**2. Arsenic**

## **2.1 Physiological and molecular impact of exposure**

Arsenic exposure largely occurs through contaminated drinking-water sources, but this problem extends well beyond known arsenic-endemic areas. In fact, it is estimated that 200 million individuals are exposed worldwide to levels deemed non-toxic by the WHO, but shown to induce molecular damage [12].

The toxic effects of arsenic are prevalent from ingestion to excretion and are largely attributed to its various metabolites (**Figure 1**). Once ingested, arsenate

**73**

**Figure 1.**

*Oncogenetics of Lung Cancer Induced by Environmental Carcinogens*

(AsV)—the most common form of the compound in the environment—is taken into cells through membrane transporters, where it is quickly reduced to arsenite (AsIII) by oxidoreductases including purine nucleotide phosphorylase (PNP) and glutathione-s-transferase omega (GSTO). AsIII is the most toxic form of arsenic, largely due to its subsequent methylation by methyltransferase enzymes such as arsenic (+3) methyltransferase (As3MT), a process exploited for promoting the excretion of arsenic [13]. However, methyl groups are provided by *S*-adenosylmethionine (SAM), a key cellular methyl group donor. Methylation of arsenic inside the cell can thus lead to the depletion of the cellular methyl pool through a high demand on SAM, which then promotes global DNA hypomethylation and aberrant histone modification [14–17]. Disruptions in the cellular methyl pool can lead to major disruptions in gene expression, which is known to contribute to malignant transformation [16]. The genomic instability and global changes in gene expression resulting from the exposure and biotransformation of arsenic is exacerbated by the widespread induction of DNA damage from toxic arsenic byproducts. In fact, arsenic has been demonstrated to cause distinct alterations in chromatin, gene expression (both coding and non-coding), as well as splicing, and transcription initiation [18]. In particular, one of the methylated species of arsenic, monomethylarsonic acid (MMAIII), can interrupt the electron transport chain in mitochondria, liberating electrons and inducing the formation of reactive oxygen species (ROS) [15, 19, 20]. ROS generated from arsenic exposure result in widespread DNA damage, including single- and double-stranded DNA breaks, DNA base oxidation leading to mutations (largely G>C → T>A transversions), adducts, deletions and even damage to mitochondrial DNA (mtDNA) [20–22]. Unsurprisingly, as oxidative stress is a known driver of tumorigenesis in multiple tissues, the DNA damage induced from arsenic exposure is thought to be a main mechanism of its carcinogenicity [23–25]. The disruption of the electron transport chain produces ROS such as hydroxyl

*DOI: http://dx.doi.org/10.5772/intechopen.81064*

*Molecular mechanisms of arsenic-induced carcinogenesis.*

*Oncogenetics of Lung Cancer Induced by Environmental Carcinogens DOI: http://dx.doi.org/10.5772/intechopen.81064*

*Oncogenes and Carcinogenesis*

Exposure to each of arsenic, asbestos, and radon has been shown to induce widespread genetic and epigenetic alterations, which may account for their strong carcinogenicity, independent of smoking status [4]. Interestingly, the molecular aberrations associated with these compounds and the onset of lung cancer in never-smokers follows a mechanism distinct from that of tobacco smoke [5]. While strict guidelines regarding exposure to these compounds have been implemented in some regions, mounting evidence suggests that carcinogenic effects may result from chronic exposure to environmental levels that are well below those currently deemed "safe" [6, 7]. Additionally, individual differences may contribute to varying

degrees of susceptibility to the carcinogenic effects of these compounds. For instance, women have been shown to have a higher incidence of lung cancer arising in never-smokers. This inequality can potentially be attributed to a historical bias towards women being more present in the home, resulting in increased exposure to high radon concentrations and polyaromatic hydrocarbons from various home combustion sources [8]. As these genetic and epigenetic aberrations might be indicative of specific molecular damage induced by these carcinogens, they may be able to be used to develop personalized approaches for risk assessment, monitoring and subsequent disease treatment. Thus, it is critical to uncover the extent of these

