Arsenic accumulation and speciation in strawberry plants exposed to inorganic arsenic enriched irrigation.

The accumulation and transformation of arsenic species have been studied in the context of hydroponic cultivation of strawberry plants. Cultivation experiments have been performed by adding inorganic arsenic at concentrations of 10, 100 and 1000 µg L-1 via root irrigation. The total arsenic content was determined by Hydride Generation-Atomic Fluorescence Spectrometry (HG-AFS). The accumulation was dependent on the concentration of arsenic added to the irrigation and the arsenic species. Arsenic (III) accumulated at higher rates than arsenic (V). A greater accumulation of arsenic was found in roots (0.44-4.10 mg kg-1) than in stems (0.43-1.27 mg kg-1) and fruits (0.22-0.30 mg kg-1). The speciation results obtained by HPLC-HG-AFS analysis indicated that the addition of As(III) resulted in a partial methylation producing monomethyl arsenic (MMA) and dimethyl arsenic (DMA). After As(V) addition, only MMA was observed and this was accompanied with a notable reduction in the ratio of As(V) to As(III).

Transfer and biological effects of arsenate from soil through a plant-aphid system to the parasitoid wasp, Aphidius colemani.

The accumulation of metalloid elements during transfer from contaminated soil to higher trophic levels may potentially result in the exposure of parasitic arthropods to toxic concentrations of these elements. This study examined the transfer of arsenate (As(V)) to aphids (Myzus persicae) from pepper plants cultivated in As(V) contaminated soils of two concentrations (2 and 6 mg As(V)/kg dry soil), and the subsequent biological effects on the aphid parasitoid, Aphidius colemani. Results showed that considerable quantities of As(V) were transferred to the plant in a concentration-dependent manner and were partitioned in the plant parts in the order of roots > stems > leaves. The accumulation of As(V) in the aphids increased with the concentrations in the plants; however, the transfer coefficient of As(V) from leaf to aphid was relatively similar and constant (0.07-0.08) at both soil As(V) concentration levels. Increased levels of As(V) significantly affected fecundity and honeydew production in aphids, but survival and developmental time were unaffected. Fecundity (mummification rate) of the parasitoid was not impaired by host As(V) contamination; however, vitality (eclosion rate) was significantly affected. Results are discussed in relation to possible ecological risks posed by the transfer of soil As(V) via the plant-arthropod system to parasitoid arthropods in agroecosystems.

Pathological and Clinical Pathological Changes Induced by Four-week, Repeated-dose, Oral Administration of the Wood Preservative Chromated Copper Arsenate in Wistar Rats.

Chromated copper arsenate (CCA) is used as a wood preservative worldwide. Exposure to it may adversely affect human health. Some events have increased human exposure to CCA, including the Great East Japan Earthquake, which generated a large amount of lumber debris from CCA-treated woods. We elucidated the toxicity due to daily exposure to CCA over a 4-week period at doses of 0, 8, 40, and 80 mg/kg/day in Wistar Hannover rats. Chromium (Cr) and arsenic (As), but not copper, were detected in the plasma samples of rats treated with various doses of CCA. Males and females showed sedation, and males had poor body weight gain. The clinical pathologies observed in both sexes included hypochromic and microcytic anemia, hepatic and renal dysfunction, and changes in lipid and glucose levels. Histopathologically, males and females showed forestomach hyperkeratosis, mucosal epithelial hyperplasia in the small intestine, rectal goblet cell hypertrophy, and lipofuscin deposition in the proximal renal tubule. Females showed diffuse hepatocellular hypertrophy with increased 8-hydroxydeoxyguanosine levels. These results indicated that oral administration of CCA mainly affected hematopoietic, gastrointestinal, hepatic, and renal systems owing to the toxic effects of As and/or Cr. Major toxic effects were observed in both sexes receiving 40 and 80 mg/kg/day.

Induction by arsenate of cell-type-specific cytotoxic effects in nerve and hepatoma cells.

