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PubMed2005

The effect of arsenicals on ultraviolet-radiation-induced growth arrest and related signaling events in human keratinocytes.

The molecular mechanisms mediating arsenic-induced carcinogenesis are not well understood. The role of confounding factors such as ultraviolet radiation (UV), add another level of complexity to the study of arsenic carcinogenesis and the cancer-risk assessment on humans. We hypothesized that arsenicals are capable of overriding the growth arrest caused by UV treatment and may lead to selective proliferation. To test this hypothesis, a primary normal human epidermal keratinocyte (NHEK) cell culture model was used. One group was pre-exposed to UVB (100 mJ/cm(2)) that arrested a majority ( approximately 95%) of cells in G0/G1 (+UV) and a second group was not exposed to UV (-UV). Treatment of cells with various arsenicals [0-12 microM of inorganic arsenite (iAs), 0-2 microM of methyl oxoarsine (MMAs III) and 0-3 microM of iododimethyl arsine (DMAs III)] indicated a concentration-dependent increase in proliferation at 24 h in the order of DMAs III > MMAs III > iAs. Flow-cytometric analyses revealed differential effects on cell cycle distribution. Analysis of a battery of cell cycle proteins (cyclin D1, cdk5, PCNA, cdc25A and cdc25C) indicated exposure-specific differential expression profiles. Increased activation of JNK phosphorylation (5-10-fold) in the +UV group and the synergistic increase with methyl arsenicals suggested that JNK might be involved in cell survival and proliferative signaling. Induction of EGF levels and increased phosphorylation of the EGF receptor by arsenicals (+UV) suggested that the EGF signaling pathway might mediate arsenical-induced cell proliferation of NHEK cells. Differential activation of ERK1/2 by arsenicals (+/-UV) suggested that EGF-mediated cell proliferation by arsenicals in UV-treated NHEK cells may not involve ERK activation. Taken together, the data suggest that both UV exposure and methylation status of the arsenicals dictate the participation of key cell cycle proteins and related signaling events in arsenical-induced cell proliferation.

Arsenicals↗
PubMed2005

Arsenic contamination of groundwater in Nawabganj, Bangladesh, focusing on the relationship with other metals and ions.

Serious arsenic contamination of groundwater in Bangladesh has been frequently reported and is of great concern. In this research, repeated water sampling from the same 10 tubewells in Nawabganj municipality, Bangladesh, was conducted and analysed, focusing on the seasonal variation of water quality and the relationship among arsenic and other metals and ions. For the seasonal variation of water quality, arsenic and iron concentrations were higher in the rainy season in general although the tendency was not consistent and it depended on the tubewell and the time. Correlation between arsenic and iron could not be observed in this study (r = -0.01) when using all cases. This was because no correlation was observed in the higher arsenic concentration range. Arsenic removal by co-precipitation with coexisting iron is known as one of the locally applicable techniques in Bangladesh, but the result from this study suggests that some additional treatments such as the extra injection of iron should be performed in some cases, especially where the arsenic concentration is high. The correlation between arsenic and other substances was also analysed. As a result, manganese (r = 0.37), molybdenum (r = 0.33) and sulfate ion (r = -0.33) significantly correlated with arsenic (p < 0.05). The negative correlation between arsenic and sulfate ion implies the dissolution of arsenic into groundwater under reductive conditions although there are some exceptional cases.

Arsenic↗
PubMed1979

Arsenic-induced bone marrow toxicity: ultrastructural and electron-probe analysis.

A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia. In this study we report an ultrastructural and electron-probe analysis of the bone marrow. Although megaloblastic anemia associated with arsenic poisoning has been described rarely, the presence of arsenic in the local bone marrow milieu has not been demonstrated previously. The ultrastructural features of arsenic-induced bone marrow toxicity are similar to those described in other dyserythropoietic states and include marked nuclear aberrations involving shape, chromatin distribution, and nuclear envelope. Using the technique of energy-dispersive x-ray analysis (electron probe) we demonstrated arsenic in bone marrow spicules; this supports the contention that arsenic can cause megaloblastic anemia. We suggest that this technique may be a useful tool in further studies that attempt to explore the mechanism of arsenic-induced hematologic toxicity. Finally, we suggest that arsenic has a direct toxic effect on DNA synthesis that results in marked disturbances of nuclear division. We recommend that the most appropriate screening procedure to evaluate possible arsenic poisoning is tissue arsenic measurements (hair and nails) rather than 24-hr urinary measurements.

