Carcinogenicity, teratogenicity and mutagenicity of arsenic

Léonard, A.; Lauwerys, Robert

doi:10.1016/0165-1110(80)90027-5

Cited by 235 publications

(102 citation statements)

References 78 publications

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“…It is ubiquitous but toxic, capable of causing acute and chronic poisoning. Arsenic is known to cause cancer and vascular disease as well as skin lesions in humans [14][15][16]. In the US, the Environmental Protection Agency has amended the maximum contaminant level, lowering the standard for arsenic in drinking water from 50 to 10 ppb.…”

Section: Introductionmentioning

confidence: 99%

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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SummaryArsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17b-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA V ), and dimethylarsinate (DMA V ). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA V or DMA V . Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17b-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.

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Section: Introductionmentioning

confidence: 99%

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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“…Occupational exposure, on the other hand, occurs mainly through inhalation via nonferrous ore smelting, semiconductor and glass manufacturing, or power generation by the burning of arsenic-contaminated coal (2,3). Epidemiological data have shown that chronic exposure of humans to inorganic arsenical compounds is associated with liver injury, peripheral neuropathy, and an increased incidence of cancer of the lung, skin, bladder, and liver (4,5). Arsenic contamination of drinking water is a serious environmental problem worldwide because of the large number of contaminated sites that have been identified and the large number of people at risk (6).…”

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confidence: 99%

Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicity

Liu

Athar

Lippai

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

430

192

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Although arsenic is a well-established human carcinogen, the mechanisms by which it induces cancer remain poorly understood. We previously showed arsenite to be a potent mutagen in humanhamster hybrid (AL) cells, and that it induces predominantly multilocus deletions. We show here by confocal scanning microscopy with the fluorescent probe 5,6-chloromethyl-2,7-dichlorodihydrofluorescein diacetate that arsenite induces, within 5 min after treatment, a dose-dependent increase of up to 3-fold in intracellular oxyradical production. Concurrent treatment of cells with arsenite and the radical scavenger DMSO reduced the fluorescent intensity to control levels. ESR spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-1-hydroxypiperidine (TEMPOL-H) as a probe in conjunction with superoxide dismutase and catalase to quench superoxide anions and hydrogen peroxide, respectively, indicates that arsenite increases the levels of superoxide-driven hydroxyl radicals in these cells. Furthermore, reducing the intracellular levels of nonprotein sulfhydryls (mainly glutathione) in A L cells with buthionine S-R-sulfoximine increases the mutagenic potential of arsenite by more than 5-fold. The data are consistent with our previous results with the radical scavenger DMSO, which reduced the mutagenicity of arsenic in these cells, and provide convincing evidence that reactive oxygen species, particularly hydroxyl radicals, play an important causal role in the genotoxicity of arsenical compounds in mammalian cells.

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“…Epidemiological data show that chronic exposure of humans to inorganic arsenic is associated with hepatic injury, peripheral neuropathy, and increased rates of a wide variety of cancers, particularly of the skin, lung, bladder, and liver (3)(4)(5). Arsenic also produces toxic effects on the female reproductive system, including ovarian dysfunction (6), aberrant embryo development and lethality (7,8), and postnatal growth retardation (9).…”

mentioning

confidence: 99%

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

Liu

Trimarchi

Navarro

et al. 2003

Journal of Biological Chemistry

196

141

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The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an antitumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome endto-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.Arsenic is a significant environmental concern worldwide because millions of people are at risk of drinking water contaminated by arsenic (1, 2). Epidemiological data show that chronic exposure of humans to inorganic arsenic is associated with hepatic injury, peripheral neuropathy, and increased rates of a wide variety of cancers, particularly of the skin, lung, bladder, and liver (3-5). Arsenic also produces toxic effects on the female reproductive system, including ovarian dysfunction (6), aberrant embryo development and lethality (7,8), and postnatal growth retardation (9). Interestingly, it also has proven useful for anti-cancer therapy (10 -12), although the mechanisms underlying its paradoxical (antineoplastic) effects remain unclear.Many possible modes of arsenic action have been proposed, including chromosomal abnormalities, oxidative stress, altered DNA repair and DNA methylation patterns, altered cell proliferation, abnormal gene amplification, and inhibition of p53 and telomerase (5, 13-18). In particular, arsenic exerts its toxicity by generating reactive oxygen species (ROS) 1 (19 -22). Mitochondria, the main source of ROS production, which also play a crucial role in the control of apoptosis (23, 24), have been implicated in arsenite-induced apoptosis (21, 25). Thus, mitochondrial dysfunction may explain the cytotoxicity and degenerative effects induced by arsenic. How ROS links arsenic exposure to carcinogenesis is still not well understood.Vertebrate telomeres consist of tandem repeats of G-rich sequence that cap the ends of chromosomes, protecting them from fusion and chromosomal instability...

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Carcinogenicity, teratogenicity and mutagenicity of arsenic

Cited by 235 publications

References 78 publications

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Induction of oxyradicals by arsenic: Implication for mechanism of genotoxicity

Oxidative Stress Contributes to Arsenic-induced Telomere Attrition, Chromosome Instability, and Apoptosis

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