Arsenic is a class I International Agency for Research on Cancer (IARC) carcinogen that threatens global health through its persistent accumulation in drinking water sources, leading to the onset of skin and lung cancers, among other diseases [9]. Asbestos fibers are naturally occurring silicate mineral fibers that have long been used in industry as building insulation, and are closely linked with not only the well-known outcome of mesothelioma, but also to 5–7% of all lung cancer cases [10]. Radon gas accounts for between 3 and 14% of all lung tumors in a given country and is the second most-common cause of lung cancer, behind smoking [11]. While the radioactive gas normally diffuses easily in open air, it can build up in indoor environments and is readily dissolved into water, which can lead to malignancies through radioactive decay and alpha particle emission [11]. Moreover, drinking water may be a particularly prevalent source of exposure to environmental carcinogens, as it is a primary route of exposure for both arsenic and radon, emphasizing the need for a focus on water contamination measurement and remediation. As arsenic, asbestos, and radon exert their carcinogenic effects through different exposure routes, they display similar, yet distinct mechanisms of genetic and epigenetic aberration, which may be useful in the identification and treatment of

In this chapter we highlight the molecular alterations induced by exposure to arsenic, asbestos, and radon in key lung cancer pathways, and finish with a discussion of the potential translational applications of environmentally-induced

Arsenic exposure largely occurs through contaminated drinking-water sources, but this problem extends well beyond known arsenic-endemic areas. In fact, it is estimated that 200 million individuals are exposed worldwide to levels deemed

The toxic effects of arsenic are prevalent from ingestion to excretion and are largely attributed to its various metabolites (**Figure 1**). Once ingested, arsenate

events associated with exposure to environmental carcinogens.

**72**

tumors caused by these agents.

**2.1 Physiological and molecular impact of exposure**

non-toxic by the WHO, but shown to induce molecular damage [12].

molecular damage.

**2. Arsenic**

**Figure 1.** *Molecular mechanisms of arsenic-induced carcinogenesis.*

(AsV)—the most common form of the compound in the environment—is taken into cells through membrane transporters, where it is quickly reduced to arsenite (AsIII) by oxidoreductases including purine nucleotide phosphorylase (PNP) and glutathione-s-transferase omega (GSTO). AsIII is the most toxic form of arsenic, largely due to its subsequent methylation by methyltransferase enzymes such as arsenic (+3) methyltransferase (As3MT), a process exploited for promoting the excretion of arsenic [13]. However, methyl groups are provided by *S*-adenosylmethionine (SAM), a key cellular methyl group donor. Methylation of arsenic inside the cell can thus lead to the depletion of the cellular methyl pool through a high demand on SAM, which then promotes global DNA hypomethylation and aberrant histone modification [14–17]. Disruptions in the cellular methyl pool can lead to major disruptions in gene expression, which is known to contribute to malignant transformation [16].

The genomic instability and global changes in gene expression resulting from the exposure and biotransformation of arsenic is exacerbated by the widespread induction of DNA damage from toxic arsenic byproducts. In fact, arsenic has been demonstrated to cause distinct alterations in chromatin, gene expression (both coding and non-coding), as well as splicing, and transcription initiation [18]. In particular, one of the methylated species of arsenic, monomethylarsonic acid (MMAIII), can interrupt the electron transport chain in mitochondria, liberating electrons and inducing the formation of reactive oxygen species (ROS) [15, 19, 20]. ROS generated from arsenic exposure result in widespread DNA damage, including single- and double-stranded DNA breaks, DNA base oxidation leading to mutations (largely G>C → T>A transversions), adducts, deletions and even damage to mitochondrial DNA (mtDNA) [20–22]. Unsurprisingly, as oxidative stress is a known driver of tumorigenesis in multiple tissues, the DNA damage induced from arsenic exposure is thought to be a main mechanism of its carcinogenicity [23–25]. The disruption of the electron transport chain produces ROS such as hydroxyl

radicals (OH∙), superoxide anion radicals (O2∙−), and hydrogen peroxide (H2O2), which can further damage cells through lipid oxidation, protein oxidation, and reduction of the mitochondrial membrane potential [26]. The subsequent liberation of cytochrome c can activate apoptotic pathways through caspases, leading to an abnormal rate of cell death. However in addition to faulty apoptotic signaling, exposure to arsenic can also lead to further aberrations in DNA-repair pathways. Here, arsenic affects the expression of genes involved in both nucleotide- (NER) and base-excision repair (BER) mechanisms, allowing the cell to continue through the cell cycle despite extensive damage and genomic instability [27–30]. Thus, arsenic exposure can induce an array of molecular damage across the genome and epigenome, culminating in malignant transformation.