Adult↗
PubMed1996

Toenail samples as an indicator of drinking water arsenic exposure.

We conducted a pilot study to assess the utility of toenail arsenic concentrations as an indicator of ingestion of arsenic-containing water. We enrolled 21 individuals whose household drinking water supply was provided by a private well, including 10 individuals who lived in areas of New Hampshire where elevated water levels of arsenic had been reported previously. Participants were interviewed regarding use of their private (unregulated) wells for drinking and cooking, and each provided a sample of water and toenail clippings. All specimens were analyzed using instrumental neutron activation analysis with a sensitivity of approximately 0.001 parts per million (ppm). Trace concentrations of arsenic were detected in 15 of the 21 well water samples and in all toenail clipping samples. Among the 10 individuals who lived in areas with reportedly high arsenic levels in the water supply, the geometric mean toenail concentration was 0.39 ppm (SE, 0.12 ppm); among the other 11 persons, the geometric mean was 0.14 ppm (SE, 0.02 ppm; P = 0.005 for the difference between the two means). The overall Spearman correlation between toenail and well water arsenic was 0.67 (P = 0.009), and among those with detectable well water levels of arsenic, the Spearman correlation was 0.83 (P = 0.0001). Based on the regression analysis of those who had detectable water levels of arsenic, a 10-fold increase in well water concentrations of arsenic was reflected by about a 2-fold increase in toenail concentrations. These results indicate that concentrations of arsenic in toenails reflect use of arsenic-containing drinking water.

Adult↗
PubMed1998

Effect of arsenosugar ingestion on urinary arsenic speciation.

We developed and evaluated a method for the determination of microgram/L concentrations of individual arsenic species in urine samples. We have mainly studied arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMAA), and dimethylarsinic acid (DMAA) because these are the most commonly used biomarkers of exposure by the general population to inorganic arsenic and because of concerns over these arsenic species on their toxicity and carcinogenicity. We have also detected five unidentified urinary arsenic species resulting from the metabolism of arsenosugars. We combined ion pair liquid chromatography with on-line hydride generation and subsequent atomic fluorescence detection (HPLC/HGAFS). Detection limits, determined as three times the standard deviation of the baseline noise, are 0.8, 1.2, 0.7, and 1.0 mu/L arsenic for arsenite, arsenate, MMAA, and DMAA, respectively. These correspond to 16, 24, 14, and 20 pg of arsenic, respectively, for a 20-muL sample injected for analysis. The excellent detection limit enabled us to determine trace concentrations of arsenic species in urine samples from healthy subjects who did not have excess exposure to arsenic. There was no need for any sample pretreatment step. We used Standard Reference Materials, containing both normal and increased concentrations of arsenic, to validate the method. Interlaboratory studies with independent techniques also confirmed the results obtained with the HPLC/HGAFS method. We demonstrated an application of the method to the determination of arsenic species in urine samples after the ingestion of seaweed by four volunteers. We observed substantial increases of DMAA concentrations in the samples collected from the volunteers after the consumption of seaweed. The increase of urinary DMAA concentration is due to the metabolism of arsenosugars that are present in the seaweed. Our results suggest that the commonly used biomarkers of exposure to inorganic arsenic, based on the measurement of arsenite, arsenate, MMAA, and DMAA, are not reliable when arsenosugars are ingested from the diet.

Arsenates↗
PubMed1998

[Drinking water supply with reference to geogenic arsenic contamination].

