Induction of chromosomal aberrations in cultured human fibroblasts by inorganic and organic arsenic compounds and the different roles of glutathione in such induction

Oya-Ohta, Yukiko; Kaise, Toshikazu; Ochi, Takafumi

doi:10.1016/0027-5107(96)00092-9

Cited by 126 publications

(59 citation statements)

References 33 publications

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“…Oya-Ohta et al (1996) reported that DMA causes chromatid breaks in human umbilical cord fibroblasts at concentrations in excess of 7 mM. In these studies, the clastogenic effects of DMA were suppressed by depletion of glutathione (GSH) with buthione sulfoximine (BSO), and DMA was still highly clastogenic to GSH-depleted cells when the cells were incubated with 5 -10 mM added GSH.…”

Section: Cytotoxicity and Genotoxicitymentioning

confidence: 76%

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

2001

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Dimethylarsinic acid (DMA) has been used as a herbicide (cacodylic acid) and is the major metabolite formed after exposure to tri-(arsenite) or pentavalent (arsenate) inorganic arsenic (iAs) via ingestion or inhalation in both humans and rodents. Once viewed simply as a detoxification product of iAs, evidence has accumulated in recent years indicating that DMA itself has unique toxic properties. DMA induces an organ-specific lesion -single strand breaks in DNA -in the lungs of both mice and rats and in human lung cells in vitro. Mechanistic studies have suggested that this damage is due mainly to the peroxyl radical of DMA and production of active oxygen species by pulmonary tissues. Multi-organ initiation-promotion studies have demonstrated that DMA acts as a promotor of urinary bladder, kidney, liver and thyroid gland cancers in rats and as a promotor of lung tumors in mice. Lifetime exposure to DMA in diet or drinking water also causes a dose-dependent increase in urinary bladder tumors in rats, indicating that DMA is a complete carcinogen. These data collectively suggest that DMA plays a role in the carcinogenesis of inorganic arsenic. Published by Elsevier Science Ireland Ltd.Keywords: Arsenic; Cancer; Dimethylarsinic acid www.elsevier.com/locate/toxicol Dimethylarsinic acid 1 (DMA; see Fig. 1) has been used as a herbicide and is also the major metabolite formed after exposure to trivalent (arsenite, AsIII) or pentavalent (arsenate, AsV) inorganic arsenic via ingestion or inhalation in both humans and most rodents (US EPA, 1975; ATSDR, 1993). Methylation of inorganic arsenic to form both DMA and methylarsonic acid (MMA) has traditionally been viewed as a mechanism to facilitate the detoxification and excretion of arsenic. This is principally because DMA, in particular, is over 10-fold less acutely toxic than inorganic arsenic (Kaise et al., 1985(Kaise et al., , 1989. However, evidence suggesting that DMA itself has unique toxic properties has accumulated in the * Corresponding author. Tel.: +1-919-5410043; fax: +1-919-5415394.E-mail address: kenyon.elaina@epa.gov (E.M. Kenyon). 1 Unless specifically stated otherwise, the abbreviation DMA refers to pentavalent dimethyl form of arsenic. The distinction is important because emerging evidence suggests that both trivalent monomethylated arsenic and trivalent DMA are more tissue-reactive and cytotoxic than their pentavalent counterparts.0300-483X/01/$ -see front matter Published by Elsevier Science Ireland Ltd. PII: S 0 3 0 0 -4 8 3 X ( 0 0 ) 0 0 4 5 8 -3

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Section: Cytotoxicity and Genotoxicitymentioning

confidence: 76%

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

2001

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“…29 Significant increases of chromosomal aberrations were observed in human fibroblasts treated with 3.8 or 7.7 µM sodium arsenite for 24 h, with the main types of aberration observed being chromatid breaks and chromatid gaps. 30 These findings suggest that DMA(III) was at least as clastogenic as arsenite, since DMA(III) significantly induced chromosomal aberrations, most of which were chromatid breaks and chromatid gaps at 2.5 and 5 µM (Table 1).…”

Section: Discussionmentioning

confidence: 92%

Genotoxicity of dimethylarsinous acid: high induction of tetraploids

Kuroda

Yoshida

Yoshimura

et al. 2005

Appl. Organometal. Chem.

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Arsenic is a carcinogen in humans. However, neither the mechanism of action nor the ultimate chemical form of arsenic which causes cancer has been clearly defined. Dimethylarsinous acid is detected in the urine of individuals who ingest arsenic-polluted drinking water. The cytogenetic study in V79 cells using iododimethylarsine, which is easily hydrolyzed to dimethylarsinous acid in water, revealed that dimethylarsinous acid was very cytotoxic (50% growth inhibition concentration; 1.1 ± 0.14 µM), and either induced aneuploids or a high rate of tetraploids (73% at 2.5 µM). Dimethylarsinous acid caused mitotic arrest, since the mitotic index at toxic dose (5 µM) was 13.9%, significantly higher than the control (2.7%). Dimethylarsinous acid significantly increased sister chromatid exchange (SCE) and chromosomal aberrations, most of which were chromatid gaps and chromatid breaks. The cytotoxicity and the activity of dimethylarsinous acid in inducing chromosomal aberration or SCE was as effective as arsenite, but the activity was much lower than that of mitomycin C, which was used as a positive control. The most potent effects of dimethylarsinous acid on the cells were induction of aneuploids, tetraploids and c-mitosis. Our results suggest that toxicity of dimethylarsinous acid is strongly related to the disturbance of the normal cell cycle.

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“…reveals that in HEL30 keratinocytes there is no change in stk25 expression at 24 hr and a slight reduction at 4 hr (0.9-fold) after exposure to 2.5 µM arsenite. GSH attenuates the damaging effects of arsenite in numerous biological systems (26,29,30), and reduction in cellular GSH exacerbates cellular responses to redox-regulating agents (31,32) and arsenic (33,34). Figure 4 demonstrates that the addition of 100 µM BSO to culture medium shifts the LC 50 of arsenite 10-fold to approximately 1 µM in NHEK, suggesting that a reduction in GSH increases the potency of arsenite.…”

Section: Resultsmentioning

confidence: 99%

Sodium arsenite-induced stress-related gene expression in normal human epidermal, HaCaT, and HEL30 keratinocytes.

Trouba

Geisenhoffer

Germolec

2002

Environ Health Perspect

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Arsenic is a carcinogen that poses a significant health risk in humans. Based on evidence that arsenic has differential effects on human, rodent, normal, and transformed cells, these studies addressed the relative merits of using normal human epidermal keratinocytes (NHEK) and immortalized human (HaCaT) and mouse (HEL30) keratinocytes when examining stressinduced gene expression that may contribute to carcinogenesis. We hypothesize that redox-related gene expression is differentially modulated by arsenic in normal versus immortalized keratinocytes. To test the hypothesis, we exposed keratinocytes to sodium arsenite for 4 or 24 hr, at which time serine threonine kinase-25 (

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Induction of chromosomal aberrations in cultured human fibroblasts by inorganic and organic arsenic compounds and the different roles of glutathione in such induction

Cited by 126 publications

References 33 publications

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

Genotoxicity of dimethylarsinous acid: high induction of tetraploids

Sodium arsenite-induced stress-related gene expression in normal human epidermal, HaCaT, and HEL30 keratinocytes.

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