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PubMed2006

Arsenic exposure and type 2 diabetes: a systematic review of the experimental and epidemiological evidence.

Chronic arsenic exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes. We identified 19 in vitro studies of arsenic and glucose metabolism. Five studies reported that arsenic interfered with transcription factors involved in insulin-related gene expression: upstream factor 1 in pancreatic beta-cells and peroxisome proliferative-activated receptor gamma in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite or arsenate. These studies provide limited insight on potential mechanisms. We identified 10 in vivo studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval, 1.69-3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority.

Air Pollutants↗
PubMed1998

Site-specific data confirm arsenic exposure predicted by the U.S. Environmental Protection Agency.

The EPA uses an exposure assessment model to estimate daily intake to chemicals of potential concern. At the Anaconda Superfund site in Montana, the EPA exposure assessment model was used to predict total and speciated urinary arsenic concentrations. Predicted concentrations were then compared to concentrations measured in children living near the site. When site-specific information on concentrations of arsenic in soil, interior dust, and diet, site-specific ingestion rates, and arsenic absorption rates were used, measured and predicted urinary arsenic concentrations were in reasonable agreement. The central tendency exposure assessment model successfully described the measured urinary arsenic concentration for the majority of children at the site. The reasonable maximum exposure assessment model successfully identified the uppermost exposed population. While the agreement between measured and predicted urinary arsenic is good, it is not exact. The variables that were identified which influenced agreement included soil and dust sample collection methodology, daily urinary volume, soil ingestion rate, and the ability to define the exposure unit. The concentration of arsenic in food affected agreement between measured and predicted total urinary arsenic, but was not considered when comparing measured and predicted speciated urinary arsenic. Speciated urinary arsenic is the recommended biomarker for recent inorganic arsenic exposure. By using site-specific data in the exposure assessment model, predicted risks from exposure to arsenic were less than predicted risks would have been if the EPA's default values had been used in the exposure assessment model. This difference resulted in reduced magnitude and cost of remediation while still protecting human health.

Algorithms↗
PubMed2004

Elk exposure to arsenic in geothermal watersheds of Yellowstone National Park, USA.

Geothermal activity in Yellowstone National Park (WY, USA) (YNP) results in elevated levels of arsenic in surface waters, aquatic vegetation, and sediments in the Upper Madison River Basin. This study was conducted to determine concentrations of arsenic in the tissues, feces, and rumen contents of elk (Cervus elaphus) residing in the Madison-Firehole (MF) River basin, and to evaluate potential arsenic exposure pathways. Concentrations of total arsenic in MF elk were significantly higher than in control elk populations, and analysis of arsenic in surface waters, elk forage, sediments, and soils suggests that the predominant arsenic exposure pathways are forage species found in aquatic and riparian habitats. Analysis of arsenic species in selected plant and elk samples indicated that the ingested forms of arsenic are predominantly inorganic, while the appearance of dimethylarsonate in elk rumen and feces suggests that arsenic is subject to methylation reactions after ingestion, potentially contributing to arsenic detoxification. Arsenic:creatinine ratios of elk urine samples analyzed across three different winters increased during winter progression and were correlated with total snow water equivalent as an index of winter severity. Exposure to arsenic and other trace elements (fluorine) may contribute to the previously observed decreased life expectancy of MF elk relative to control populations.

Animals↗
PubMed2002

Some aspects of arsenic toxicity and carcinogenicity in living organism with special regard to its influence on cardiovascular system, blood and bone marrow.