Geogenic Arsenic in Drinking Water. Drinking water production of surface spring water in southern Lower Saxony (Niedersachsen, Germany) was reduced because of microbiological contaminations and unreliably variable water reserves. Surface spring water in general has a low arsenic content. As a consequence ground water has been increasingly used for drinking water. Thus, high geogenic concentrations of arsenic in the central "Buntsandstein" in southern Lower Saxony caused high arsenic contents in the groundwater. Under the regulation of the German Drinking Water Ordinance (1986) the limit for total arsenic (40 micrograms/l) was exceeded in 2% of 150 fountains, wells and sources in southern Lower Saxony. Because of the well-known cancerogenic potential of arsenic the limit for total arsenic in drinking water was reduced from 40 micrograms/l to 10 micrograms/l suspending the new standard value until January 1996. This regulation based on new calculations revealing a skin cancer risk of roughly 6:10,000 and a mortality risk of roughly 1:10(6) in respect of lifetime in case of arsenic concentrations of 10 micrograms As/l drinking water. After that limit change 40% of 150 wells and sources in southern Lower Saxony exceeded the arsenic limit of 10 micrograms/l drinking water. As a matter of fact, it became necessary for a large number of water supply works to eliminate arsenic from the drinking water by technical means or to dilute drinking water with high concentrations of arsenic.

Arsenic↗
PubMed1993

Risk factors for exposure to arsenic at a hazardous waste site.

Communities surrounding the Rocky Mountain Arsenal (RMA), a Superfund site in Colorado, were studied in order to determine whether exposures to arsenic were greater among persons who resided there than among residents of a comparison area. A census was conducted in areas adjacent to the RMA and in a comparison area 12-15 miles distant. From a stratified random sample, 469 persons were interviewed and urine samples obtained. Arsenic was detected in urine from 43 (9.2%) of the 469 persons sampled at a detection limit of 10 ppb. Trace levels of arsenic (detectable, but non-quantifiable) were found in 184 (39.2%) of those persons sampled. Neither the frequency of detection, the arithmetic mean nor the geometric mean values for urine arsenic was found to be statistically different when persons living near the site were compared to persons from the more distant comparison area. Therefore, the data were pooled across the study areas to evaluate risk factors for exposure to arsenic in this population-based sample. Multivariate logistic regression analyses were conducted to evaluate the risk of arsenic exposure associated with variables included in the interviews while controlling for confounding. Pathways for exposure to arsenic were evaluated through analysis of residence history, occupation, hobbies, dietary habits, water supply, housing and activity patterns. Children of Hispanic origin or non-white race, children who drank less than three glasses of water daily, and children who spent more time outdoors had an increased risk of having > or = 10 ppb of arsenic in their urine. Among adults, younger persons, especially those less than 40 years of age, persons of Hispanic origin or nonwhite race, and those employed in occupations where arsenic is likely to be found had an increased risk of having > or = 10 ppb of urine arsenic. Consumption of red wine or fish during the week prior to sampling was associated with trace levels of arsenic in urine.

Adolescent↗
PubMed2003

Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis.

Arsenic can induce apoptosis and is an efficient drug for the treatment of acute promyelocytic leukemia. Currently, clinical studies are investigating arsenic as a therapeutic agent for a variety of malignancies. In this study, Hodgkin/Reed-Sternberg (HRS) cell lines served as model systems to characterize the role of nuclear factor-kappaB (NF-kappaB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IkappaB kinase (IKK) as well as NF-kappaB activity and induced apoptosis in HRS cell lines containing functional IkappaB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3-like activity. Furthermore, arsenic treatment down-regulated NF-kappaB target genes, including tumor necrosis factor-alphareceptor-associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IkappaB proteins or with a weak constitutive IKK/NF-kappaB activity showed no alteration of the NF-kappaB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-kappaB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-kappaB-p65 in L540Cy HRS cells, which protected the cells from arsenic-induced apoptosis. In addition, treatment of NOD/SCID mice with arsenic trioxide induced a dramatic reduction of xenotransplanted L540Cy Hodgkin tumors concomitant with NF-kappaB inhibition. We conclude that inhibition of NF-kappaB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-kappaB activity might be a powerful treatment option for Hodgkin lymphoma.

Animals↗
PubMed2005

Arsenic speciation in terrestrial birds from Yellowknife, Northwest Territories, Canada: the unexpected finding of arsenobetaine.

