Arsenic exposure and the induction of human cancers

Abstract

Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations.

Figure 1

Genome-wide identification of arsenic-related and smoking independent DNA copy number alterations in lung squamous cell carcinoma (SqCC). Genomic copy number profiles for lung SqCC biopsies (n = 52) were obtained using whole genome aCGH. SqCC tumors from smokers (n = 42), comprised (n = 30) samples from North American with no known arsenic exposure, and (n = 12) samples from Northern Chile from individuals chronically exposed to arsenic. SqCC tumors from never smokers (n = 10) were from chronically arsenic-exposed individuals from Northern Chile. (a) Frequency plot of arsenic-related and smoking independent copy number differences in SqCC. The frequency of DNA gain/loss for each probe was calculated and plotted for each group, where smokers (dark green) and never smokers (red). Regions exhibiting similar alteration in both groups are denoted in yellow. The magnitude of green and red bars represents percent alteration for each probe per group (0–100%, with blue vertical lines representing 50% frequency). DNA gains and losses are represented to the right and left of each chromosome, respectively. Analysis was restricted to autosomes, with any differences based on sex subtracted from further analysis. A high frequency of copy number alteration, previously undescribed for SqCC were evident in arsenic exposed tumors from never smokers, particularly for chromosome 3q. (b) Detail of DNA losses at 10q11.23 specific to never smokers are highlighted in a light-blue rectangle. PARG, previously shown to mediate cell death in response to genotoxic stimuli (PMID: 19571039), is indicated in red. (c) Recurrent DNA gain found in never smokers at 19q13.33. This segment contains the POLD1 gene, a DNA polymerase delta complex, involved in DNA replication and repair (red probe).

Figure 2

Schematic representation of proposed arsenic-induced carcinogenic mechanisms. Arsenic can enter cells in both tri- or pentavalent forms (As^III or As^V). Inside cells, As^V is converted to As^III, with subsequent methylation to monomethylated (MMA) and dimethylated (DMA) species. The methylation of inorganic arsenic consumes both S-adenosylmethionine (SAM) and glutathione (GSH). Cellular damage derived from arsenic biotransformation can occur through generation of reactive oxygen species (ROS), and through epigenetic mechanisms: changes in DNA methylation patterns (by depletion of cellular pools of methyl group), histone modification, and altered expression of microRNAs (miRNAs).