This paper gathers data on the most current aspects of arsenic action, especially its influence on the cardiovascular system, blood and bone marrow. A potential carcinogenic mechanism of arsenic is also discussed. Arsenic is a potent toxicant that may exist in several valencies and in a number of inorganic and organic forms. Most cases of arsenic-induced toxicity in humans are due to exposure to inorganic arsenic, and there is an extensive database on the human health effects of common arsenic oxides and oxyacids. Exposure of humans living near hazardous waste sites may involve inhalation of arsenic dusts in the air, ingestion of arsenic in water, food or soil, or dermal contact with contaminated soil or water. The exposure to arsenic via the inhalation route is responsible for the increased risk of lung cancer, although respiratory irritation, nausea and skin effects may also occur. The oral route of exposure to arsenic predominates in the general population. The most common effects of arsenic ingestion are gastrointestinal irritation, peripheral neuropathy, vascular lesions, anemia, skin diseases, including skin cancer and other cancers of the internal organs like bladder, kidney, liver or lung. Relatively little information is available on the effects of direct dermal contact with inorganic arsenicals, but several studies indicate local irritation and dermatitis as the major ones.

Anemia↗
PubMed2006

[2000 Chinese total dietary study--the dietary arsenic intakes].

OBJECTIVE: To assess the safety of dietary arsenic intakes in different areas in China. METHODS: Using the total dietary study method, the analytical samples were obtained in different areas by food consumption survey, food aggregation, food sampling and preparation. The levels of dietary total and inorganic arsenic were determined by the hydride generation atomic absorption spectrometry and atomic fluorospectrophotometry. The dietary total and inorganic arsenic intakes in different areas were obtained by timing the food consumption data and the arsenic content in different dietary samples. The safety of dietary arsenic was evaluated in Chinese four regions and average adults by using the dietary inorganic arsenic PTWI recommended by WHO. RESULTS: The results indicate that the dietary arsenic intake is safety in different regions. Only a few samples in some areas exceed tolerance limits of China national standard. Dietary total and inorganic arsenic (of PTWI) intakes in four different regions (north1, north2, south1, south2 and average adults) were 0.220 mg and 0.094 mg (69.3%), 0.254 mg and 0.098 mg (72.2%), 0.296 mg and 0.048 mg (35.6%), 0.335 mg and 0.077 mg (57.3%), 0.276 mg and 0.079 mg (58.6%) respectively. Mainly sources of dietary arsenic intake were cereals, vegetables and beverage and water. CONCLUSION: It is the first time that the dietary total arsenic and inorganic arsenic intakes of the adult were investigated in Chinese total diet study. The result shows that the total and inorganic arsenic intakes in Chinese people are safe.

Adult↗
PubMedDate not supplied

Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns.

Information on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenate salts and arsenic trioxide. Inorganic arsenic has been extensively studied as a teratogen in animals. Data from animal studies demonstrate that arsenic can produce developmental toxicity, including malformation, death, and growth retardation, in four species (hamsters, mice, rats, rabbits). A characteristic pattern of malformations is produced, and the developmental toxicity effects are dependent on dose, route, and the day of gestation when exposure occurs. Studies with gavage and diet administration indicate that death and growth retardation are produced by oral arsenic exposure. Arsenic is readily transferred to the fetus and produces developmental toxicity in embryo culture. Animal studies have not identified an effect of arsenic on fertility in males or females. When females were dosed chronically for periods that included pregnancy, the primary effect of arsenic on reproduction was a dose-dependent increase in conceptus mortality and in postnatal growth retardation. Human data are limited to a few studies of populations exposed to arsenic from drinking water or from working at or living near smelters. Associations with spontaneous abortion and stillbirth have been reported in more than one of these studies, but interpretation of these studies is complicated because study populations were exposed to multiple chemicals. Thus, animal studies suggest that environmental arsenic exposures are primarily a risk to the developing fetus. In order to understand the implications for humans, attention must be given to comparative pharmacokinetics and metabolism, likely exposure scenarios, possible mechanisms of action, and the potential role of arsenic as an essential nutrient.

Animals↗
PubMed2000

Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells.

