Oral Exposure of Dimethylarsinic Acid, a Main Metabolite of Inorganic Arsenics, in Mice Leads to an Increase in 8-Oxo-2′-deoxyguanosine Level, Specifically in the Target Organs for Arsenic Carcinogenesis

Yamanaka, Kazuhiro; Takabayashi, Fumiyo; Mizoi, Mutsumi; An, Yan; Hasegawa, Akira; Okada, Shoji

doi:10.1006/bbrc.2001.5551

Cited by 98 publications

(51 citation statements)

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“…Oral administration of high concentrations of dimethylarsinate to mice caused DNA strand breaks in the lung (1500 mg/kg b.w., one single dose, Yamanaka and Okada, 1994;Yamanaka et al, 1989), increased the urinary level of 8-hydroxy-2'deoxyguanosine (8-OHdG) lesions (50 mg/kg bw, one single dose, Yamanaka et al, 2001) and the 8-OHdG DNA levels in the lung and liver (400 mg/L in drinking water, four weeks, Yamanaka et al, 2001), but not in the bladder, skin, spleen or kidney. In contrast, dimethylarsinate administered to rats, significantly increased the level of 8-OHdG in the bladder (200 mg/L in drinking water, two weeks (Wei et al, 2002), 0.02 % in drinking water, 20 days (Kinoshita et al, 2007)) and kidney (10 mg/kg b.w., four weeks, each five days, Vijayaraghavan et al, 2001).…”

Section: Organic Arsenicmentioning

confidence: 99%

“…Dimethylarsinate and dimethylarsinite might also catalyse ROS generation in vitro and in vivo via the formation of intermediary dimethylarsine and radical arsenic species; however, these observations were restricted to very high concentrations of dimethylarsinate (Yamanaka et al, 1989(Yamanaka et al, , 1990(Yamanaka et al, , 1991(Yamanaka et al, , 1997(Yamanaka et al, , 2000(Yamanaka et al, , 2001. In consequence, the US EPA concluded recently, that the principle mode of action of dimethylarsinate, namely induced bladder cancer in rats, does not appear to be mediated via the ROSinduced DNA damage pathway (US EPA SAB, 2007).…”

Section: Organic Arsenicmentioning

confidence: 99%

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Scientific Opinion on Arsenic in Food

2009

EFSA Journal

877

220

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The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) assessed the risks to human health related to the presence of arsenic in food. More than 100,000 occurrence data on arsenic in food were considered with approximately 98 % reported as total arsenic. Making a number of assumptions for the contribution of inorganic arsenic to total arsenic, the inorganic arsenic exposure from food and water across 19 European countries, using lower bound and upper bound concentrations, has been estimated to range from 0.13 to 0.56 µg/kg bodyweight (b.w.) per day for average consumers, and from 0.37 to 1.22 µg/kg b.w. per day for 95 th percentile consumers. Dietary exposure to inorganic arsenic for children under three years of age is in general estimated to be from 2 to 3-fold that of adults. The CONTAM Panel concluded that the provisional tolerable weekly intake (PTWI) of 15 µg/kg b.w. established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) is no longer appropriate as data had shown that inorganic arsenic causes cancer of the lung and urinary bladder in addition to skin, and that a range of adverse effects had been reported at exposures lower than those reviewed by the JECFA. The CONTAM Panel modelled the dose-response data from key for providing consumption information and calculating exposure, the partners of the EFSA project on the "Individual food consumption data and exposure" coordinated by Ghent University (Department of Public Health, University Hospital, Ghent University, Belgium), and RIKILT (Institute of Food Safety, Wageningen, The Netherlands) for the accessibility of the exposure assessment tools. 4 Table of contents shows now the fourth level of subheadings. 5 An error in the interpretation of the total number of the population in the study of Rahman et al. (2006a) was discovered (Table 41). The BMDL was recalculated and as a consequence it was not considered a potential reference point. The text in the opinion, Table 43 and Appendix were revised accordingly. In addition, the header of the "total number of cases" was replaced by "total number of individuals" in Tables 40-42 and the erroneous units were corrected to µg/L in the text below SUMMARYArsenic is a metalloid that occurs in different inorganic and organic forms, which are found in the environment both from natural occurrence and from anthropogenic activity. The inorganic forms of arsenic are more toxic as compared to the organic arsenic but so far most of the occurrence data in food collected in the framework of official food control are still reported as total arsenic without differentiating the various arsenic species. The need for speciation data is evident because several investigations have shown that especially in seafood most of the arsenic is present in organic forms that are less toxic. Consequently, a risk assessment not taking into account the different species but considering total arsenic as being present exclusively as inorganic arsenic would lead to a considerable overestimation of the health risk rel...

