogenesis is based on the reaction with DNA to form a variety of adducts that are excised by specific DNA glycosylases (Samadder et al. 2012; Vattanasit et al. 2014). It is also found that methylated forms of trivalent arsenic (monomethylarsonic acids (MAs), dimethylarsinic acids (DMAs)) are the only arsenic compounds that can damage naked DNA and do not require exogenously added enzymatic or chemical activation systems (Pierce et al. 2012; Yager et al. 2013). Finally, the focus of attention on the comparison between the effect of metabolism on toxicity and the effect of metabolism on carcinogenicity would also be desirable.

Oxidative stress: the precursor of carcinogenesis

Arsenic causes oxidative stress by damaging redox-sensitive signaling molecules, viz. NO, S-nitrosothiols, activating protein-1 (AP-1), NF-kappaB, p53, and p21 ras by metal-induced signal transduction pathways leading to the activation of NF-kappaB, a transcription factor governing the expression of the earliest response genes involved in a number of human diseases, including cancers (Koedrith and Seo, 2011; Prabu and Muthumani 2012; Stamatelos et al. 2013) (Fig. 1). Arsenic is established to cause oxidative status of cells either directly (via Fenton-type reactions with endogenous hydrogen peroxide) or indirectly by affecting cellular antioxidative defenses such as glutathione (Tandon et al. 2012; Gupta et al. 2013; Vattanasit et al. 2014). Metallothioneins (MTs) are small cysteine-rich, sulfhydryl-rich, metal-binding proteins which bind a number of metals with high affinity and decrease its level in serum (Ganger et al. 2016; Farooq et al. 2016). As(III) has a high affinity for thiols and appears to interact predominantly with DNA repair enzymes, but it is also a potent inducer of MT biosynthesis (Ganger et al. 2016). Oxidative stress resulted to reduce SOD and catalase activity that are important intracellular reductants for arsenic methylation and arsenic transport (Das et al. 2012; Gupta et al. 2013). Those are the two most important radical scavenging enzymes and body’s secondary defense against oxygen enzyme metabolites produced due to transitional heavy metals (Das et al. 2012). Both are two basic subcellular defense of antioxidant enzymes that counteracts free radicals produced during xenobiotic exposure (Wang et al. 2012; Rana et al. 2014). It is due to production of superoxide (O2−) and hydroxyl ions during persistent arsenic metabolism through a chain of reactions (Das et al. 2012; Jain et al. 2012) with downregulation of synthesis of antioxidant. The molecular mechanism of arsenic stress consists in the activation of mitogen-activated protein (MAP) kinases, extracellular regulated kinase (ERK), c-jun terminal kinase (JNK), and p38, which induce the immediate early genes: c-fos, c-jun, and egr-1, responsible for the heat shock protein synthesis and cell transformation (González-Chávez Mdel et al. 2011; Pan et al. 2013). Catalase, inhibitors of calcium, nitric oxide synthase, superoxide dismutase, and myeloperoxidase may modulate arsenite-induced DNA damage (Samuel et al. 2011; Lin et al. 2012a,b). Lipid peroxidation level (LPO) is a basic cellular deteriorating process induced by oxidative stress and occurs rapidly in the tissue rich in highly oxidizable polyunsaturated fatty acids (Kucukkurt et al. 2015; Jalaludeen et al. 2016). Arsenic causes elevation of LPO by lowering level of SH groups and antioxidant enzymes (Patel and Kalia 2013). It can be demonstrated in association with cellular injury from arsenic toxicity. It also provides a logical link between free radical initiated processes and resultant membrane dysfunction (Singh et al. 2014). Continued feeding of arsenic-contaminated water caused decrease in intracellular concentration of glutathione (GSH) and glutathione peroxidase (GSH-Px)/catalase