Article

Dietary administration of sodium arsenite to rats: Relations between dose and urinary concentrations of methylated and thio-metabolites and effects on the rat urinary bladder epithelium

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.63). 04/2010; 244(2):99-105. DOI: 10.1016/j.taap.2009.12.026
Source: PubMed

ABSTRACT Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in drinking water is carcinogenic to humans, inducing skin, urinary bladder and lung tumors. In vivo, inorganic arsenic is metabolized to organic methylated arsenicals including the highly toxic dimethylarsinous acid (DMA(III)) and monomethylarsonous acid (MMA(III)). Short-term treatment of rats with 100 microg/g trivalent arsenic (As(III)) as sodium arsenite in the diet or in drinking water induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation and hyperplasia. The objectives of this study were to determine if these arsenic-induced urothelial effects are dose responsive, the dose of arsenic at which urothelial effects are not detected, and the urinary concentrations of the arsenical metabolites. We treated female F344 rats for 5 weeks with sodium arsenite at dietary doses of 0, 1, 10, 25, 50, and 100 ppm. Cytotoxicity, cell proliferation and hyperplasia of urothelial superficial cells were increased in a dose-responsive manner, with maximum effects found at 50 ppm As(III). There were no effects at 1 ppm As(III). The main urinary arsenical in As(III)-treated rats was the organic arsenical dimethylarsinic acid (DMA(V)). The thio-metabolites dimethylmonothioarsinic acid (DMMTA(V)) and monomethylmonothioarsinic acid (MMMTA(V)) were also found in the urine of As(III)-treated rats. The LC(50) concentrations of DMMTA(V) for rat and human urothelial cells in vitro were similar to trivalent oxygen-containing arsenicals. These data suggest that dietary As(III)-induced urothelial cytotoxicity and proliferation are dose responsive, and the urothelial effects have a threshold corresponding to the urinary excretion of measurable reactive metabolites.

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    • "Regarding the toxicity between the tri-and pentavalent arsenicals, the trivalent forms are demonstrated to be more cytotoxic and genotoxic than that of pentavalent forms (Kitchin and Conolly, 2010; Liu et al., 2001; Mass et al., 2001; Styblo et al., 1999). Although some of the pentavalent thiolated arsenic metabolites have shown to be much more toxic to cells in a similar manner as trivalent arsenicals are found in human and animal urine (Chilakapati et al., 2010; Naranmandura et al., 2009; Ochi et al., 2008; Suzuki et al., 2010), it has been demonstrated that toxicity of pentavalent thioarsenicals is mainly through their reduction to the trivalent form, dimethylarsinous acid (DMA III ) in cells (Naranmandura et al., 2011a). Thereby, trivalent arsenic species "
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    ABSTRACT: The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMAIII) and compared with that of trivalent arsenite (iAsIII) and monomethylarsonous acid (MMAIII). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMAIII, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAsIII or MMAIII. The generation of reactive oxygen species (ROS) after DMAIII exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMAIII. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMAIII-induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAsIII and MMAIII. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMAIII-induced cytotoxicity.
    Toxicology and Applied Pharmacology 03/2012; 260(3):241-9. DOI:10.1016/j.taap.2012.02.017 · 3.63 Impact Factor
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    • "Regarding the toxicity between the tri-and pentavalent arsenicals, the trivalent forms are demonstrated to be more cytotoxic and genotoxic than that of pentavalent forms (Kitchin and Conolly, 2010; Liu et al., 2001; Mass et al., 2001; Styblo et al., 1999). Although some of the pentavalent thiolated arsenic metabolites have shown to be much more toxic to cells in a similar manner as trivalent arsenicals are found in human and animal urine (Chilakapati et al., 2010; Naranmandura et al., 2009; Ochi et al., 2008; Suzuki et al., 2010), it has been demonstrated that toxicity of pentavalent thioarsenicals is mainly through their reduction to the trivalent form, dimethylarsinous acid (DMA III ) in cells (Naranmandura et al., 2011a). Thereby, trivalent arsenic species "
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    • "In some studies, thio-DMA V even exerted stronger cytotoxicity as compared to arsenite [27] [28] [29]. Moreover, Ochi et al. provided evidence for a genotoxic potential of thio-DMA V in cultured hamster cells [25], whereas no detailed data exist regarding the genotoxicity of thio-DMA V in human cells. "
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    ABSTRACT: We synthesised and toxicologically characterised the arsenic metabolite thiodimethylarsinic acid (thio-DMA(V)). Successful synthesis of highly pure thio-DMA(V) was confirmed by state-of-the-art analytical techniques including (1)H-NMR, HPLC-FTMS, and HPLC-ICPMS. Toxicological characterization was carried out in comparison to arsenite and its well-known trivalent and pentavalent methylated metabolites. It comprised cellular bioavailability as well as different cytotoxicity and genotoxicity end points in cultured human A549 lung cells. Of all arsenicals investigated, thio-DMA(V) exerted the strongest cytotoxicity. Moreover, thio-DMA(V) did not induce DNA strand breaks and an increased induction of both micronuclei and multinucleated cells occurred only at beginning cytotoxic concentrations, indicating that thio-DMA(V) does not act via a genotoxic mode of action. Finally, to assess potential implications of thio-DMA(V) for human health, further mechanistic studies are urgently necessary to identify the toxic mode of action of this highly toxic, unusual pentavalent organic arsenical.
    Journal of Toxicology 10/2011; 2011:373141. DOI:10.1155/2011/373141
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