Arsenite as the Probable Active Species in the Human Carcinogenicity of Arsenic: Mouse Micronucleus Assays on Na and K Arsenite, Orpiment, and Fowler's Solution

Tinwell, H.; Stephens, S. C.; Ashby, J.

doi:10.2307/3431125

Cited by 20 publications

(13 citation statements)

References 16 publications

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“…Similar results were reported by MacGregor et al [1990], who ascribed the increase in MN in folate-deficient mice to decreased thymine synthesis and perturbations in nucleotide pools. Sodium arsenite exposure also increased MN frequency in both folate-deficient and folate-sufficient mice, consistent with earlier reports [Tinwell et al, 1991;Tice et al, 1997]. Arsenic's clastogenic effects are well established and may result from DNA damage induced in a variety of ways, including through oxidative stress and interference with DNA repair processes [NRC, 1999].…”

Section: Discussionsupporting

confidence: 86%

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

McDorman

Collins

Allen

2002

Environ and Mol Mutagen

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Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on arsenic genotoxicity was evaluated using a mouse peripheral blood micronucleus (MN) assay. In duplicate experiments, male C57Bl/6J mice were fed folate-deficient or folate-sufficient diets for 7 weeks. During week 7, mice on each diet were given four consecutive daily doses of sodium arsenite (0, 2.5, 5, or 10 mg/kg) via oral gavage. Over the course of the study the folate-deficient diet produced an approximate 60% depletion of red blood cell folate. Folate deficiency by itself was associated with small but significant increases in MN in normochromatic erythrocytes (NCEs) and polychromatic erythrocytes (PCEs). Arsenic exposure was associated with significant increases in MN-PCEs in both folate-deficient and folate-sufficient mice. MN-PCE frequencies at the 10 mg/kg dose of arsenic were increased 4.5-fold over vehicle control in folate-deficient mice and 2.1-fold over control in folate-sufficient mice. At the 5 and 10 mg/kg doses of arsenic, MN-PCE levels were significantly higher (1.3-fold and 2.4-fold, respectively) in folate-deficient mice compared to folate-sufficient mice. Very few MN from either control or treated animals in either experiment exhibited kinetochore immunostaining, suggesting that the MN were derived from chromosome breakage rather than from whole chromosome loss. These results indicate that folate deficiency enhances arsenic-induced clastogenesis at doses of 5 mg/kg and higher.

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Section: Discussionsupporting

confidence: 86%

Dietary folate deficiency enhances induction of micronuclei by arsenic in mice†

McDorman

Collins

Allen

2002

Environ and Mol Mutagen

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“…Arsenite is the most likely environmental carcinogenic species (Tinwell et al, 1991). This laboratory established mouse model to study skin carcinogenesis associated with arsenite exposure and demonstrated that non-toxic (10mg/l) concentration of arsenite in drinking water enhances UV irradiation-induced skin carcinoma in the Skh1 hairless mice (Rossman et al, 2001; Burns et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure

Komissarova¹,

Rossman²

2010

Toxicology and Applied Pharmacology

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Arsenite is an environmental pollutant. Exposure to inorganic arsenic in drinking water is associated with elevated cancer risk, especially in skin. Arsenite alone does not cause skin cancer in animals, but arsenite can enhance the carcinogenicity of solar UV. Arsenite is not a significant mutagen at non-toxic concentrations, but it enhances the mutagenicity of other carcinogens. The tumor suppressor protein P53 and nuclear enzyme PARP-1 are both key players in DNA damage response. This laboratory demonstrated earlier that in cells treated with arsenite, the P53-dependent increase in p21WAF1/CIP1 expression, normally a block to cell cycle progression after DNA damage, is deficient. Here we show that although long-term exposure of human keratinocytes (HaCaT) to a nontoxic concentration (0.1μM) of arsenite decreases the level of global protein poly(ADP-ribosyl)ation, it increases poly(ADP-ribosyl)ation of P53 protein and PARP-1 protein abundance. We also demonstrate that exposure to 0.1μM arsenite depresses the constitutive expression of p21 mRNA and P21 protein in HaCaT cells. Poly(ADP-ribosyl)ation of P53 is reported to block its activation, DNA binding and its functioning as a transcription factor. Our results suggest that arsenite's interference with activation of P53 via poly(ADP-ribosyl)ation may play a role in the comutagenic and cocarcinogenic effects of arsenite.

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“…Although epidemiological evidence demonstrates a strong association between arsenic and human cancers [IARC, 1980;NRC, 2000], its mode of action is not known. Arsenite is the most likely environmental carcinogenic species [Tinwell et al, 1991]. Arsenite alone is able to induce chromosome aberrations and aneuploidy [Gurr et al, 1993;reviewed in Rossman, 1998] and also acts as a co-mutagen, probably by inhibiting DNA repair [Li and Rossman, 1989;Lee-Cheng et al, 1994].…”

Section: Introductionmentioning

confidence: 99%