level associated with significant lipid peroxidation. The protective role of GSH against cell damage is confirmed by the significant inverse correlation liver diseases induced by different metals like iron (Sankar et al. 2015; Singh et al. 2014). Arsenic-induced protein damage from oxidative stress may occur either directly or as a result of lipid peroxidation (Xie et al. 2014) suggesting failure of antioxidant defense system. Protein carbonyl served as a validated marker for protein oxidation. Reaction of free radicals with side chains of lysine, arginine, proline, theonine, and glutamic acid residues of protein leads to the formation of carbonyl derivatives (Tokar et al. 2014). Arsenic increased level of the protein carbonyl by inducing free radical generation or inhibition of antioxidant enzymes (Vélez-Alavez et al. 2013; Rana et al. 2015). Arsenic-induced increase level of protein carbonyl results to overproduction of ROS by overproduction of superoxide, hydroxyl, and peroxyl radicals (Rana et al. 2015). Nitric oxide (NO), a reactive free radical generated from L-arginine by NO synthase, is well recognized as a physiological messenger molecule (Talukdar 2013; Sharma and Sharma 2013). Excessive amount of NO, however, is potentially toxic to cellular system and has been implicated in numerous pathological situations and chronic inflammation (Takahashi et al. 2013). Also, NO is a cytotoxic agent involved as a mediator in inflammatory disorders, and because of its cytotoxicity, overproduction is deleterious to cell (Edwards et al. 2013). Arsenic causes significant increase in NO production that is responsible for erythrocytic damage and inflammatory changes. Exposure to arsenic results in overproduction of ROS by initiating oxidative stress, which is another risk factor for vascular dysfunction. It is related to inhibition of NO synthase (eNOS), that ultimately causes excessive NO production (Takahashi et al. 2013). Free radicals are also implicated to alter the intracellular thiol homeostasis during the metabolism of various xenobiotics (Ebert et al. 2014) GSH-Px is the major enzyme that removes hydrogen peroxide generated by superoxide dismutase in cytosol and mitochondria (Zhao et al. 2012) by oxidizing the GSH to GSSG (Talukdar and Talukdar 2014). GSH together with the GPx can detoxify free radicals into non-toxic products. The sharp rise of GSH-Px and catalase activity at arsenic toxicity is due to adaptation on part of the system to counteract the oxidative stress. Prolonged exposure of arsenic causes progressive decrease of GSH-Px and catalase activity suggesting failure of adaptive mechanism towards chronic arsenic insult. This depletion of protein sulfhydryl possibly means its increased utilization towards GSH synthesis. GSH depletion has been shown to affect PSH pool which is necessary for the preservation of protein function during oxidative stress (Bhattacharya and Haldar 2013). GSH is the main detoxifying antioxidant and the first line of defense against the oxidative stress induced by various exogenous and endogenous compounds (Hohnholt et al. 2015). The glutathione-related enzymes GPx and GR play a key role in the protection of cells from free radical-generated toxicity. A positive correlation between depletion of protein sulfhydryl groups and loss of cell viability has been observed by Bhattacharya and Haldar (2013). Loss of protein thiols preceded cell death and occurred more rapidly in cells with decreased levels of GSH. Arsenic causes inhibition of GPx and GR activity with diminution of intracellular glutathione level and leads to the increased concentration of free radicals resulting in the oxidative stress (Ilyas and Rehman 2015). Weak antioxidant defense system with increased ROS would leave cells vulnerable to oxidative DNA damage (Luo et al. 2015).

