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PubMed1995

Effect of arsenic exposure on alveolar macrophage function. II. Effect of slightly soluble forms of As(III) and As(V).

The pulmonary toxicity of a substance depends on a number of chemical and physical characteristics, including the solubility of the compounds. In the lung, insoluble forms of metals may be more tumorigenic than soluble forms despite the fact that this effect has not been quantitated and the mechanism of action has not been elucidated. The toxic effects of slightly soluble forms of As(III) and As(V) were evaluated by determining alteration in function of pulmonary alveolar macrophages (PAM) following in vivo and in vitro exposure. Male Sprague-Dawley rats were used throughout. Twenty-four hours following intratracheal instillation of 1 mg/kg (as arsenic) of either arsenic trisulfide (As(III)) or calcium arsenate (As(V)), PAM were lavaged and analyzed for alterations in superoxide (O2-), and tumor necrosis factor (TNF-alpha) production. There were no differences in bronchoalveolar lavage fluid TNF-alpha. PAM lavaged from As(V)-exposed animals showed significant increases in O2- production and in basal release of TNF-alpha. PAM lavaged from animals receiving As(III) did not show significant alterations. To test the direct effects of arsenic, PAM were lavaged from control animals and exposed to concentrations of 0.1 to 300 micrograms/ml arsenic in vitro for up to 24 hr. Doses used were not cytotoxic to PAM, since LDH release was not significantly increased. Significant dose-dependent inhibition of O2- production was only evident after 24 hr exposure to arsenicals. Both As(III) and As(V) produced inhibition at concentrations of 10 micrograms/ml. Suppression of LPS-induced release of TNF-alpha also occurred at similar concentrations for both arsenicals (4-5 micrograms/ml). Neither arsenical inhibited prostaglandin E2 production. Measurement of soluble arsenic concentrations indicated dissolution of the compounds could not account for all of the effects seen. Arsenic-induced alteration in PAM function may compromise host defense.

Animals↗
PubMed2006

Arsenic methylation capability and hypertension risk in subjects living in arseniasis-hyperendemic areas in southwestern Taiwan.

BACKGROUND: Cumulative arsenic exposure (CAE) from drinking water has been shown to be associated with hypertension in a dose-response pattern. This study further explored the association between arsenic methylation capability and hypertension risk among residents of arseniasis-hyperendemic areas in Taiwan considering the effect of CAE and other potential confounders. METHOD: There were 871 subjects (488 women and 383 men) and among them 372 were diagnosed as having hypertension based on a positive history or measured systolic blood pressure >or=140 mm Hg and/or diastolic blood pressure >or=90 mm Hg. Urinary arsenic species were determined by high-performance liquid chromatography-hydride generator and atomic absorption spectrometry. Primary arsenic methylation index [PMI, defined as monomethylarsonic acid (MMA(V)) divided by (As(III)+As(V))] and secondary arsenic methylation index (SMI, defined as dimethylarsinic acid divided by MMA(V)) were used as indicators for arsenic methylation capability. RESULTS: The level of urinary arsenic was still significantly correlated with cumulative arsenic exposure (CAE) calculated from a questionnaire interview (p=0.02) even after the residents stopped drinking the artesian well water for 2-3 decades. Hypertensive subjects had higher percentages of MMA(V) and lower SMI than subjects without hypertension. However, subjects having CAE >0 mg/L-year had higher hypertension risk than those who had CAE=0 mg/L-year disregard a high or low methylation index. CONCLUSION: Inefficient arsenic methylation ability may be related with hypertension risk.

Adult↗
PubMed2004

Physiologically based pharmacokinetic modeling of arsenic in the mouse.

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process.

Acute Disease↗
PubMed2005

Serum acetyl cholinesterase as a biomarker of arsenic induced neurotoxicity in sprague-dawley rats.

