Arsenic Exposure and the Induction of Human Cancers

Table 1

Changes in functions associated to arsenic-related carcinogenicity.

Type of alteration	Cell model/type	As species	Reference
Associated to oxidative stress
DNA strand break	Human fetal lung fibroblast (2BS cells)	As^III	[121]
DNA strand break	Human alveolar epithelial type II (L-132) cells	DMA^V	[122]
Single-strand DNA breaks, DNA-protein adducts, sister chromatid exchanges	Human fibroblast cell lines	As^III	[123]
Formation of apurinic/apyrimidinic sites	Human alveolar epithelial cell line (L-132)	DMA	[124]
Induction of 8-OHdG	Human breast cancer MCF-7 adenocarcinoma epithelial cells	As^III	[125]
Increases 8-oxo-G levels through (CH3)2AsOO		DMA^V	[126, 127]
Presence markers for oxidative stress were detected, including 8-oxodG	Mouse bronchiolar Clara cells	DMA^V	[128]
Double-strand DNA breaks	Mammalian cells		[96]
Epigenetic changes in DNA methylation/histones modification/miRNA expression
Alteration of methylation in p53 promoter	A549 cell line	As^III; As^V	[106]
Inductor of hypermethylation of the p16INK4a and RASSF1A CpG islands in nontumor lung tissues (including hyperplasia and adenoma) and lung adenocarcinomas	Lungs of mice exposed during 18 months	As^V	[107]
Increase of dimethylated H3K9	Human BEAS-2B cell line	As^III	[112]
Increased H3K9 dimethylation and decreased H3K27 tri-methylation (gene silencing), increasing H3K4 tri-methylation (gene-activating mark), increases histone methyltransferase G9a protein levels	Human A549 cell line	As^III	[112]
Changes to histone H3 acetylation, DNA promoter methylation, and decreases expression of the DBC1, FAM83A, ZSCAN12, and C1QTNF6 genes	Human nontumorogenic cell lines		[113]
Altered expression of hsa-miR-210, -22, -34a, -221, and -222	Human lymphoblastoid cells	As^III	[116]
Reduction in levels of miR-200	Immortalized p53-knocked down human bronchial epithelial cells (HBECs)	As^III	[117]
Decrease in expression of miRNA-9, -181b, -124, and -125b	Chick embryos	As^III	[118]
Other changes
Amplification of the dihydrofolate reductase gene	Mouse 3T6 cells	As^III	[129]
MAPK activation; phosphorylation of ATF-2 and c-Jun, elevated IL-8 release	Human BEAS 2B line	As^III	[130]
Induction of p53-independent expression of GADD45 protein (a G2/M cell-cycle checkpoint protein)	Human BEAS 2B line	As^III	[131]
Stabilization of GADD45 alpha mRNA through nucleolin	Human BEAS 2B line	As^III	[132]
Mostly decreased expression for transcripts involved in angiogenesis, lipid metabolism, oxygen transport, apoptosis, cell cycle, and immune response	Lung of mice exposed	As^III	[133]
Induction of the expression of genes involved with cancer, the cell cycle, cellular proliferation, DNA replication, recombination and repair, lipid metabolism, cell-cell signaling and interaction, molecular transport, and immunological disease pathways in Ogg1^−/− mice	Lungs of Ogg1^−/− mutant mice exposed	DMA^V	[134]
Enhanced centrosome amplification in p53-compromised cells. Resistance to arsenite-induced G2/M cell cycle arrest and arsenite-induced apoptosis in p53-compromised cells. Reductions in arsenite-induced enhancement of p53, p21, and Gadd45a expressions (at 5–10 μM), Higher (200%) cell colony formation in p53-inhibited BEAS-2B cells (5 μM)	H1355 cells (human lung adenocarcinoma cell line with mutation in p53) Human BEAS-2B line p53-inhibited BEAS-2B cells	As^III	[135]
Increased expression of ER-alpha and genes related to estrogen signaling in the fetal lung of female mice	Lung samples from gestation day 18 female fetal C3H mice	As^III	[136]
Downregulation of (validated genes): Tpi1, Ldha, and Pgk1. Upregulation of (validated genes): Cox6a2; ^Variable: Id1, Gpnmb	Rat lung epithelial cell line (L2)	As^III	[137]
Increased cell viability (≤0.5 μM). Downregulation of APE1 and Polβ mRNA (above 1 μM)	GM847-immortalized human lung fibroblast	As^III	[138]
Increased plating efficiency (cell growth advantage), micronuclei incidence (marker of chromosomal instability), gene amplification (PALA resistance), invasive capabilities; anchorage-independent growth (oncogenic transformation); lost of β4 integrin expression; upregulated phosphorylation of Rb and ERK; decreased expression of p53 protein	h-TERT-immortalized human small airway epithelial cells	As^III	[139]