Fig. 1
figure 1

Pathological mechanisms involved in arsenic-induced carcinogenicity (adapted from Singh et al. 2011)

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Apoptosis induction by arsenic

Apoptosis is an active and gene-directed programmed cell death. Its role is to maintain tissue homeostasis and to eliminate excess or dysfunctional cells (Walker et al. 2010). Apoptosis is characterized by several morphological changes which include cell shrinkage, membrane blebbing, chromatin condensation, and nuclear fragmentation (Lowe and Lin 2000). It is also characterized by biochemical features such as caspase cascade and cleavage of various caspase substrates (caspase 3 and 9 activation) (Lowe and Lin 2000; Gewie 2003). In apoptosis, the functional integrity of the plasma membrane is long maintained (Stellar 1995).

Although arsenic can be poisonous, and chronic arsenic exposure from industrial or natural sources can cause serious toxicity, arsenic has been used therapeutically for more than 2400 years (Antman 2001). Previously, arsenic is incorporated into feed as a substance to promote the growth of livestock and poultry. Arsenic trioxide (As2O3) was administered as a primary antileukemic agent until it was replaced by radiation therapy. It may induce clinical remission in patients suffering from acute promyelocytic leukemia (APL) through induction of apoptosis and activation of caspases (Wang and Ren 2015). Antman et al. (2001) demonstrated that until supplanted by modern chemotherapy, arsenic trioxide after radiation was considered the most effective treatment for chronic myelogenous leukemia (CML) and other types of leukemia. They also revealed that arsenic trioxide has a major role in the therapy of APL, other hematologic cancers, and solid tumors with hematologic malignancies. This supplement is based on the proceedings of that meeting that arsenic trioxide increases the activity of caspase 3, inhibits cell growth, and induces apoptosis involving p53 overexpression (Wang et al. 2011). Arsenic retards growth at low concentrations, but higher concentration of arsenic causes apoptosis with activation of c-Jun NH2-terminal kinases, depolarization of mitochondrial membrane, generation of cytochrome c, activation of caspases, DNA fragmentation, and ultimately cell death (Kim et al. 2011). It activates p38, JNK, and caspase 3 dose dependently. Wang et al. (2011) observed that inorganic arsenic trioxide (As2O3) and melarsoprol were recently shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia and chronic B cell leukemia cell lines by inhibiting vascular endothelial growth factor (VEGF), activating caspases with p53 overexpression. It causes declined activity of enzymes containing vicinal sulfhydryl groups with inhibition of repair of pyrimidine dimers from DNA. Arsenite and arsenate could induce transactivation of AP-1 (Kim et al. 2011). This induction of AP-1 activity by arsenic appears to occur through activation of MAP kinases and protein kinase C (PKC) because increased AP-1 activity by arsenite could be blocked by either treating cells with PD98059, a MAP kinase Erk kinase (MEK)1 inhibitor, or overexpression of dominant-negative PKCα (Calviño et al. 2011). Furthermore, both arsenite and arsenate could induce transactivation of AP-1 in AP-1-luciferase reporter transgenic mice. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant-negative Erk2 into cells (Eguchi et al. 2011), whereas expression of dominant-negative Erk2 did not inhibit JNKs or mitogen-activated protein kinase Erk kinase 1/2. Therefore, arsenite-induced cell transformation was blocked in cells expressing dominant-negative Erk2 (Calviño et al. 2011). In contrast, overexpression of dominant-negative JNK1 increased cell transformation even though it inhibited arsenite-induced JNK activation (Martinez-Finley et al. 2011). Arsenic also induced AP-1 and nuclear factor kappa B (NF-κB) activation (Banerjee et al. 2011). Blocking NF-κB activation by dominant-negative inhibitory kappa Βα inhibited arsenic-induced apoptosis and enhanced arsenic-induced cell transformation (Calviño et al. 2011). Arsenic induced activation of JNKs at a similar dose range that was effective for induction of apoptosis in JB6 cells (Banerjee et al. 2011)

DNA damage and mutagenicity and carcinogenicity

Arsenic is a well-known genotoxigen and mutagen (Maiti et al. 2012). DNA strand breaks come from excision of oxidative DNA adducts and DNA-protein cross-links (Huang et al. 2013). Catalase, inhibitors of calcium, nitric oxide synthase, superoxide dismutase, and myeloperoxidase may modulate arsenite-induced DNA damage. Arsenite induces DNA adducts through calcium-mediated production of peroxynitrite, hypochlorus acid, and hydroxyl radicals (Chen et al. 2012). Arsenicals have also been shown to induce MTs in the liver, kidney, spleen, stomach, intestine, heart, and lung (Falnoga et al. 2012). MT may also be involved in carcinogenesis by metals such as Ni(II), Cr(VI), and As(III). MT appears to be involved in a redox reaction with As(III) that generates oxidants (Gautam et al. 2012). Heat shock proteins are produced in arsenic-induced cells, and it is capable to play a role in the acquisition of tolerance to agents which induce their synthesis (Markopoulos et al. 2013; Weng et al. 2014). Because of oxidative stress, the central component of heat shock response and arsenic-related effects occurs in various tissues. So, oxidative processes play important role to be as indicator for arsenic-induced mutagenesis and carcinogenesis (Sinha and Roy 2011). Epidemiology studies suggest that a large portion of arsenite-induced DNA strand breaks come from excision of oxidative DNA adducts and DNA-protein cross-links (Martinez et al. 2011). Arsenite induces DNA adducts through calcium-mediated production of peroxynitrite, hypochlorus acid, and hydroxyl radicals (Sinha and Roy 2011). Different experimental reports indicate that reactive oxygen species (hydroxyl radicals) play an important causal role in the genotoxicity of arsenical compounds in mammalian cells (Jasso-Pineda et al. 2012; Lin et al. 2012a,b; Flora et al. 2012).