Biomethylation is considered a major detoxification pathway for inorganic arsenicals (iAs). According to the postulated metabolic scheme, the methylation of iAs yields methylated metabolites in which arsenic is present in both pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsenicals are less acutely toxic than iAs. However, little is known about the toxicity of trivalent methylated species. In the work reported here the toxicities of iAs and trivalent and pentavalent methylated arsenicals were examined in cultured human cells derived from tissues that are considered a major site for iAs methylation (liver) or targets for carcinogenic effects associated with exposure to iAs (skin, urinary bladder, and lung). To characterize the role of methylation in the protection against toxicity of arsenicals, the capacities of cells to produce methylated metabolites were also examined. In addition to human cells, primary rat hepatocytes were used as methylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated arsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most cell types. Pentavalent arsenicals were significantly less cytotoxic than their trivalent analogs. Among the cell types examined, primary rat hepatocytes exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no apparent correlation between susceptibility of cells to arsenic toxicity and their capacity to methylate iAs. These results suggest that (1) trivalent methylated arsenicals, intermediary products of arsenic methylation, may significantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute toxicity of trivalent arsenicals.

Aged↗
PubMed2001

Assessment of arsenic level in the hair of the nonoccupational Egyptian population: pilot study.

Arsenic level of hair samples of apparently healthy Egyptian was measured by means of hydride atomic absorption spectrophotometery. It ranged between 0.04 and 1.04 mg As/kg hair, about 55% of the analysed hair samples were within the range of allowable values (0.08-0.25 mg As/kg hair), but 45% were not. There were no considerable sex-related differences (0.303 and 0.292 mg As/kg hair for males and females, respectively). Different educational levels did not influence it either, when the effect of the age had been excluded. Children and adolescents proved to be more susceptible to arsenic as their mean levels (0.353 microg/g), and were significantly higher than those in the adults (0.233 microg/g). Smoking and some dietary habits had an important role in the elevation of arsenic levels among the nonoccupational Egyptian population: 60% of smokers and 66.7% of indoor passive smokers had arsenic levels >0.25 mg As/kg hair. Arsenic levels were also dependent on the kind of smoking, as hair arsenic of the subject smoking molasses tobacco was found to be significantly higher than that of cigarette smokers (0.459 and 0.209 mg As/kg hair, respectively). The frequency of meat and fish consumption per week was also found to be positively, significantly correlated with arsenic levels. On the other hand, the frequency of consumption of fruits, fresh and cooked vegetables, milk and milk products per week beneficially influenced the arsenic level of the hair samples examined. Arsenic content of the consumed water in Egypt was 0.001 mg/l, which is below the maximum drinking water level allowed by World Health Organisation (WHO). Therefore, the arsenic content of domestic tap water hardly contributed to the arsenic exposure of the Egyptian population in the regions of the study. It is likely that exposure routes by smoking, fish and animal protein consumption are the principal cause of arsenic accumulation in the general Egyptian population.

Adolescent↗
PubMed2006

Trivalent arsenicals are bound to proteins during reductive methylation.

Inorganic arsenic is converted to methylated metabolites, and most is excreted in urine as dimethylarsinic acid in humans and animals. The present study was conducted to investigate the metabolism of arsenic and identify hepatic and renal metabolites of arsenic after an intravenous injection of arsenite (0.5 mg As/kg body weight) in rats. Similar levels of arsenic were found in the soluble (SUP) and nonsoluble sediment (SED) fractions of both organs after 1 h. More than 80% of the SUP arsenic was bound to high molecular weight (HMW) proteins in both organs. Arsenic bound to the HMW and SED proteins were oxidized with H(2)O(2) and released in the pentavalent forms (arsenate, monomethylarsonic, and dimethylarsinic acids). The relative ratios of the three arsenicals changed depending on organ, fraction (HMW and SED), and time. Since the arsenic metabolites/intermediates were liberated from proteins by oxidation with H(2)O(2) and recovered in the pentavalent forms, and only tri- but not pentavalent arsenicals were bound to proteins in vitro, it was deduced that arsenic metabolites bound to proteins during the successive methylation pathway are in the trivalent forms; that is, successive methylation reaction takes place with simultaneous reductive rather than stepwise oxidative methylation. Thus, on the basis of the present observations, it was proposed that inorganic arsenic was successively methylated reductively in the presence of glutathione, rather than a stepwise oxidative methylation, and pentavalent arsenicals (MMA(V) and DMA(V)) were present as end products of metabolism, rather than intermediates. We also discussed the in vitro formation of dimethylthioarsenicals after incubating dimethylarsinous acid with liver homogenate.