The aim of the study was to compare the effect of sodium arsenate (AsV) on two different cell types: 158N murine oligodendrocytes and HepG2 human hepatoma cells. Exposure of 158N cells to AsV (0.1-400 µM; 48 h) induced a biphasic cytoxic effect defined as hormesis. Thus, low concentrations of AsV stimulate cell proliferation, as shown by phase-contrast microscopy, cell counting with trypan blue, and crystal violet assay, whereas high concentrations induce cell death associated with a loss of cell adhesion. These side effects were confirmed by staining with propidium iodide and cell cycle analysis, characterized by the presence of a subG1 peak, a criterion of apoptosis. The effects of AsV on mitochondrial function, as determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, the measurement of mitochondrial transmembrane potential with 3,3'-dihexyloxacarbocyanine iodide, and the rate of mitochondrial adenosine triphosphate confirm the impact of AsV on the mitochondria. In contrast to 158N cells, HepG2 cells were susceptible to all AsV concentrations as shown by microscopic observations, by counting with trypan blue. However, no alteration is noted in the cell membrane integrity, which indicated an apoptotic mode of cell death, and this side effect is confirmed by the cycle analysis, which revealed a subG1 peak. Of note, there was a loss of MTT, suggesting that AsV induces mitochondrial complex II dysfunction. Altogether, our data show that the cytotoxic characteristics of AsV depend on the cell type considered.

Effects of Sodium Arsenite and Arsenate in Testicular Histomorphometry and Antioxidants Enzymes Activities in Rats.

The main source of environmental arsenic exposure in most countries of the world is drinking water in which inorganic forms of arsenic predominate. The present study was aimed to test the impact of two different compounds of inorganic arsenic in histomorphometric and enzymatic parameters in the testes by oral exposition. Adult Wistar male rats were exposed to sodium arsenite and arsenate in drinking water, testing for each chemical form the concentrations of 0.01 and 10 mg/L per 56 days. The animals intoxicated with arsenic, mainly sodium arsenite, showed reduction in the percentage of seminiferous epithelium and in proportion and volume of Leydig cells. Moreover, there was an increase in the percentage of tunica propria, lumen, lymphatic space, blood vessels, and macrophages. The activity of superoxide dismutase (SOD) did not change among the groups. However, the activity of catalase (CAT) decreased in animals exposed to both arsenic compounds. In addition, the higher concentration of arsenic, mainly as sodium arsenite, caused vacuolization in the seminiferous epithelium. The body and testes weight as well as testosterone concentration remained unchanged among the groups. In conclusion, exposition to arsenic, mainly as sodium arsenite, caused alteration in histomorphometric parameters and antioxidant defense system in the testes.

Arsenic efflux from Microcystis aeruginosa under different phosphate regimes.

Phytoplankton plays an important role in arsenic speciation, distribution, and cycling in freshwater environments. Little information, however, is available on arsenic efflux from the cyanobacteria Microcystis aeruginosa under different phosphate regimes. This study investigated M. aeruginosa arsenic efflux and speciation by pre-exposing it to 10 µM arsenate or arsenite for 24 h during limited (12 h) and extended (13 d) depuration periods under phosphate enriched (+P) and phosphate depleted (-P) treatments. Arsenate was the predominant species detected in algal cells throughout the depuration period while arsenite only accounted for no greater than 45% of intracellular arsenic. During the limited depuration period, arsenic efflux occurred rapidly and only arsenate was detected in solutions. During the extended depuration period, however, arsenate and dimethylarsinic acid (DMA) were found to be the two predominant arsenic species detected in solutions under -P treatments, but arsenate was the only species detected under +P treatments. Experimental results also suggest that phosphorus has a significant effect in accelerating arsenic efflux and promoting arsenite bio-oxidation in M. aeruginosa. Furthermore, phosphorus depletion can reduce arsenic efflux from algal cells as well as accelerate arsenic reduction and methylation. These findings can contribute to our understanding of arsenic biogeochemistry in aquatic environments and its potential environmental risks under different phosphorus levels.

Evaluation of arsenate content of rice and rice bran purchased from local markets in the People's Republic of China.