Arsenic is carcinogenic (Fig. 2) due to its mutagenic activity and causes sister chromatid exchange and chromosomal breakage through clastogenesis (Singh et al. 2011; Samuel et al. 2011). Arsenic does not act through classic genotoxic and mutagenic mechanism, but rather at the level of tumor promotion by modulating the signaling pathways responsible for cell growth (Koedrith and Seo 2011). It affects signaling pathways by hampering cell growth with tumor promotion. DMA has been used as herbicide and is the major metabolite formed after exposure to trivalent (arsenite) or pentavalent (arsenate) inorganic arsenic. It increases mitotic damages with induction of aneuploidy and single-strand breaks in DNA (Bartel et al. 2011). The mitotic damage includes inclusion of peroxyl radical with production of ROS. It has a genotoxic effect by promoting organ-oriented cancers with production of micronuclei (Wnek et al. 2011; Adetutu et al. 2013). Some researcher suggested that arsenic can be used for chemoprophylaxis for prevention of cancer with p53 mutation when it is used in low concentration. Arsenic can induce DNA amplification with hypermethylation of cytosine in the promoter region of the tumor suppresor gene p53, leading to the cell transformation and secretion of growth factors: granulocyte macrophage colony-stimulating factor (GM-CSF), transforming growth factor alpha (TGF-alpha), and the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) (Selvaraj et al. 2012; Kesari et al. 2012; Xie et al. 2014) The chromosomal aberrations, oxidative stress, altered DNA repair, altered DNA methylation patterns, altered growth factors secretion, enhanced cell proliferation, promotion or progression of tumor, gene amplification, and, finally, suppresion of p53 gene are common phenomenon for c-myc overexpression and apoptosis cellular hyperproliferation, DNA hypomethylation (Chen et al. 2013a,b; Xie et al. 2014) (Fig. 3). Arsenic inhibits transcription of the hTERT gene, which encodes the reverse transcriptase subunit of human telomerase (Wnek et al. 2011; Coelho et al. 2013). The decreased telomerase activity leads to chromosomal lesions, which promote either genomic instability and carcinogenesis or cancer cell death (Wnek et al. 2011; Jiang et al. 2013). Arsenic can cause mutagenicity by altering DNA repair processes, inhibiting DNA ligase with deletions and point mutations (Litwin et al. 2013). It also causes chromosomal aberrations that include apoptosis, hormone receptor production cell cycle regulation, growth factor, signal transduction, stress response, and cytokine production of different oncogenes (Adetutu et al. 2013; Coelho et al. 2013). The cancer develops first of all in the lung and skin (ca basocellulare, squamous cell carcinoma), although it can involve the bladder, liver, and kidney. AP-1 is a functionally pleomorphic transcription factor regulating diverse gene activities. Increased AP-1 binding activities caused by activation of MAP kinase pathway could be one of the precursor markers in arsenic-induced cancers (Adetutu et al. 2013; Xie et al. 2014). In the absence of normal p53 functioning, co-mutagenic effects of arsenic cause DNA damage by elevating positive growth signaling pathway, defective DNA repair, increased expression of cyclin D1, and p53-dependent p21 expression elevation. The phenomenon exerts DNA damage and cell transformation (Litwin et al. 2013; Chen et al. 2013a,b).