Animals↗
PubMed2000

Effect of arsenic trioxide on human hepatoma cell line BEL-7402 cultured in vitro.

AIM:To study the effect of a varying concentrations of arsenic trioxide on human hepatoma cell line BEL-7402 cultured in vitro and its mechanism of action.METHODS:The BEL-7402 cells were treated with arsenic trioxide (at the concentrations of 0.5 1 2&mgr;mol/L, respectively) for 4 successive days. The cell growth and proliferation were observed by cell counting and cell-growth curve. Morphologic changes were studied with electronmicroscopy. Flow cytometry was used to assay cell-DNA distribution and the protein expression of Bcl-2 and Bax detected by immunocytochemical method.RESULTS:The cell growth was significantly inhibited by varying concentrations of arsenic trioxide as revealed by cell counting and cell-growth curve, which was dose- and time-dependent. Arsenic trioxide treatment at 0.5, 1 and 2&mgr;mol/L resulted in a sub-G1 cell peak, the apoptosis rate of the control group was 9.31% and that of 0.5&mgr;mol/L arsenic trioxide 15.53%, no significant difference was seen between the two.The apoptosis rates of 1,2&mgr;mol/L arsenic trioxide were 19.10% and 21.87% respectively, which were much higher (both P < 0.05). Decrease of G(0)/G(1) phase cells and increase of S phase cells were observed by flow cytometry, suggesting the inhibition effect of 0.5, 1, 2&mgr;mol/L arsenic trioxide on BEL-7402 cell lay in the G(0)/G(1) phase. Morphologic changes such as intact cell membrane, nucleic condensation, apoptotic body formation were seen under transmission electronmicrescopy, whereas the 0.5mol/L arsenic trioxide-treated BEL-7402 cells showed decrease of nucleocytoplasmic ratio, round nucleus, well-differentiated organelles in the cytoplasm. The processes and microvilli on the cell surface of the experimental groups under scanning electron microscopy were significantly decreased. High expressions of Bcl-2 and Bax were detected in 1 and 2&mgr;mol/L arsenic trioxide-treated cells, these were 46%, 87.33% and 83.08%, 95.83% respectively, among which that of Bax was more significant. Arsenic trioxide treatment at 0.5&mgr;mol/L resulted in a higher expression level of Bcl-2 and lower expression level of Bax,which were 8.81% and 3.83% respectively, as compared with that of the control group (15.33%) (P(1)<0.01, P(2)<0.01).CONCLUSION:Arsenic trioxide not only inhibited proliferation but also induced apoptosis of human hepatoma cell line BEL-7402. The induced-apoptosis effect of 1,2&mgr;mol/L arsenic trioxide was related to the expression level of Bcl-2 and Bax.

Journal Article↗
PubMed2004

Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan.

CONTEXT: Arsenic has been documented as a lung carcinogen in humans in only a few follow-up studies, which were limited by a small number of cases or the lack of information on cigarette smoking. OBJECTIVES: To elucidate the dose-response relationship between ingested arsenic and lung cancer and to assess the effect of cigarette smoking on the arsenic-lung cancer association. DESIGN, SETTING, AND PARTICIPANTS: A total of 2503 residents in southwestern and 8088 in northeastern arseniasis-endemic areas in Taiwan were followed up for an average period of 8 years. Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire interview. MAIN OUTCOME MEASURES: The incidence of lung cancer was ascertained through linkage with national cancer registry profiles in Taiwan (January 1985-December 2000). The joint effect of arsenic and cigarette smoking was estimated by both etiologic fraction and synergy index. RESULTS: There were 139 newly diagnosed lung cancer cases during a follow-up period of 83,783 person-years. After adjustment for cigarette smoking and other risk factors, there was a monotonic trend of lung cancer risk by arsenic level in drinking water of less than 10 to 700 microg/L or more (P<.001). The relative risk was 3.29 (95% confidence interval, 1.60-6.78) for the highest arsenic level compared with the lowest. The etiologic fraction of lung cancer attributable to the joint exposure of ingested arsenic and cigarette smoking ranged from 32% to 55%. The synergy indices ranged from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smoking on lung cancer. CONCLUSIONS: There was a significant dose-response trend of ingested arsenic on lung cancer risk, which was more prominent among cigarette smokers. The risk assessment of lung cancer induced by ingested arsenic should take cigarette smoking into consideration.