In previous studies, inorganic arsenic and total arsenic concentrations in rice bran have been much higher than those in polished rice obtained from the same whole paddy rice. However, the arsenic species distribution between rice and bran is still unknown, especially for arsenite (AsIII) and arsenate (AsV). To characterize the arsenic species in rice and bran and explain the elevated concentrations of inorganic arsenic and total arsenic, four arsenic species, AsIII, AsV, dimethylarsinic acid, and monomethylarsonic acid, were evaluated. Rice and bran samples (n = 108) purchased from local markets in the People's Republic of China were analyzed using high-performance liquid chromatography with hydride generation and atomic fluorescence spectrometry and then microwave extraction. As expected, most of the arsenic was found in bran, with bran/rice ratios of 6.8 for total arsenic species and 6.4 for inorganic arsenic. Among four arsenic species, the maximum bran/rice ratio was 104.7 (335/3.2 µg kg(-1)) for AsV followed by 1.2 (69.2/56.1) for AsIII, 1.3 (6.7/5.2) for dimethylarsinic acid, and 4.0 (0.8/0.2) for monomethylarsonic acid. Thus, the large difference in arsenic concentration between rice and bran was mostly due to the difference in the AsV concentration, which account for 96 and 95 % of the difference for total arsenic species and inorganic arsenic, respectively. Therefore, the possibility of AsV contamination in rice bran and its by-products needs more study. This study is the first in which concentrations of AsIII and AsV in rice and bran have been documented, revealing that a higher percentage of AsV occurs in bran than in rice.

Protective effect of dietary flaxseed oil on arsenic-induced nephrotoxicity and oxidative damage in rat kidney.

Arsenic, a naturally occurring metalloid, is capable of causing acute renal failure as well as chronic renal insufficiency. Arsenic is known to exert its toxicity through oxidative stress by generating reactive oxygen species (ROS). Flaxseed, richest plant based dietary source of ω-3 polyunsaturated fatty acids (PUFAs) and lignans have shown numerous health benefits. Present study investigates the protective effect of flaxseed oil (FXO) on sodium arsenate (NaAs) induced renal damage. Rats prefed with experimental diets (Normal/FXO diet) for 14days, were administered NaAs (20mg/kg body weight i.p.) once daily for 4days while still on the experimental diets. NaAs nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. Administration of NaAs led to a significant decline in the specific activities of brush border membrane (BBM) enzymes both in kidney tissue homogenates and in the isolated membrane vesicles. Lipid peroxidation and total sulfhydryl groups were altered upon NaAs treatment, indicating the generation of oxidative stress. NaAs also decreased the activities of metabolic enzymes and antioxidant defence system. Histopathological studies supported the biochemical findings showing extensive damage to the kidney by NaAs. In contrast, dietary supplementation of FXO prior to and alongwith NaAs treatment significantly attenuated the NaAs-induced changes.

Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity.

BACKGROUND: In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity varies widely and depends on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. METHODS: Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. RESULTS: When the dams in Mthfr(+/-)×Mthfr(+/-) matings were treated with 7.2 mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr(+/+)×Mthfr(+/-), Mthfr(+/-)×Mthfr(+/-) and Mthfr(-/-)×(Mthfr+/-)) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote×wild-type versus wild-type×nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. CONCLUSIONS: Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure.

Urinary arsenic speciation profiles in mice subchronically exposed to low concentrations of sodium arsenate in drinking water.

Arsenic is a proven human carcinogen. Although the mechanism of its carcinogenicity is still largely unknown, methylation is thought to have an important role to play in arsenic toxicity. In this study, urinary methylation profiles were investigated in female C57BL/6J black mice given drinking water containing 500 µg arsenate (As(V))/L, 250 µg As(V)/L, or 100 µg As(V)/L as sodium arsenate for 2 months. The concentrations of arsenic chosen reflected those in the drinking water often encountered in arsenic-endemic areas. Urine samples were collected from the mice at the end of the exposure period, and the arsenic species were analyzed by high performance liquid chromatography-inductively coupled plasma-mass spectrometry. All detectable arsenic species showed strong linear correlation with the administered dosage. The methylation patterns were similar in all three groups with a slight decrease of dimethylarsinic acid/As(V) ratio in the 500-µg/L group, which corresponded to the significantly higher arsenic retention in the tissue. The results indicate that urinary arsenic could be used as a good biomarker for internal dose and potential biological effects. Different doses of arsenic exposure could result in different degrees of methylation, excretion, and tissue retention, and this may contribute to the understanding of arsenic carcinogenicity.

