Mechanism of arsenic carcinogenesis: an integrated approach

Rossman, Toby G.

doi:10.1016/j.mrfmmm.2003.07.009

Cited by 507 publications

(318 citation statements)

References 270 publications

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“…The relationship between the induction of this gene and metal carcinogenesis is still unknown. However, the DNA damage inductions by As, Cd, and Ni were reported previously in mammalian cells [Hartwig, 1995;Denkhaus and Salnikow, 2002;Rossman, 2003;Waalkes, 2003] and might be associated with the induction of DNA repair genes.…”

Section: Discussionmentioning

confidence: 79%

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Kawata

Shimazaki

Okabe

2008

Environ and Mol Mutagen

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Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradecanoylphorbol-13-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in Asexposed cells, whereas the number of cell-cycle associated genes was increased in Cd-and Niexposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG1, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen. 50:46-59, 2009.

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Section: Discussionmentioning

confidence: 79%

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Kawata

Shimazaki

Okabe

2008

Environ and Mol Mutagen

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“…Oxidative stress response is characteristic of in vitro arsenic exposure [Kasai, 1997;Helbock et al, 1999;Mei et al, 2002;Rossman, 2003;Ding et al, 2005;Gentry et al, 2010] and of in vivo exposure at higher arsenic Environmental and Molecular Mutagenesis. DOI 10.1002/em concentrations [Kitchin and Ahmad, 2003].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of gene expression changes in human primary uroepithelial cells following 24‐Hr exposures to inorganic arsenic and its methylated metabolites

Yager

Gentry

Thomas

et al. 2012

Environ and Mol Mutagen

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Gene expression changes in primary human uroepithelial cells exposed to arsenite and its methylated metabolites were evaluated to identify cell signaling pathway perturbations potentially associated with bladder carcinogenicity. Cells were treated with mixtures of inorganic arsenic and its pentavalent or trivalent metabolites for 24 hr at total arsenic concentrations ranging from 0.06 lM to 18 lM. One series (five samples) was conducted with arsenite and pentavalent metabolites and a second (10 samples) with arsenite and trivalent metabolites. Similar gene expression responses were obtained for pentavalent or trivalent metabolites. A suite of eight gene changes was consistently identified across individuals that reflect effects on key signaling pathways: oxidative stress, protein folding, growth regulation, metallothionine regulation, DNA damage sensing, thioredoxin regulation, and immune response. No statistical significance of trend (NOSTASOT) analysis of these common genes identified lowest observed effect levels (LOELs) from 0.6 to 6.0 lM total arsenic and no observed effect levels (NOELs) from 0.18 to 1.8 lM total arsenic. For the trivalent arsenical mixture, benchmark doses (BMDs) ranged from 0.13 to 0.92 lM total arsenic; benchmark dose lower 95% confidence limits (BMDLs) ranged from 0.09 to 0.58 lM total arsenic. BMDs ranged from 0.53 to 2.7 lM and BMDLs from 0.35 to 1.7 lM for the pentavalent arsenical mixture. Both endpoints varied by a factor of 3 across individuals. This study is the first to examine gene expression response in primary uroepithelial cells from multiple individuals and to identify no effect levels for arsenical-induced cell signaling perturbations in normal human cells exposed to a biologically plausible concentration range.Environ. Mol. Mutagen. 54:82-98, 2013. V V C 2012 Wiley Periodicals, Inc.

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“…Indeed, our preliminary data showed that levels of lipid peroxidation as well as 8-oxo-dG are higher in the As-8w-HOS cells (data not shown). These results suggest that altered iron homeostasis contributes to the observed arsenite-induced oxidative stress [4]. Considering that the chemical properties of arsenite do not favor direct oxidant formation, our finding of altered iron homeostasis provides a plausible explanation of one of the mechanisms by which arsenite increases oxidative stress.…”

Section: Discussionmentioning

confidence: 54%

“…Although arsenite does not react directly with DNA, it induces oxidant production and oxidative DNA damage [44], which is considered to be a contributor to arsenic-mediated carcinogenesis [4]. The chemical structure of iron and its capacity to drive one-electron reactions make iron a major component in the production and metabolism of free radicals in biological systems [45].…”

Section: Discussionmentioning

confidence: 99%

“…Arsenic compounds were the only compounds that IARC considered to have sufficient evidence for human carcinogenicity. Some studies confirm that arsenite is not significantly mutagenic in bacterial or mammalian cell detection systems, so it is sometimes considered a tumor promoter and, more recently, was shown to be a co-carcinogen in mouse models [4,5]. Other studies show that arsenite is a complete transplacental carcinogen in mice [6], while dimethylarsinic acid, a major metabolite of arsenic in most mammals, including humans, causes bladder cancer in F344 rats [7].…”

Section: Introductionmentioning

confidence: 99%

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Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenitetransformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.

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Mechanism of arsenic carcinogenesis: an integrated approach

Cited by 507 publications

References 270 publications

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis

Evaluation of gene expression changes in human primary uroepithelial cells following 24‐Hr exposures to inorganic arsenic and its methylated metabolites

Altered iron homeostasis involvement in arsenite-mediated cell transformation

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