The surrounding area of Yellowknife, Northwest Territories, Canada, is known for naturally and anthropogenically elevated concentrations of arsenic. Five bird species (gray jay [Perisoreus canadensis], American tree sparrow [Spizella arborea], dark-eyed junco [Junco hyemalis], yellow-rumped warbler [Dendroica coronata], and spruce grouse [Dendragapus canadensis]) were collected from this area. Their tissues were analyzed for total arsenic and for arsenic species, allowing us to report, to our knowledge for the first time, the arsenic characterization in terrestrial birds. Total arsenic concentrations were determined in the terrestrial birds by inductively coupled plasma-optical emission spectrometry, whereas arsenic speciation analysis was performed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry. Total arsenic concentrations were substantially higher in the terrestrial bird species studied from Yellowknife compared with those reported previously in the literature. The primary arsenic species detected in two of the bird species studied was arsenobetaine. Normally, arsenobetaine is not formed or retained by terrestrial animals. Thus, the birds in the present study were thought to be highly adapted compared with other terrestrial animals, because they were able to form and/or retain this relatively nontoxic arsenic compound. This adaptation is thought to be a consequence of the elevated concentrations of arsenic in the Yellowknife area.

Animals↗
PubMed2003

Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide.

Inorganic arsenic is a well-documented human carcinogen that targets the skin. The induction of oxidative stress, as shown with arsenic, may have a bearing on the carcinogenic mechanism of this metalloid. The transcription factor Nrf2 is a key player in the regulation of genes encoding for many antioxidative response enzymes. Thus, the effect of inorganic arsenic (as sodium arsenite) on Nrf2 expression and localization was studied in HaCaT cells, an immortalized human keratinocyte cell line. We found, for the first time, that arsenic enhanced cellular expression of Nrf2 at the transcriptional and protein levels and activated expression of Nrf2-related genes in these cells. In addition, arsenic exposure caused nuclear accumulation of Nrf2 in association with downstream activation of Nrf2-mediated oxidative response genes. Arsenic simultaneously increased the expression of Keap1, a regulator of Nrf2 activity. The coordinated induction of Keap1 expression and nuclear Nrf2 accumulation induced by arsenic suggests that Keap1 is important to arsenic-induced Nrf2 activation. Furthermore, when cells were pretreated with scavengers of hydrogen peroxide (H(2)O(2)) such as catalase-polyethylene glycol (PEG-CAT) or Tiron, arsenic-induced nuclear Nrf2 accumulation was suppressed, whereas CuDIPSH, a cell-permeable superoxide dismutase (SOD) mimic compound that produces H(2)O(2) from superoxide (*O(2)(-)), enhanced Nrf2 nuclear accumulation. These results indicate that H(2)O(2), rather than *O(2)(-), is the mediator of nuclear Nrf2 accumulation. Additional study showed that arsenic causes increased cellular H(2)O(2) production and that H(2)O(2) itself has the ability to increase Nrf2 expression at both the transcription and protein levels in HaCaT cells. Taken together, these data clearly show that arsenic increases Nrf2 expression and activity at multiple levels and that H(2)O(2) is one of the mediators of this process.

Arsenites↗
PubMed2003

Accurate quantification and transformation of arsenic compounds during wet ashing with nitric acid and microwave assisted heating.

