1. Introduction

Long-term exposure to arsenic has resulted in the largest mass poisoning of the human population, making more than 100 million people defenseless against cancer and other arsenic-related diseases [1, 2]. Epidemiological studies have revealed that arsenic exposure

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

spans a wide geographical area spread across continents, with contaminations originating from soil, water, air and even food. Arsenic pollution gets aggravated through natural processes like volcanic eruptions, weathering, and biological activity. Anthropogenic activities, such as ore smelting, mining, well drilling and combustion of fossil fuels, also accelerate infusion of arsenic into places of human habitation [3]. Owing to its toxic nature, arsenic is a threat not only to humans but also to other living species. Figure 1 illustrates natural and anthropogenic sources of arsenic.

damage and tumor promotion. Inorganic arsenic has been recognized as a potent human carcinogen. A number of epidemiological studies have found that human populations exposed to arsenic are prone to different types of cancers including that of the bladder, lung, skin, liver and kidney [4, 5]. Human body responds to arsenic ingestion through a set of concerted metabolic actions starting with methylation of the inorganic arsenic to monomethylarsonic (MMAV) acid, which is then methylated again to dimethylarsinic acid (DMAV) to permit its excretion through urine. However, this response may result in persistent methyl exhaustion in the event of chronic arsenic exposure leading to hypomethylation of DNA, which can alter the gene expression making the cells susceptible to carcinogenesis [6]. Interestingly, arsenic alone is considered to be a very weak mutagen; however, its synergistic association with genotoxic agents like ultraviolet radiation is reported to make it a potent mutagen [7]. Notwithstanding, the diverse mechanisms of arsenic toxicity need far greater elucidation, though the health

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

http://dx.doi.org/10.5772/intechopen.74758

59

From the mechanistic standpoint, arsenic binding to cellular proteins can be a plausible mechanism of toxicity based on two hypotheses premised on functional disruption arising out of (a) sulfhydryl groups in proteins forming covalent bond with arsenite [8] and (b) the phosphate groups in proteins replaced by an arsenate. Arsenic binding to a specific protein could change the conformation and interaction with other functional proteins [9]. Therefore, many studies have been undertaken to examine the direct binding of arsenic to proteins, for the understand-

All proteins with functionally important and conserved cysteine (Cys) residues, whose sulfhydryl groups are reactive nucleophiles or form disulfide bonds, are potential targets of functional disruption during chronic arsenic exposure. One such protein with conserved cysteines is the gap junction protein, connexin 43 (Cx43), belonging to the connexin family, and is the most commonly expressed member in different cell types. Our recent study showed that direct arsenic binding to this protein causes alteration in trafficking and the absence of gap junctional plaques on cell surface, resulting in propensity for cell proliferation. Given the hazardous nature of arsenic, the qualitative and quantitative analysis of arsenic is a much needed requirement. The conventional methods like neutron activation analysis and X-ray analysis, atomic absorption spectrometry (HG-AAS) and stripping voltammetry are very costly as well as complex. So, the quest for easy and cost-effective method continues till date. One such method gaining reputation in the field relies on optical sensors which have been discussed in this chapter. This chapter summarizes numerous traits of arsenic toxicity and emphasizes the interaction of arsenic with proteins to evaluate the chemical, biological, and physiological

2. Biogeochemical cycle: transformation and mobilization of arsenic

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

ing mechanisms of arsenic toxicity and designing therapeutics against it.

hazards are well understood.

consequences.

in nature

Many mechanisms of arsenic-induced carcinogenicity have been proposed like DNA repair inhibition, oxidative stress, epigenetic events, effect on signal transduction and genotoxic damage. Studies have been focused to understand the molecular mechanisms of arsenicinduced carcinogenesis with an emphasis on oxidative stress and related signal transduction pathways. One of the hallmarks of oxidative stress is generation of reactive oxygen species (ROS) which triggers the antioxidant pathways as a cellular defense response. Two of the major players of cellular defence response on arsenic exposure are nuclear factor (erythroidderived 2)-like 2 (Nrf2) and Parkinson's disease protein 7 (DJ-1), and their interplay results in activation and upregulation of several genes like glutathione-S-transferase A2 (GSTA2), NAD (P)H dehydrogenase quinone 1 (NQO1) and thioredoxin (Trx). There has been increasing evidence correlating arsenic exposure to reactive oxygen species (ROS) generation, DNA