The relative importance of waterborne and dietborne arsenic exposure on survival and growth of juvenile rainbow trout.

Previous work demonstrated reduced growth of rainbow trout receiving diets containing environmentally relevant concentrations of arsenic, but did not address the relative and combined potency of waterborne and dietborne exposures. In the current study, juvenile rainbow trout were exposed for 28d to a range of arsenic concentrations in water and in a live oligochaete diet, separately and in combination. In clean water, fish fed worms previously exposed to arsenate at 4 or 8mg As/L showed pronounced reductions in growth, but fish exposed to these same water concentrations and a clean diet experienced less or no effect. Increasing waterborne arsenate to 16 or 32mg As/L had substantial effects on both growth and survival, and simultaneous exposure via both routes intensified growth effects, but not mortality. Growth reduction was strongly correlated to total arsenic accumulation in the fish tissue, regardless of the route of exposure, but mortality was better correlated to waterborne arsenic concentration. The relative concentration of total arsenic in fish viscera and in the remaining carcass was not a useful indicator of exposure route. Speciation analysis showed that most arsenate was converted to arsenite within the worms, but organoarsenic species were not found. The greater toxicity of dietborne exposure when fish and prey were exposed to the same waterborne arsenate concentration emphasizes the need to address dietborne exposure when assessing the aquatic risks of arsenic contamination. This is of particular concern because risk from dietary exposure may occur at even lower water concentrations than used here when prey organisms are exposed for longer periods and via multiple routes.

Arsenic- and cadmium-induced toxicogenomic response in mouse embryos undergoing neurulation.

Arsenic (As) and cadmium (Cd) are well-characterized teratogens in animal models inducing embryotoxicity and neural tube defects (NTDs) when exposed during neurulation. Toxicological research is needed to resolve the specific biological processes and associated molecular pathways underlying metal-induced toxicity during this timeframe in gestational development. In this study, we investigated the dose-dependent effects of As and Cd on gene expression in C57BL/6J mouse embryos exposed in utero during neurulation (GD8) to identify significantly altered genes and corresponding biological processes associated with embryotoxicity. We quantitatively examined the toxicogenomic dose-response relationship at the gene level. Our results suggest that As and Cd induce dose-dependent gene expression alterations representing shared (cell cycle, response to UV, glutathione metabolism, RNA processing) and unique (alcohol/sugar metabolism) biological processes, which serve as robust indicators of metal-induced developmental toxicity and indicate underlying embryotoxic effects. Our observations also correlate well with previously identified impacts of As and Cd on specific genes associated with metal-induced toxicity (Cdkn1a, Mt1). In summary, we have identified in a quantitative manner As and Cd induced dose-dependent effects on gene expression in mouse embryos during a peak window of sensitivity to embryotoxicity and NTDs in the sensitive C57BL/6J strain.

Genome-wide analysis of DNA methylation and gene expression changes in the mouse lung following subchronic arsenate exposure.

Alterations in DNA methylation have been proposed as a mechanism for the complex toxicological effects of arsenic. In this study, whole-genome DNA methylation and gene expression changes were evaluated in lungs from female mice exposed for 90 days to 50 ppm arsenate (As) in drinking water. DNA methylation changes were measured using reduced representation bisulfite deep sequencing. Differential methylation was observed in approximately 700 and 1900 start and transcribed regions, respectively. The start regions showed bias toward decreased methylation. No bias was observed in the transcribed region. A comparison of absolute methylation levels in the control animals with treatment-related changes in methylation showed that baseline methylation levels play a role in determining which genes are methylated. Genes with low absolute methylation levels in the start region showed a trend toward increased As-related methylation and decreased expression. Genes with high levels of methylation in the transcribed region showed a trend toward decreased As-related methylation, but no change in expression. No overall correlation between treatment-related changes in methylation and expression was identified. Among genes showing differential methylation in the start region and differential expression, only 57% showed an inverse correlation. The results suggest that differential methylation following As treatment may only play a permissive role in regulating expression. Despite the low correlation, the subset of 17 genes that showed an inverse relationship between As-related methylation and expression included a substantial number that has been demonstrated to play a functional role in cancer-related processes and other effects consistent with arsenic exposure.