Arsenous acid, dimethylarsinic acid (DMA), methylarsonic acid (MA), arsenic acid, arsenobetaine bromide (AB), trimethylarsine oxide (TMAO), arsenocholine iodide (AC), and tetramethylarsonium iodide (TETRA) were heated in a microwave autoclave with nitric acid to 100-300 degrees C. The arsenic compounds in the digests were separated with anion- and cation-exchange chromatography and determined with an inductively coupled plasma mass spectrometer as arsenic-specific detector. Arsenous acid was completely oxidized to arsenic acid at 100 degrees C. For a complete oxidation of MA and DMA to arsenic acid temperatures > 220 degrees C and > 280 degrees C were necessary. AB decomposed to arsenic acid via TMAO. Complete conversion was only obtained after heating the sample for 90 min to 300 degrees C. For a complete conversion of TMAO similar harsh conditions were necessary. AC was already substantially degraded to TMAO, TETRA and two unknown compounds at 100 degrees C. The unknown arsenic compounds were found only in the digests up to 160 degrees C. Quantitative conversion of AC to arsenic acid went also via TMAO. At temperatures above 220 degrees C TETRA started to convert to TMAO, which then was further converted to arsenic acid. To investigate whether the results obtained for the arsenic standards are transferable to real samples, the certified reference material DORM-2 was also heated in nitric acid with variable digestion temperatures and times. For an almost complete conversion of the AB present in DORM-2 90 min at 300 degrees C were necessary. Total organic carbon (TOC) was less < 0.2% when DORM-2 was heated at temperatures > or = 260 degrees C for 60 min. UV photo-oxidation of DORM-2 was investigated as an alternative sample decomposition. Only 6% of AB was converted to arsenic acid when DORM-2 was irradiated for 2 h at 1000 W. In contrast to microwave heating substantial amounts of MA were observed as degradation product.

Journal Article↗
PubMed1997

Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression.

Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming S-adenosyl-methionine (SAM) in the process. The fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis. Here we test the hypothesis that arsenic-induced initiation results from DNA hypomethylation caused by continuous methyl depletion. The hypothesis was tested by first inducing transformation in a rat liver epithelial cell line by chronic exposure to low levels of arsenic, as confirmed by the development of highly aggressive, malignant tumors after inoculation of cells into Nude mice. Global DNA hypomethylation occurred concurrently with malignant transformation and in the presence of depressed levels of S-adenosyl-methionine. Arsenic-induced DNA hypomethylation was a function of dose and exposure duration, and remained constant even after withdrawal of arsenic. Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells. Acute arsenic or arsenic at nontransforming levels did not induce global hypomethylation of DNA. Whereas transcription of DNA MeTase was elevated, the MeTase enzymatic activity was reduced with arsenic transformation. Taken together, these results indicate arsenic can act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression, and they constitute a tenable theory of mechanism in arsenic carcinogenesis.

Animals↗
PubMed2006

Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations.

In West Bengal, India more than 6 million people are exposed to high levels of arsenic through drinking water. Since, only 15-20% of the exposed individuals show arsenic-induced skin lesions, it is assumed that genetic variation might play an important role in arsenic toxicity and carcinogenicity. Arsenic exposure often leads to the development of hyperkeratosis, the precursor of arsenic-induced skin cancer. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) is a nucleotide excision repair pathway gene, and its SNPs have been implicated in several types of epithelial cancers. We investigated the possible association of ERCC2 codon 751 A-->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair. For this association study, 318 unrelated arsenic exposed subjects (165 with hyperkeratosis and 153 without any arsenic-induced skin lesions), drinking water contaminated with arsenic to a similar extent, were recruited. Genotyping was done through PCR-RFLP procedure. Lys/Lys genotype was significantly over-represented in the arsenic-induced hyperkeratosis-exhibiting group [odds ratio (OR) = 4.77, 95% confidence interval (CI) = 2.75-8.23]. A statistically significant increase in both CA/cell and percentage of aberrant cells was observed in the individuals with AA genotype compared to those with AC or CC genotype combined (P < 0.01) in each of the two study groups, as also, in the total study population. This study indicates that ERCC2 codon 751 Lys/Lys genotype is significantly associated with arsenic-induced premalignant hyperkeratosis and is possibly due to sub-optimal DNA repair capacity of the ERCC2 codon 751 Lys/Lys genotype.

Adult↗
PubMed1980

Low-level arsenic exposure in wood processing plants.