Fig. 2
figure 2

Potential molecular targets for arsenic (adapted from Miller et al. 2002)

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Fig. 3
figure 3

Possible molecular mechanism of arsenic-induced toxicity

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Inhibition of DNA repair by arsenic

It is well documented that inorganic arsenic, a strong, widespread human carcinogen, causes induction of oxidative DNA damage with interference with DNA repair pathways. Modulation of the cellular DNA damage response and DNA repair are important molecular mechanisms contributing to its carcinogenicity (Ebert et al. 2011). Methylated arsenicals are responsible to interfere with DNA repair in cellular and subcellular systems. Walter et al. (2007) demonstrated that at the trivalent methylated metabolites, MMA(III) and DMA(III) inhibit poly(ADP-ribosyl)ation in cultured human HeLa S3 cells at concentrations as low as 1 nM, thereby showing for the first time an inactivation of an enzymatic reaction related to DNA repair by the trivalent methylated arsenicals at very low environmentally relevant concentrations. Trivalent arsenic inhibits the activity of isolated poly(ADP-ribosyl)ation that plays a major role in DNA repair, in cell cycle control, and thus in the maintenance of genomic stability; these findings could in part explain DNA repair inhibition and the genotoxic and carcinogenic effects of arsenic (Walter et al. 2007). Whereas, Ebert et al. (2011) narrated that the trivalent methylated metabolites exerted strong effects during carcinogenic process on the investigated several base excision repair (BER) key players at cytotoxic concentrations. p53 function has been shown to be inactivated by arsenite and MMA(III). MMA(III) led to a marked impairment of p53 induction in response to benzo[a]pyrenediolepoxide with reduction of p53 DNA binding involved in arsenical-induced DNA repair inhibition (Hartwig 2013). MMA(III) were shown to inhibit the association of the damage recognition protein to the site of UVC-induced DNA damage with diminished gene expression of xeroderma pigmentosum group (XPC) and xeroderma pigmentosum complementation group (XPE) and a reduced XPC protein level; this may be explained by reduced activity of p53, which serves as a transcription factor for both DNA repair genes, perhaps due to unfolding of the zinc-binding structure within the DNA-binding domain.

Methylation and genotoxicity

Arsenic has been shown to be genotoxic in a wide variety of different experimental setups and biological end points. Inorganic arsenic is enzymatically methylated by consuming S-adenosyl methionine (SAM) and binds with methyltransferases by donating methyl for methylation to cause carcinogenesis (Chen et al. 2013a,b; Hsieh et al. 2014) Methyltransferase (AS3MT) polymorphisms were also associated with AS3MT expression in peripheral blood, such that polymorphisms associated with efficient methylation were associated with reduced expression of the AS3MT gene (Engström et al. 2011). They also documented that the effect of the polymorphisms is of importance for risk assessment of As, because a low methylation efficiency is associated with increased risk for As toxicity. Treatment with sodium arsenite induced a significant decrease in DNA migration with significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow (Qu et al. 2010). Arsenic plays a role as co-stimulant of mitosis similar to interleukin-1 during carcinogenic process, like carcinogenic progressors (Ren et al. 2011; Su et al. 2012). In vitro arsenic acts as clastogen to induce chromosomal mutagenicity like micronuclei, chromosomal aberrations, sister chromatid exchanges with elevated aneugenic potentiality (Chung et al. 2011). It inhibits ligase and polimerase activities with point mutations by interfering of regulation of DNA repair or integrity. Co-clastogenic effects of arsenite may be mediated by its interference (inhibition) with DNA repair activities with chromosomal aberrations induced by a DNA cross-linking agent, 1,3-butadiene diepoxide, and without alteration of sister chromatid exchanges (Gardner et al. 2011; Tripathi et al. 2012a). As a result, inorganic arsenic exposure causes congenital malformations without toxic reactions in the mother organism (Ríos et al. 2012; Yager et al. 2013). Arsenic also induces acquired or inherent human gene polymorphisms with inter-individual variability in response to accelerate activity of methyltransferases in human and animal being (Hossain et al. 2012; Sumi and Himeno 2012).