Adult↗
PubMed2003

Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water.

Arsenic is well established as a human carcinogen, but its precise mechanism of action remains unknown. Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents. The molecular mechanism underlying arsenic inhibition of nucleotide excision repair after UV irradiation (Hartwig et al., Carcinogenesis 1997;18:399-405) is unknown, but could be due to decreased expression of critical genes involved in nucleotide excision repair of damaged DNA. This hypothesis was tested by analyzing expression of repair genes and arsenic exposure in a subset of 16 individuals enrolled in a population based case-control study investigating arsenic exposure and cancer risk in New Hampshire. Toenail arsenic levels were inversely correlated with expression of critical members of the nucleotide excision repair complex, ERCC1 (r(2) = 0.82, p < 0.0001), XPF (r(2) = 0.56, p < 0.002), and XPB (r(2) = 0.75, p < 0.0001). The internal dose marker, toenail arsenic level, was more strongly associated with changes in expression of these genes than drinking water arsenic concentration. Our findings, based on human exposure to arsenic in a US population, show an association between biomarkers of arsenic exposure and expression of DNA repair genes. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.

Adult↗
PubMed1984

Prenatal and developmental toxicology of arsenicals.

A variety of species, including the human, have been shown to be susceptible to the embryotoxic effects of inorganic arsenic. Malformations of the axial skeleton, neurocranium, viscerocranium, eyes, and genitourinary systems as well as prenatal death followed a bolus dose of trivalent or pentavalent inorganic arsenic. Trivalent arsenic was more teratogenic than pentavalent arsenic; in contrast, the methylated metabolites of arsenic possessed only limited teratogenic activity. Administration of inorganic arsenic to mammals results in concentration of arsenic within the placenta and small amounts are deposited within the embryo. Studies concerning the pathogenesis of arsenic-induced axial skeletal lesions revealed early failure of neural fold elevation and a subsequent, persistent failure of closure of the neural tube. Physical factors, drugs and heavy metals may modify the response to a teratogenic dose of inorganic arsenic. Medical problems associated with industrial or agricultural arsenicalism are most often typified by chronic exposure; future studies should emphasize those routes of administration and types of exposure that are characteristic of arsenic intoxication.

Abnormalities, Drug-Induced↗
PubMed2005

Arsenic contamination in water, soil, sediment and rice of central India.

Arsenic contamination in the environment (i.e. surface, well and tube-well water, soil, sediment and rice samples) of central India (i.e. Ambagarh Chauki, Chhattisgarh) is reported. The concentration of the total arsenic in the samples i.e. water (n = 64), soil (n = 30), sediment (n = 27) and rice grain (n = 10) were ranged from 15 to 825 microg L(-1), 9 to 390 mg kg(-1), 19 to 489 mg kg(-1) and 0.018 to 0.446 mg kg(-1), respectively. In all type of waters, the arsenic levels exceeded the permissible limit, 10 microg L(-1). The most toxic and mobile inorganic species i.e. As(III) and As(V) are predominantly present in water of this region. The soils have relatively higher contents of arsenic and other elements i.e. Mg, Al, Si, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Ga, Zr, Sn, Sb, Pb and U. The mean arsenic contents in soil of this region are much higher than in arsenic soil of West Bengal and Bangladesh. The lowest level of arsenic in the soil of this region is 3.7 mg kg(-1) with median value of 9.5 mg kg(-1). The arsenic contents in the sediments are at least 2-folds higher than in the soil. The sources of arsenic contamination in the soil of this region are expected from the rock weathering as well as the atmospheric deposition. The environmental samples i.e. water, soil dust, food, etc. are expected the major exposure for the arsenic contamination. The most of people living in this region are suffering with arsenic borne diseases (i.e. melanosis, keratosis, skin cancer, etc.).