Biological responses of duckweed (Lemna minor L.) exposed to the inorganic arsenic species As(III) and As(V): effects of concentration and duration of exposure.

The accumulation of arsenic (As) and physiological responses of Lemna minor L. under different concentration (0, 1, 4, 16 and 64 microM) and duration (1, 2, 4 and 6 days) of two species As, NaAsO(2) and Na(2)HAsO(4).7H(2)O, were studied in hydroponics. The accumulation of both As species depended on As concentration and exposure duration. The highest accumulation of As was found as 17408 and 8674 microg g(-1), for plants exposed to 64 microM of As(III) and As(V), respectively, after 6 days. Two-way ANOVA analyses indicated that, for plants exposed to arsenite (As(III)), exposure duration had a greater effect than concentration on As accumulation. Conversely, exposure concentration had a greater effect on As accumulation in plants exposed to arsenate (As(V)). Arsenic exposure levels, approaching 16 microM for As(III) and 64 microM for As(V), did not significantly affect EC values. Beyond these exposure concentrations, EC values increased in a manner that depended on duration. Significant effect of As(III) on lipid peroxidation was observed at 1 microM application whereas, this effect started to be significant after an exposure to 16 microM As(V). For both As(III) and As(V), photosynthetic pigment levels slightly increased for the first day with respect to the control, followed by a gradual decline at higher concentrations and durations. An increase in protein content and enzyme activity was observed at moderate exposure conditions, followed by a decrease. Significant positive correlations were determined between accumulated As and ion leakage and lipid peroxidation. Negative correlations were found between accumulated As and total chlorophyll and protein content. Our results suggested that exposure duration and concentration had a strong synergetic effect on antioxidant enzyme activity. The findings of the present study may be useful when this plant is used as a phytoremediator in arsenic-polluted water.

Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate.

The arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a 43 kDa protein that catalyzes methylation of inorganic arsenic. Altered expression of AS3MT in cultured human cells controls arsenic methylation phenotypes, suggesting a critical role in arsenic metabolism. Because methylated arsenicals mediate some toxic or carcinogenic effects linked to inorganic arsenic exposure, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be instructive. This study compared retention and distribution of arsenic in As3mt knockout mice and in wild-type C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [(73)As]-arsenate. Mice were radioassayed for up to 96 h after dosing; tissues were collected at 2 and 24 h after dosing. At 2 and 24 h after dosing, livers of As3mt knockouts contained a greater proportion of inorganic and monomethylated arsenic than did livers of C57BL/6 mice. A similar predominance of inorganic and monomethylated arsenic was found in the urine of As3mt knockouts. At 24 h after dosing, As3mt knockouts retained significantly higher percentages of arsenic dose in liver, kidneys, urinary bladder, lungs, heart, and carcass than did C57BL/6 mice. Whole body clearance of [(73)As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 h after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 h, As3mt knockouts retained about 20% and C57BL/6 mice retained less than 2% of the dose. These data confirm a central role for As3mt in the metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation, indicating a close linkage between the metabolism and retention of arsenicals.

Time course of arsenic species in the brain and liver of mice after oral administration of arsenate.

The understanding of the biomethylation process of arsenic is essential to uncover the mechanisms of arsenic toxicity. This work analyzes the time course of arsenic species in the brain and liver of adult mice, after a single oral administration of three arsenate doses [2.5, 5.0 and 10 mg As(V)/kg]. Quantification of arsenic species was performed by means of liquid chromatography coupled to atomic fluorescence 2, 5, 8, 12 and 24 h after administration. The results show that 2 h after arsenate administration inorganic arsenic arrives to the liver and its concentration diminishes gradually until becoming non-detectable at 12 h. Arsenic takes longer to appear in the brain and it is present only as dimethyl arsinic acid. Since arsenic concentration decreases in liver while it increases in the brain, this suggests that the arsenic metabolite reaches the brain after formation in the liver. Importantly, the fact that dimethyl arsinic acid is no longer present after 24 h suggests the existence of a mechanism to clear this metabolite from brain tissue.

Evolution of arsenate toxicity in nodulated white lupine in a long-term culture.