In October 1978, seven construction workers building a pier in Monterey, California, developed symptoms consistent with arsenic intoxication and had elevated urinary levels of arsenic. The wood used for the pier had been pressure-treated with an arsenic preservative. To evaluate the potential acute medical hazards of preserving wood with arsenic, we evaluated employees at three California plants where arsenic preservatives are mixed and applied to wood. Histories, physical examinations, and urine specimens for arsenic analysis were collected from 44 workers exposed to arsenic and from 37 controls in three woodworking plants where arsenic is not used. A comparison of the groups failed to show any significant differences in history or physical examination. Adjustment for age, length of employment, and smoking histories did not alter the pattern. Urinary arsenic concentration was found to increase with increased exposure. These results do not imply absence of chronic or delayed toxicity, nor do they preclude the presence of a more subtle toxicity such as nerve conduction deficits. The data indicate existence of an arsenic exposure hazard in wood processing.U

Adolescent↗
PubMed2004

Arsenic hazards to humans, plants, and animals from gold mining.

Arsenic sources to the biosphere associated with gold mining include waste soil and rocks, residual water from ore concentrations, roasting of some types of gold-containing ores to remove sulfur and sulfur oxides, and bacterially enhanced leaching. Arsenic concentrations near gold mining operations are elevated in abiotic materials and biota: maximum total arsenic concentrations measured were 560 microg/L in surface waters, 5.16 mg/L in sediment pore waters, 5.6 mg/kg DW in bird liver, 27 mg/kg DW in terrestrial grasses, 50 mg/kg DW in soils, 79 mg/kg DW in aquatic plants, 103 mg/kg DW in bird diets, 225 mg/kg DW in soft parts of bivalve molluscs, 324 mg/L in mine drainage waters, 625 mg/kg DW in aquatic insects, 7,700 mg/kg DW in sediments, and 21,000 mg/ kg DW in tailings. Single oral doses of arsenicals that were fatal to 50% of tested species ranged from 17 to 48 mg/kg BW in birds and from 2.5 to 33 mg/kg BW in mammals. Susceptible species of mammals were adversely affected at chronic doses of 1-10 mg As/kg BW or 50 mg As/kg diet. Sensitive aquatic species were damaged at water concentrations of 19-48 microg As/L, 120 mg As/kg diet, or tissue residues (in the case of freshwater fish) > 1.3 mg/kg fresh weight. Adverse effects to crops and vegetation were recorded at 3-28 mg of water-soluble As/L (equivalent to about 25-85 mg total As/kg soil) and at atmospheric concentrations > 3.9 microg As/m3. Gold miners had a number of arsenic-associated health problems, including excess mortality from cancer of the lung, stomach, and respiratory tract. Miners and schoolchildren in the vicinity of gold mining activities had elevated urine arsenic of 25.7 microg/L (range, 2.2-106.0 microg/L). Of the total population at this location, 20% showed elevated urine arsenic concentrations associated with future adverse health effects; arsenic-contaminated drinking water is the probable causative factor of elevated arsenic in their urine. Proposed arsenic criteria to protect human health and natural resources are listed and discussed. Many of these proposed criteria do not adequately protect sensitive species.

Animals↗
PubMed2004

Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells.