Arsenic↗
PubMed2005

Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats.

Chronic arsenic toxicity is a widespread problem, not only in India and Bangladesh but also in various other regions of the world. Exposure to arsenic may occur from natural or industrial sources. The treatment that is in use at present employs administration of thiol chelators, such as meso 2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised with number of limitations due to their lipophobic nature, particularly for their use in cases of chronic poisoning. During chronic exposure, arsenic gains access into the cell and it becomes mandatory for a drug to cross cell membrane to chelate intracellular arsenic. To address this problem, analogs of DMSA having lipophilic character, were examined against chronic arsenic poisoning in experimental animals. In the present study, therapeutic efficacy of meso 2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), monoisoamyl DMSA (MiADMSA) were compared in terms of reducing arsenic burden, as well as recovery in the altered biochemical variables particularly suggestive of oxidative stress. Adult male Wistar rats were given 100-ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 50 mg/Kg (orally) once daily for 5 consecutive days. Arsenic exposure resulted in marked elevation in reactive oxygen species (ROS) in blood, inhibition of ALAD activity and depletion of GSH. These changes were accompanied by significant decline in blood hemoglobin level. MiADMSA was the most effective chelator in reducing ROS in red blood cells, and in restoring blood ALAD compared to two other chelators. Brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased, while ROS and TBARS increased significantly following arsenic exposure. There was a significant increase in the activity of glutathione-S-transferase (GST) with a corresponding decline in its substrate i.e. glutathione. Among all the three chelators, MiADMSA showed maximum reduction in the level of ROS in brain. Additionally, administration of MiADMSA was most effective in counteracting arsenic induced inhibition in brain ALAD, SOD and GPx activity. Based on these results and in particular higher metal decorporation from blood and brain, we suggest MiADMSA to be a potential drug of choice for the treatment of chronic arsenic poisoning. However, further studies are required for the choice of appropriate dose, duration of treatment and possible effects on other major organs.

5-Aminolevulinate Synthetase↗
PubMed2005

Placental transfer of arsenic to fetus of Dall's porpoises (Phocoenoides dalli).

Concentrations of total arsenic and individual arsenic compounds were determined in liver, muscle, kidney and blubber of mother and fetus of Dall's porpoises collected from off Sanriku, Japan, in the year 2000 to characterize the placental transfer of arsenic to fetus in cetaceans. Arsenic was detected in all the tissues of Dall's porpoises. Total arsenic concentrations in liver, kidney, muscle and blubber were 0.76, 0.69, 0.35 and 0.55 microg/g wet wt, respectively, for mother and 0.28, 0.23, 0.26 and 0.07 microg/g wet wt, respectively, for fetus. In all the tissues, concentrations of total arsenic in mother Dall's porpoise were higher than in fetus. Arsenic speciation revealed that arsenobetaine was the major arsenic compound in liver, kidney and muscle of both mother and fetus. The percentage of arsenobetaine to total arsenic ranged from 76.0 to 91.0% in the tissues. Dimethylarsinic acid, arsenocholine, methylarsonic acid and an unidentified arsenic compound were also detected in tissues of both mother and fetus as minor constituents, whereas tetramethylarsonium ion was not detected in tissues of the fetus. These results suggest that arsenobetaine, dimethylarsinic acid, arsenocholine and methylarsonic acid are transferable from mother to fetus in Dall's porpoises. To our knowledge, this is the first report on placental transfer of arsenic compounds to fetus in marine mammals.