Reduction and prevention of cancer by heavy metal detoxification

  1. (a)

    Phytochelation:

    Chelation therapy for chronic arsenic toxicity is thought to be the specific therapy for relief of systemic clinical manifestations and reduction of arsenic stores in the body, reducing subsequent cancer risk (Guha Mazumder 2008). Metal ions in living organisms can bind with other specific ligand molecules in a phenomenon called chelation (Rai et al. 2011; Tsai et al. 2012). Whenever plants are exposed to heavy metals like arsenic, protein ligand molecules bind with metal called phytochelation (PC) (Mishra et al. 2013; Machado-Estrada et al. 2013). Growing evidences suggest that plants, the ultimate food source for humans, are exposed to various biotic and abiotic stresses because of changing climate that adversely affects their growth and development (Islam et al. 2015). They also revealed that heavy metals, viz. arsenic, coming from anthropogenic sources are accumulated in plants. It is well documented that plants can tolerate arsenic using several mechanisms like phytochelation, vacuole sequestration, and activation of antioxidant defense systems. Several signaling mechanisms have evolved in plants that involve the use of proteins, calcium ions, hormones, reactive oxygen species, and nitric oxide as signaling molecules to cope with arsenic toxicity by activating their defense systems with identification of suitable gene targets. It is synthesized from GSH by the enzyme PC synthetase and end up forming GSH oligomers which help for binding metal with PC (Tripathi et al. 2012b). Due to ionic exchange, metallic ion-bound PCs are transported into vacuoles and successfully isolated from cellular proteins and reduce heavy metal ion-induced damage by binding with ionic status of metals (Tsai et al. 2012; Dave et al. 2013; Mishra et al. 2013). A study evaluating the efficacy of specific chelation therapy with dimercaptosuccinic acid (DMSA) for patients suffering from chronic arsenic toxicity has not yielded better efficacy than control subjects treated with placebo (Ahmad et al. 2001). But in another study, chelating agent dimercaptopropanesulfonate (DMPS) is beneficial to cause significant improvement of clinical score among drug-treated cases compared to controls in a single blind placebo control trial. DMPS appears to be biotransformed in humans to acyclic and cyclic disulfides. Whereas DMSA in humans is biotransformed almost completely to a DMSA/CySH (1:2) mixed disulfide (Maiorino et al. 1989), a DMPS-cysteine mixed disulfide has been found only in minute amounts after administration of DMPS (Guha Mazumder 2008). Various chelating agents, viz. BAL, DMSA, and DMPS, are efficacious in averting morbidity and mortality in acute/or chronic arsenicosis. Oral treatment with retinoids (vitamin A analogs) may have promise in the treatment of chronic cutaneous manifestation of arsneicosis and may also have impact on the development of neoplasia (Guha Mazumder et al. 2001). Selenium, an antioxidant nutrient that antagonizes many of the effects of As in biological systems, also merits attention as a potential therapeutic agent for patients with history of chronic As exposure (Guha Mazumder et al. 1997).

  2. (b)

    Accelerated repair of DNA interstrand cross-links (ISCs)