Humans are exposed to arsenic and their organic derivatives, which are widely distributed in the environment, via food, water, and to a lesser extent, via air. Following uptake, inorganic arsenic undergoes biotransformation to mono- and dimethylated metabolites. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In the present study, the genotoxic effects and the cellular uptake of inorganic arsenic [arsenate, As(i)(V); arsenite, As(i)(III)] and the methylated arsenic species monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], dimethylarsinous acid [DMA(III)], trimethylarsenic oxide [TMAO(V)] were investigated in Chinese hamster ovary (CHO-9) cells. The chemicals were applied at different concentrations (0.1 microM to 10 mM) for 30 min and 1 h, respectively. Cytotoxic effects were investigated by the trypan blue extrusion test and genotoxic effects by the assessment of micronucleus (MN) induction, chromosome aberrations (CA), and sister chromatid exchanges (SCE). Intracellular arsenic concentrations were determined by ICP-MS techniques. Our results show that MMA(III) and DMA(III) induce cytotoxic and genotoxic effects to a greater extent than MMA(V) or DMA(V). Viability was significantly decreased after incubation (1 h) of the cells with > or = 1 microM As(i)(III), > or = 1 microM As(i)(V), > or = 500 microM MMA(III), > or = 100 microM MMA(V), and 500 microM DMA(V) and > or = 0.1 microM DMA(III). TMAO(V) was not cytotoxic at concentrations up to 10 mM. A significant increase of the number of MN, CA and SCE was found for DMA(III) and MMA(III). As(i)(III + V) induced CA and SCE but no MN. TMAO(V), MMA(V) and DMA(V) were not genotoxic in the concentration range tested (up to 5 mM). The nuclear division index (NDI) was not affected by any of the tested arsenic compounds after a recovery period of 14 to 35 h. When the uptake of the chemicals was measured by ICP-MS analysis, it was found that only 0.03% MMA(V) and DMA(V), and 2% MMA(III), As(i)(III) and (V) were taken up by the cells. In comparison, 10% of the DMA(III) dose was taken up. The total intracellular concentration of all arsenic compounds increased with increasing arsenic concentrations in the culture medium. Taken together, these data demonstrate that arsenic compounds in the trivalent oxidation state exhibit the strongest genotoxic effects. Trivalent organoarsenic compounds are more membrane permeable than the pentavalent species. The potency of the DNA damage decreases in the order DMA(III) > MMA(III) > As(i)(III and V) > MMA(V) > DMA(V) > TMAO(V). We postulate that the induction of genotoxic effects caused by the methylated arsenic species is primarily dependent upon their ability to penetrate cell membranes.

Animals↗
PubMed2003

Variability in human metabolism of arsenic.

Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary excretion. While there is debate as to the role of methylation in activation/detoxification, variations in arsenic metabolism may affect individual risks of toxicity and carcinogenesis. Using data from three populations, from Mexico, China, and Chile, we have analyzed the distribution in urine of total arsenic and arsenic species (inorganic arsenic (InAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA). Data were analyzed in terms of the concentration of each species and by evaluating MMA:DMA and (MMA+DMA):InAs ratios. In all persons most urinary As was present as DMA. Male:female differences were discernible in both high- and low-exposure groups from all three populations, but the gender differences varied by populations. The data also indicated bimodal distributions in the ratios of DMA to InAs and to MMA. While the gene or genes responsible for arsenic methylation are still unknown, the results of our studies among the ethnic groups in this study are consistent with the presence of functional genetic polymorphisms in arsenic methylation leading to measurable differences in toxicity. This analysis highlights the need for continuing research on the health effects of As in humans using molecular epidemiologic methods.

Arsenic↗
PubMed2003

Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles.

Large interindividual variability in urinary arsenic profiles, following chronic inorganic arsenic exposure, is well-known in humans. To understand this variability, we studied the relationship between polymorphisms in the gene for human monomethylarsonic acid (MMA(V)) reductase/hGSTO1 and the urinary arsenic profiles of individuals chronically exposed to arsenic in their drinking water. To ensure that we did not overlook rare polymorphisms, not included in the public databases, we amplified and sequenced all six exons of the gene and their flanking regions, using DNA isolated from peripheral blood samples of 75 subjects, living in the vicinity of Torreon, Mexico. Four groups, based on the levels of arsenic (9-100 microg/L) in their drinking water, were studied. We identified six novel polymorphisms and two reported previously. The novel polymorphisms were a three base pair deletion (delGGC) in the first intron; a G > C transversion, leading to a serine-to-cysteine substitution at amino acid 86; a G > T transversion and a A > T transversion in intron 5; a G > A transition resulting in glutamate-to-lysine substitution in amino acid 208; and a C > T transition producing an alanine-to-valine substitution in amino acid 236. Two subjects displayed significant differences in patterns of urinary arsenic; they had increased levels of urinary inorganic arsenic and reduced levels of methylated urinary arsenic species as compared to the rest of the study population. These two subjects had the same unique polymorphisms in hGSTO1 in that they were heterozygous for E155del and Glu208Lys. The identified SNPs may be one of the reasons for the large interindividual variability in the response of humans to chronic inorganic arsenic exposure. The findings suggest the need for further studies to identify unambiguously specific polymorphisms that may account for interindividual variability in the human response to chronic inorganic arsenic exposure.

Adolescent↗