Adipose Tissue↗
PubMed2003

Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate.

Exposure to the human carcinogen inorganic arsenic (iAs) occurs daily. However, the disposition of arsenic after repeated exposure is not well known. This study examined the disposition of arsenic after repeated po administration of arsenate. Whole-body radioassay of adult female B6C3F1 mice was used to estimate the terminal elimination half-life of arsenic after a single po dose of [(73)As]arsenate (0.5 mg As/kg). From these data, it was estimated that steady-state levels of whole-body arsenic could be attained after nine repeated daily doses of [(73)As]arsenate (0.5 mg As/kg). The mice were whole-body radioassayed immediately before and after the repeated dosing. Excreta were collected daily and analyzed for arsenic-derived radioactivity and arsenicals. Whole-body radioactivity was determined 24 h after the last repeated dose, and five mice were then euthanized and tissues analyzed for radioactivity. The remaining mice were whole-body radioassayed for 8 more days, and then their tissues were analyzed for radioactivity. Other mice were administered either a single or nine repeated po doses of non-radioactive arsenate (0.5 mg As/kg). Twenty-four hours after the last dose, the mice were euthanized, and tissues were analyzed for arsenic by atomic absorption spectrometry (AAS). Whole-body radioactivity was rapidly eliminated from mice after repeated [(73)As]arsenate exposure, primarily by urinary excretion in the form of dimethylarsinic acid (DMA(V)). Accumulation of radioactivity was highest in bladder, kidney, and skin. Loss of radioactivity was most rapid in the lung and slowest in the skin. There was an organ-specific distribution of arsenic as determined by AAS. Monomethylarsonic acid was detected in all tissues except the bladder. Bladder and lung had the highest percentage of DMA(V) after a single exposure to arsenate, and it increased with repeated exposure. In kidney, iAs was predominant. There was a higher percentage of DMA(V) in the liver than the other arsenicals after a single exposure to arsenate. The percentage of hepatic DMA(V) decreased and that of iAs increased with repeated exposure. A trimethylated metabolite was also detected in the liver. Tissue accumulation of arsenic after repeated po exposure to arsenate in the mouse corresponds to the known human target organs for iAs-induced carcinogenicity.

Administration, Oral↗
PubMed2004

Glutathione modulates recombinant rat arsenic (+3 oxidation state) methyltransferase-catalyzed formation of trimethylarsine oxide and trimethylarsine.

Humans and other species enzymatically convert inorganic arsenic (iAs) into methylated metabolites. Although the major metabolites are mono- and dimethylated arsenicals, trimethylated arsenicals have been detected in urine following exposure to iAs. The AS3MT gene encodes an arsenic (+3 oxidation state) methyltransferase, which catalyzes both the oxidative methylation of trivalent arsenicals and the reduction of pentavalent arsenicals. In reaction mixtures containing recombinant rat AS3MT (rrAS3MT) and radiolabeled arsenite, mono- and dimethylated arsenicals and a third radiolabeled product can be resolved by thin-layer chromatography. Hydride generation atomic absorption spectrometry and electrospray ionization mass spectrometry identified the third reaction product as trimethylarsine oxide. The addition of glutathione to reaction mixtures containing radiolabeled arsenite and rrAS3MT increased the yield of methylated and dimethylated arsenicals but suppressed the formation of trimethylarsine oxide. Although a dimethylarsenic-glutathione complex was rapidly converted to trimethylarsine oxide, the addition of a molar excess of glutathione to dimethylarsenic suppressed the production of trimethylarsine oxide. The nonquantitative recovery of radioarsenic from reaction mixtures suggested that AS3MT catalyzed the formation of a volatile arsenical. This volatile species was identified as trimethylarsine. Thus, AS3MT catalyzes the formation of all products in a reaction sequence leading from an inorganic to a volatile methylated arsenical. The regulation of this pathway by intracellular glutathione may be an important determinant of the pattern and extent of formation of arsenicals.

Animals↗