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Section: Organic Arsenicmentioning

confidence: 99%

Section: Organic Arsenicmentioning

confidence: 99%

Scientific Opinion on Arsenic in Food

2009

EFSA Journal

877

220

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“…It indicates that MT -/-mice were more sensitive to DMAA and MT played a protective role against the toxicities to main organs. Yamanaka [7] reported that DMAA in mice could be further metabolized and converted into dimethylarsine radicals and dimethyl arsenic peroxy radicals. Marked formation of 8-oxod G was observed in the lung and liver, which are the target organs for arsenic carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…DMAA itself can be used as herbicide and pesticide and also naturally exists in some seafood. Recent studies have revealed that DMAA is a genotoxic, multi-site promoter of carcinogenesis as well as a complete carcinogen in rodents [5][6][7] , which provides a novel clue to investigate the mechanism of arsenicals in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Chen¹,

Gu²,

Chen³

et al. 2003

WJG

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AIM:To better clarify the main target organs of dimethylarsinic acid toxicity and the role of metallothionein (MTs) in modifying dimethylarsinic acid (DMAA) toxicity. METHODS:MT-I/II null (MT -/-) mice and the corresponding wild-type mice (MT +/+ ), six in each group, were exposed to DMAA (0-750 mg/kg body weight) by a single oral injection. Twenty four hours later, the lungs, livers and kidneys were collected and undergone pathological analysis, induction of apoptotic cells as determined by TUNEL and MT concentration was detected by radio-immunoassay. RESULTS:Remarkable pathological lesions were observed at the doses ranging from 350 to 750 mg/kg body weight in the lungs, livers and kidneys and MT +/+ mice exhibited a relatively slight destruction when compared with that in dose matched MT -/-mice. The number of apoptotic cells was increased in a dose dependent manner in the lungs and livers in both types of mice. DMAA produced more necrotic cells rather than apoptotic cells at the highest dose of 750 mg/kg, however, no significant increase was observed in the kidney. Hepatic MT level in MT +/+ mice was significantly increased by DMAA in a dose-dependent manner and there was no detectable amount of hepatic MT in untreated MT -/-mice. CONCLUSION:DMAA treatment can lead to the induction of apoptosis and pathological damage in both types of mice. MT exhibits a protective effect against DMAA toxicity.

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“…Oxidative damage to DNA Oxidative DNA damage is induced by free radicals produced from the reactions of methylated arsenic compounds with molecular oxygen (dimethylarsenic peroxyl radical or superoxide anion radical) (Eblin et al 2006;Nesnow et al 2002;Yamanaka and Okada 1994;Yamanaka et al 1989Yamanaka et al , 1991Yamanaka et al , 2001, iron (Ahmad et al 1999(Ahmad et al , 2000(Ahmad et al , 2002 …”

Section: Genotoxicitymentioning

confidence: 99%

Methylarsenic compounds [MAK Value Documentation, 2014]

Hartwig

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated methylarsenic compounds considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. Methylarsenic compounds are the carcinogenic metabolites of arsenic and its inorganic compounds, which are proven human carcinogens. Methylated arsenic compounds are able to interfere with all important cellular processes. In mice and rats, dimethylarsinic acid was clearly carcinogenic. Trimethylarsine oxide caused liver adenomas in F344 rats and with methylarsenic acid, preneoplastic liver effects were found. If all aspects are considered, methylarsenic compounds are classified in Carcinogen Category 1. Methylarsenic compounds are genotoxic in vitro and in vivo. As they are bioavailable and can reach the germ cells, they are classified in Category 3 A for Germ Cell Mutagens. Methylarsenic compounds are genotoxic carcinogens, for which no safe systemic exposure can be estimated. It must be assumed that even small amounts absorbed percutaneously increase the carcinogenic risk. Therefore, methylarsenic compounds are designated with an “H” (for substances that can be absorbed through the skin in toxicologically relevant amounts). Dimethylarsinic acid induced developmental toxicity in rats. Apart from a well‐documented case report, there are no clear findings available to conclude a skin‐sensitizing potential in humans.

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Oral Exposure of Dimethylarsinic Acid, a Main Metabolite of Inorganic Arsenics, in Mice Leads to an Increase in 8-Oxo-2′-deoxyguanosine Level, Specifically in the Target Organs for Arsenic Carcinogenesis

Cited by 98 publications

References 22 publications

Scientific Opinion on Arsenic in Food

Scientific Opinion on Arsenic in Food

Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid

Methylarsenic compounds [MAK Value Documentation, 2014]

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