White lupine is an As-resistant legume that is of interest for phytoremediation of As-contaminated soils. To achieve successful phytoremediation, monitoring of the nutritional status of the selected plant species during the entire culture cycle is required to maintain a plant cover with high biomass production. A long-term pot experiment was carried out with nodulated lupine grown on perlite with 10 and 100 microM As concentrations. The reproductive period (from 10 weeks) was the most sensitive phenologic stage of white lupine to long-term As exposure. The 10 microM As treatment increased the uptake and translocation of micronutrients, except for Cu, mainly at flowering with As levels in pods below the statutory limit (1 mg kg (-1) fresh weight). However, the 100 microM As treatment induced significant differences compared to the control. These findings confirm the relatively high resistance of white lupine to arsenate and support the use of this species in phytoremediation and/or revegetation of As-contaminated sites, with special attention on P and Cu nutrition at flowering.

Novel thioarsenic metabolites in human urine after ingestion of an arsenosugar, 2',3'-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-beta-D-riboside.

The presence of arsenic-containing carbohydrates, arsenosugars, in many seafoods raises questions of human health concerning the ingestion and metabolism of these compounds. A previous study investigating the metabolites in human urine after the ingestion of a common arsenosugar 2',3'-dihydroxypropyl 5-deoxy-5-dimethylarsinoyl-beta-d-riboside (oxo-arsenosugar) showed that the arsenic was rapidly excreted in the urine and was present as at least 12 metabolites, only three of which could be identified. In this repeat study with oxo-arsenosugar and using high-performance liquid chromatography/inductively coupled plasma mass spectrometry, we report the identification of seven arsenic metabolites, which together accounted for 88% of the total urinary arsenic collected over 61 h. The metabolites included previously reported human urinary arsenicals dimethylarsinate (DMA), oxo-dimethylarsenoethanol (oxo-DMAE), and trimethylarsine oxide, in addition to new human metabolites oxo-dimethylarsenoacetate (oxo-DMAA), thio-dimethlyarsenoacetate (thio-DMAA), thio-dimethylarsenoethanol (thio-DMAE), and the thio-arsenosugar. Cytotoxicity testing of the major metabolites DMA, oxo-DMAE, thio-DMAE, oxo-DMAA, and thio-DMAA showed that they were nontoxic even at 10 mM, except for DMA, which showed some toxic effects at 1 mM.

Urinary arsenic speciation and porphyrins in C57Bl/6J mice chronically exposed to low doses of sodium arsenate.

Arsenic has been classified as a human carcinogen based on epidemiological data however the mechanism of its carcinogenicity is still unclear. Urinary biomarkers for chronic arsenic exposure would be valuable as an early warning indicator for timely interventions. In this study, young female C57Bl/6J mice were given drinking water containing 0, 100, 250 and 500 microg Asv/L as sodium arsenate ad libitum for 12 months. Urine was collected bimonthly for urinary arsenic methylation assay and porphyrin analysis. All detectable arsenic species showed strong linear correlation with administered dosage and the arsenic methylation patterns were similar in all three treatment groups. No significant changes of methylation patterns were observed over time for either the control or test groups. Urinary coproporphyrin III was significantly increased in the 8th month in 250 and 500 microg/L groups and remained significantly dose-related after 10 and 12 months. Coproporphyrin I also showed a significant dose-response relationship after 12 months. Our results confirm that urinary arsenic is a useful biomarker for internal dose. The alteration of porphyrin profile suggests that arsenic can affect the heme metabolism and this may occur prior to the onset of arsenic induced carcinogenesis.

Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg.AC) mice.

Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received sodium arsenite [(As(III)] in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo. Because the liver is a known target of arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided drinking water containing As(III), sodium arsenate [As(V)], monomethylarsonic acid [(MMA(V)], and 1,000 ppm dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of arsenic treatment, TPA at a dose of 1.25 microg/200 microL acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving arsenic. In some cases arsenic exposure reduced body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global DNA hypomethylation. cDNA microarray and reverse transcriptase-polymerase chain reaction analysis revealed that all arsenicals altered the expression of numerous genes associated with toxicity and cancer. However, organic arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic arsenicals resulted in toxic manifestations, hepatic arsenic accumulation, global DNA hypomethylation, and numerous gene expression changes. These effects may play a role in arsenic-induced hepatotoxicity and carcinogenesis and may be of particular toxicologic relevance.