Arsenic is an environmental toxicant, and one of the major mechanisms by which it exerts its toxic effect is through an impairment of cellular respiration by inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorus in a variety of biochemical reactions. Recent studies have pointed out that arsenic toxicity is associated with the formation of reactive oxygen species, which may cause severe injury/damage to the nervous system. The main objective of this study was to conduct biochemical analysis to determine the effect of arsenic trioxide on the activity of acetyl cholinesterase; a critical important nervous system enzyme that hydrolyzes the neurotransmitter acetylcholine. Four groups of six male rats each weighing an average 60 +/- 2 g were used in this study. Arsenic trioxide was intraperitoneally administered to the rats at the doses of 5, 10, 15, 20mg/kg body weight (BW), one dose per 24 hour given for five days. A control group was also made of 6 animals injected with distilled water without chemical. Following anaesthesia, blood specimens were immediately collected using heparinized syringes, and acetyl cholinesterase detection and quantification were performed in serum samples by spectrophotometry. Arsenic trioxide exposure significantly decreased the activity of cholinesterase in the Sprague-Dawley rats. Acetyl cholinesterase activities of 6895 +/- 822, 5697 +/- 468, 5069 +/- 624, 4054 +/- 980, and 3158 +/- 648 U/L were recorded for 0, 5, 10, 15, and 20 mg/kg, respectively; indicating a gradual decrease in acetyl cholinesterase activity with increasing doses of arsenic. These findings indicate that acetyl cholinesterase is a candidate biomarker for arsenic-induced neurotoxicity in Sprague-Dawley rats.

Acetylcholinesterase↗
PubMed1995

Determination of total arsenic in serum and packed cellsof patients with renal insufficiency.

In order to investigate the arsenic level in serum and packed cells of patients with renal insufficiency, total arsenic (As) concentrations were determined with hydride generation atomic absorption spectrometry (HGAAS) in serum (S) and packed cells (PC) of 31 non-dialyzed patients. The accuracy of the method was tested by the analysis of arsenic in 3 certified reference materials. Patients showed a three-fold increase of arsenic concentrations in serum and a two-fold increase of arsenic in packed cells compared with controls. Patients (n=10) with higher serum creatinine (>2.0 mg/dL), urea (>0.70 g/L) and urinary protein (mean+/-SD: 1.12+/-0.82 g/L) showed higher arsenic concentrations (5.8+/-3.3 microg/L in serum and 18.0+/-16.7 microg/kg in packed cells) compared with those with lower creatinine (<1.6 mg/dL), urea (<0.6 g/L) and urinary protein (mean+/-SD: 0.27+/-0.82 g/L) (n=16, serum arsenic 1.2+/-1.2 microg/L, packed cells arsenic 2.6+/-1.9 microg/kg). The significant differences (both p < 0.001) in S and PC-arsenic levels of patients in group I and II implies a relationship between the arsenic level and the degree of chronic renal insufficiency.

Journal Article↗
PubMed2004

Uptake and accumulation behaviour of angiosperms irrigated with solutions of different arsenic species.

Uptake and metabolisation of arsenic as a function of both the plant type and the chemical form of arsenic were examined. For this purpose two different plant species (Silene vulgaris and Plantago major) were selected that differed in their vitality and accumulation behaviour on arsenic-loaded substrates. The plants were cultivated on soil and irrigated with aqueous solutions of an inorganic arsenic compound (arsenious acid) and an organic compound (dimethylarsinate). The arsenic species accumulated in the parts of the plants above ground were extracted by PLE and determined using IC-ICP-MS. The concentrations and metabolisation products of arsenic found in the extracts indicate different mechanisms of arsenic uptake and transformation in both angiosperms. The arsenic species pattern showed that S. vulgaris was more arsenic--tolerable than P. major which is attributed to a low arsenate to arsenite concentration ratio in the plant compartments. S. vulgaris was also able to demethylate and reduce dimethylarsinate to form arsenite in a high extent. P. major accumulated only eight times lower concentration of arsenic, and the arsenate to arsenite concentration ratio shifted to higher values. Metabolisation products of dimethylarsinate did not occur under the present experimental conditions. The vitality of the angiosperms seems to be very dependent on the ability of the plant to reduce arsenate to arsenite.