Figure 1. Mobilization of arsenic into environment.

damage and tumor promotion. Inorganic arsenic has been recognized as a potent human carcinogen. A number of epidemiological studies have found that human populations exposed to arsenic are prone to different types of cancers including that of the bladder, lung, skin, liver and kidney [4, 5]. Human body responds to arsenic ingestion through a set of concerted metabolic actions starting with methylation of the inorganic arsenic to monomethylarsonic (MMAV) acid, which is then methylated again to dimethylarsinic acid (DMAV) to permit its excretion through urine. However, this response may result in persistent methyl exhaustion in the event of chronic arsenic exposure leading to hypomethylation of DNA, which can alter the gene expression making the cells susceptible to carcinogenesis [6]. Interestingly, arsenic alone is considered to be a very weak mutagen; however, its synergistic association with genotoxic agents like ultraviolet radiation is reported to make it a potent mutagen [7]. Notwithstanding, the diverse mechanisms of arsenic toxicity need far greater elucidation, though the health hazards are well understood.

spans a wide geographical area spread across continents, with contaminations originating from soil, water, air and even food. Arsenic pollution gets aggravated through natural processes like volcanic eruptions, weathering, and biological activity. Anthropogenic activities, such as ore smelting, mining, well drilling and combustion of fossil fuels, also accelerate infusion of arsenic into places of human habitation [3]. Owing to its toxic nature, arsenic is a threat not only to humans but also to other living species. Figure 1 illustrates natural and

Many mechanisms of arsenic-induced carcinogenicity have been proposed like DNA repair inhibition, oxidative stress, epigenetic events, effect on signal transduction and genotoxic damage. Studies have been focused to understand the molecular mechanisms of arsenicinduced carcinogenesis with an emphasis on oxidative stress and related signal transduction pathways. One of the hallmarks of oxidative stress is generation of reactive oxygen species (ROS) which triggers the antioxidant pathways as a cellular defense response. Two of the major players of cellular defence response on arsenic exposure are nuclear factor (erythroidderived 2)-like 2 (Nrf2) and Parkinson's disease protein 7 (DJ-1), and their interplay results in activation and upregulation of several genes like glutathione-S-transferase A2 (GSTA2), NAD (P)H dehydrogenase quinone 1 (NQO1) and thioredoxin (Trx). There has been increasing evidence correlating arsenic exposure to reactive oxygen species (ROS) generation, DNA

anthropogenic sources of arsenic.

58 Arsenic - Analytical and Toxicological Studies

Figure 1. Mobilization of arsenic into environment.

From the mechanistic standpoint, arsenic binding to cellular proteins can be a plausible mechanism of toxicity based on two hypotheses premised on functional disruption arising out of (a) sulfhydryl groups in proteins forming covalent bond with arsenite [8] and (b) the phosphate groups in proteins replaced by an arsenate. Arsenic binding to a specific protein could change the conformation and interaction with other functional proteins [9]. Therefore, many studies have been undertaken to examine the direct binding of arsenic to proteins, for the understanding mechanisms of arsenic toxicity and designing therapeutics against it.

All proteins with functionally important and conserved cysteine (Cys) residues, whose sulfhydryl groups are reactive nucleophiles or form disulfide bonds, are potential targets of functional disruption during chronic arsenic exposure. One such protein with conserved cysteines is the gap junction protein, connexin 43 (Cx43), belonging to the connexin family, and is the most commonly expressed member in different cell types. Our recent study showed that direct arsenic binding to this protein causes alteration in trafficking and the absence of gap junctional plaques on cell surface, resulting in propensity for cell proliferation. Given the hazardous nature of arsenic, the qualitative and quantitative analysis of arsenic is a much needed requirement. The conventional methods like neutron activation analysis and X-ray analysis, atomic absorption spectrometry (HG-AAS) and stripping voltammetry are very costly as well as complex. So, the quest for easy and cost-effective method continues till date. One such method gaining reputation in the field relies on optical sensors which have been discussed in this chapter. This chapter summarizes numerous traits of arsenic toxicity and emphasizes the interaction of arsenic with proteins to evaluate the chemical, biological, and physiological consequences.
