2. Biogeochemical cycle: transformation and mobilization of arsenic in nature

Arsenic is commonly mobilized into the environment due to both natural and anthropogenic processes. The natural processes include geological (weathering of rocks and volcanic eruptions) and biological (microbial activity) events (Figure 1). Ancient or recent volcanic activities results in the inclusion of arsenic in the environment [10]. The earth's atmosphere also has a significant presence of arsenic species owing to wind erosion processes, sea spray, hot springs, volcanic emissions, forest fires and volatilization (in cold climates). Human activities like pharmaceutical manufacturing, glassmaking industry, wood processing, chemical weapons, burning of arsenic-rich fossil fuels and electronics industry also contribute to the addition of arsenic compounds into the environment [11]. Industrial by-products and wastes, ore smelting, mineral mining and well drilling can also mobilize and intensify arsenic into the environment.

which is considered as a marker indicating oxidative stress of DNA. Arsenic was capable of inducing specific DNA lesions consistent with oxidative damage like 8-OHdG generation. Moreover, 8-OHdG has also been detected in the skin of patients with arsenic-related Bowen's disease and in the liver of rats exposed to dimethylarsinic acid (DMAV). These results indicate that ROS generation is a major pathway for arsenic-mediated genotoxicity in mammalian cells

Mechanisms of Arsenic-Induced Toxicity with Special Emphasis on Arsenic-Binding Proteins

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Glutathione and other aminothiols such as cysteine and cysteamine comprise the non-protein sulfhydryls (NPSHs) in a cell and have significant free radical scavenging abilities. Therefore, depletion of intracellular glutathione levels is known to have an effect on arsenic mutagenesis. Studies have shown that pretreatment of cells with an inhibitor of glutathione biosynthesis (buthionine sulfoximine) reduces NPSH levels in the cell, resulting in enhancement of both the cytotoxicity and mutagenicity of arsenic. In contrast, glutathione and cysteine pretreatments

In a similar way, various antioxidants also have a significant effect on arsenic-induced genotoxicity. The balance between the rate of generation of free radicals and the rate of their removal by various antioxidant enzymes dictates the deleterious effect of oxidative stress. Enzymes like superoxide dismutase (SOD) and catalase are capable of partially suppressing both the toxicity and the mutagenic potential of sodium arsenite. These enzymes catalyze the dismutation of superoxide anions and prevent the formation of hydroxyl radicals by removal of hydrogen peroxide, respectively. Therefore, catalase and SOD are capable of reducing the mutagenic potential of arsenic. This is also consistent with other reports which reveal the ability of sodium arsenite to induce heme oxygenase, an oxidative stress protein, and peroxidase in various human cell lines. Moreover, the arsenite-induced occurrence of sister chromatid exchanges is reduced by SOD in cultured human

In mammalian liver, the methylation of arsenic to MMA and DMA occurs at a high level by an incompletely characterized methyltransferase (Figure 3) using S-adenosylmethionine (SAM) as a methyl donor. SAM is a global methyl donor, required for DNA methylations, and its depletion can lead to hypomethylation of DNA resulting in alteration of gene expression like

DNA methylation is an epigenetic modification that plays an important role in controlling the expression of various genes. Methylation generally occurs at cytosine residues located in symmetrical CpG nucleotide sequences, and its alteration, both in the global and regional levels, has been associated with oncogenesis. Methylation of CpG islands in the promoter region suppresses gene expression, as 5-methylcytosine interferes with the binding of transcription factors or other DNA-binding proteins causing reduced transcription. On the other hand, promoter hypomethylation causes overexpression of associated genes. Therefore, aberrant DNA methylation could be an underlying epigenetic mechanism causing altered gene expression that contributes towards the formation of cancers. This has been studied well in hepatocytes where chronic arsenic exposure induces hepatic DNA hypomethylation, which can potentially lead to aberrant gene expression and oncogenic growth in the liver, therefore suggesting a plausible mechanism of hepatocarcinogenesis (major cellular effects of arsenic are

c-Myc, c-Met, cyclin D1 and induction of carcinogenesis [17, 18].

are capable of protecting mammalian cells against the toxic effects of arsenite [16].

[14, 15].

lymphocytes [16].

summarized in Figure 4) [18].

Microbial metabolisms like arsenate reduction, arsenite oxidation and methylation processes are also a determining factor of the occurrence of the various arsenic oxidation states in the environment. Reduction of arsenate to arsenite by arsenate reductase enzymes is a common feature in the microbial world, while incidences of oxidation of arsenite to arsenate have also been reported in contaminated environments. These reactions also contribute to the protective and/or energy metabolisms of the bacteria from various arsenic-induced stress conditions (Figure 2) [12, 13].