Arsenates↗
PubMed2005

Prospective protective role of melatonin against arsenic-induced metabolic toxicity in Wistar rats.

Subchronic exposure to arsenic is associated with alteration of glucose homeostasis. Arsenic treatment (as sodium arsenite) of male Wistar rats (weighing 130-150 g) at a dose of 5.55 mg kg(-1) body weight (equivalent to 35% of LD(50)) (i.p.) per day for a period of 30 days produced hypoglycemia, with associated increased urinary excretion of glucose and depletion of liver glycogen and pyruvic acid contents. Mobilization of free amino acids from kidney to liver was facilitated by arsenic treatment. Arsenic exposure significantly decreased the glutamate-pyruvate transaminase activity in kidney. Glucose 6-phosphatase activity in liver tissue was also significantly decreased after arsenic treatment. In addition to these, liver lactate dehydrogenase activity was elevated due to arsenic treatment. Melatonin supplementation (i.p.) at a dose of 10 mg kg(-1) day(-1) for last five days prior to sacrifice reversed most of the above changes caused by arsenic. Melatonin, being a potent free radical scavenger may reduce arsenic-induced free radical production, and thereby, eliminating its toxic effects. So, arsenic-induced hypoglycemia, with associated glycogenolytic as well as glycolytic activities of liver can be partially counteracted by melatonin supplementation. Accordingly, it may be suggested that melatonin can serve as a prospective protective agent against arsenic-induced metabolic toxicity.

Alanine Transaminase↗
PubMed2004

Arsenic inhibition of the JAK-STAT pathway.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. Chronic exposure to arsenic has been found to cause immunotoxicity and has been associated with the suppression of hematopoiesis (anemia and leukopenia). Here, we report the novel finding of arsenic-mediated inactivation of the JAK-STAT signaling pathway by its direct interaction with JAK tyrosine kinase. Pretreatment with sodium arsenite strongly inhibited IL-6-inducible STAT3 tyrosine phosphorylation in HepG2 cells and did not affect its serine phosphorylation. As a result, sodium arsenite completely abolished STAT activity-dependent expression of suppressors of cytokine signaling (SOCS). Both cellular and subcelluar experiments showed that the inhibition of JAK-STAT signaling resulted from JAK tyrosine kinase's direct interaction with arsenite, and that arsenic's suppression of JAK tyrosine kinase activity also occurred in the interferon gamma (IFNgamma) pathway. The ligand-independent inhibition by arsenic indicates that JAK was the direct target of arsenic action. Other inflammatory stimulants, stress agents, and metal cadmium failed to induce similar effects on the tyrosine phosphorylation of STAT3 as arsenic does. Our experiments also revealed that arsenic inactivation of the JAK-STAT pathway occurred independent of arsenic activation of MAP kinases. Taken together, our findings indicate that arsenic directly inhibits JAK tyrosine kinase activity and suggest that this direct interference in the JAK-STAT pathway may play a role in arsenic-associated pathogenesis.

Arsenites↗
PubMed2006

Enhanced expression of multidrug resistance-associated protein 2 and reduced expression of aquaglyceroporin 3 in an arsenic-resistant human cell line.