    A cross-link is a bond that links one polymer chain to another. They can be covalent bonds or ionic bonds. “Polymer chains” can refer to synthetic polymers or natural polymers (such as proteins). Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite (Da-Tian et al. 2002). Arsenic is reported to cause DNA modifications such as aneuploidy, micronuclei formation, chromosomal aberrations, deletion mutations, sister chromatid exchange, and DNA-protein cross-linking via ROS generation (Pierce et al. 2012). ROS, which includes the hydroxyl radical (HO), the superoxide radical (O2−), and hydrogen peroxide (H2O2), causes alteration of homeostasis mechanism between antioxidant and prooxidant molecules resulting to oxidative stress-related damage to cellular components such as proteins, DNA, and lipids (Mauro et al. 2016). Intracellular antioxidant agents inhibit oxidation process by removing ROS with interaction with free radicals in ROS (Koedrith and Seo 2011). Therefore, various photochemicals are helpful to initiate the activities of intracellular antioxidants, including GSH, heme oxygenase 1 (HO-1), superoxide dismutase (SOD), NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), and catalases. Also, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, a regulator and transcription factor of antioxidant elements, stimulates antioxidative genes through binding to antioxidant response element, that is in the promoter region of antioxidative gene in reaction to oxidative stress (Sinha and Roy 2011). Nrf2 prevents oxidative stress by quenching ROS. Phytochemical substances, which include carotenoids and flavonoids, are found abundantly in vegetables and fruits (Adetutu et al. 2013; Dua et al. 2015). They are also important antioxidants that enter into the body through regular ingestion of those foods. They play important role for preventing oxidative damage and protect carcinogenesis by chelating with heavy metal moiety (Ramos Elizagaray and Soria 2014). To reduce As intake through the consumption of contaminated food, identification of the mechanisms for As accumulation and detoxification in plant is a prerequisite to develop efficient phytoremediation methods and safer crops with reduced As levels (Tripathi et al. 2012a,b). They also demonstrated that transcriptome, proteome, and metabolome analysis of any organism reflects the total biological activities at any given time which are responsible for the adaptation of the organism to the surrounding environmental conditions. Arsenomic, i.e., As transport and accumulation, approach deals with transcriptome, proteome, and metabolome alterations during As exposure. Although various studies have been performed to understand modulation in transcriptome in response to As, many important questions need to be addressed regarding the translated proteins of plants at proteomic and metabolomic level, resulting in various ecophysiological responses (Tripathi et al. 2012a,b; Islam et al. 2015). Mukhopadhyay et al. (2003) reported that in the yeast Saccharomyces cerevisiae, there are two parallel pathways for arsenite elimination: (1) Acr3p is a plasma membrane carrier protein that extrudes arsenite from the cells and (2) Ycf1p is a vacuolar ATPase that catalyzes the sequestration of As(III)-glutathione conjugates in the vacuole.

Conclusion

We analyzed the major sources of exposure, toxicity, and carcinogenic mechanisms of arsenic in this review. Some heavy metals are significant toxicants and carcinogens. They directly or indirectly cause health hazards both in human being and animals through food chain. Industrial development undertakes a risk of heavy metal exposure via production and consumption of commercial products containing heavy metal compounds. Alteration of genetic polymorphisms occurs due to arsenic-induced carcinogenetic effect. Oxidative stress-mediated pathways are the precursor of carcinogenesis. The trivalent form of arsenic exhibits greater genotoxic effects than the pentavalent counterparts as it could be easily taken up by the cells. Arsenic-induced oxidative DNA damage, like any such damage, can be repaired by specific DNA repair machinery. However, both inorganic and organic form of arsenic has been shown to impair nucleotide excision repair and base excision repair processes. Both inorganic and organic arsenic exposure may cause carcinogenicity as it increases oxidative DNA damage and chromosomal aberration and interferes with cellular signaling pathways. Arsenic induces skin cancer by acting synergistically with sunlight and blocking DNA repair, stimulating angiogenesis, altering DNA methylation patterns, dysregulating cell cycle control, and blocking physiological apoptosis. Plants play important role by several signaling mechanisms under arsenic stress and will give an insight of the different sensory systems in plants to mitigate arsenic-induced cytotoxicity. A good understanding of these signaling pathways can help in raising the plants which can perform better in arsenic-contaminated soil and water. I suggest that antioxidative phytochemicals and chelating agents will be helpful for combating heavy metal-induced cancers. Furthermore, complex mechanisms by pathway analysis give a hint to understand a novel thought for research on the heavy metal-induced cancers and diseases. Furthermore, it provides the knowledge about several pathways that can be exploited to develop plant cultivars which are resistant to arsenic stress or can reduce its uptake to minimize the risk of arsenic toxicity through food chain thus ensuring food security. Further studies are also required to compare different molecular events as methylation patterns of upregulating and downregulating genes in arsenic exposure-related tumors with the same tumor types from non-arsenic endemic areas.