Arsenic-resistant cells (R15), derived from a human lung adenocarcinoma cell line (CL3), were 10-fold more resistant to sodium arsenite (As(III)). Because R15 cells accumulated less arsenic than parental CL3 cells, this arsenic resistance may be due to higher efflux and/or lower uptake of As(III). We therefore compared expression of the multidrug resistance-associated proteins MRP1, MRP2, and MRP3 in these two cell lines. MRP2 expression was 5-fold higher in R15 cells than in CL3 cells, whereas MRP1 and MRP3 expression levels were similar. Furthermore, verapamil and cyclosporin A, inhibitors of multidrug resistance transporters, significantly reduced the efflux of arsenic from R15. Thus, increased arsenic extrusion by MRP2 may contribute to arsenic resistance in R15 cells. We also examined the expression of several aquaglyceroporins (AQPs), which mediate As(III) uptake by cells. Little AQP7 or AQP9 mRNA was detected by reverse transcription-PCR in either cell line, whereas AQP3 mRNA expression was 2-fold lower in R15 cells than in CL3 cells. When AQP3 expression in CL3 cells was knocked down by RNA interference, CL3 cells accumulated less arsenic and became more resistant to As(III). Conversely, overexpression of AQP3 in human embryonic kidney 293T cells increased arsenic accumulation, and the cells were more susceptible to As(III) than 293T cells transfected with vector alone. These results suggest that AQP3 is involved in As(III) accumulation. Taken together, our results suggest that enhanced expression of MRP2 and lower expression of AQP3 are responsible for lower arsenic accumulation in arsenic-resistant R15 cells.

Aquaglyceroporins↗
PubMed2006

Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure.

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-alpha (ER-alpha) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-beta-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. In utero arsenic exposure also induced overexpression of alpha-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-alpha expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-alpha expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-alpha activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood.

Animals↗
PubMed1997

Environmental arsenic exposure of children around a former copper smelter site.

Arsenic residues in the communities surrounding former smelters remain a public health concern, especially for infants and children. To evaluate environmental exposure among these children, a population-based cross-sectional study was conducted in the vicinity of a former copper smelter in Anaconda, Montana. A total of 414 children less than 72 months old were recruited. First morning voided urine samples and environmental samples were collected for arsenic measurements. The geometric mean of speciated urinary arsenic was 8.6 microg/liter (GSD = 1.7, N = 289). Average arsenic levels of different types of soil ranged from 121 to 236 microg/g and were significantly related to proximity and wind direction to the smelter site. The same significant relationship was observed for interior dust arsenic. Speciated urinary arsenic was found to be significantly related to soil arsenic in bare areas in residential yards (P < 0.0005). In general, elevated excretion of arsenic was demonstrable and warranted parents' attention to reduce exposure of their children to environmental arsenic.

Air Pollution, Indoor↗
PubMed1990

Arsenic distribution in rabbits after Lewisite administration and treatment with British anti-Lewisite (BAL).

The standard treatment of Lewisite (dichloro(2-chlorovinyl)arsine) poisoning is by chelation with BAL (British anti-Lewisite, dimercaptopropanol). The present study investigated the effect of BAL treatment on the distribution of arsenic after Lewisite administration. Lewisite was administered subcutaneously at the LD10 and LD40 of the compound. Without BAL treatment arsenic was eliminated with a half-life in blood of between 55 and 75 hr and a blood clearance of 120 ml/hr/kg. Arsenic had a large volume of distribution of several liters per kilogram, indicating extensive distribution in tissues. The highest tissue concentrations, more than seven times blood concentrations, were found in the liver, lung, and kidneys. These organs maintained an approximately constant concentration ratio with blood during the sampling period. Concentrations in tissues with a blood-to-tissue barrier, such as the brain and the spinal cord, rose between 4 and 96 hr while blood concentrations declined more than fourfold over the same time period. BAL treatment by four equal, maximally tolerated doses over 12 hr substantially reduced arsenic concentrations in blood and tissues. For example, at 24 hr the concentrations in brain and liver (target organs for arsenic toxicity) were reduced by 65 to 89% over the range of Lewisite doses administered. The total exposure of brain and spinal cord was reduced by more than two-thirds by BAL treatment. Further, the blood clearance of arsenic was increased. BAL treatment enhanced the elimination of arsenic in two ways: by decreasing the tissue-to-blood partitioning which mobilizes arsenic into the blood stream, and by increasing the clearance of arsenic.

Adipose Tissue↗
PubMed2006

Oxidative stress indices and plasma biochemical parameters during oral exposure to arsenic in rats.

An experiment was conducted to study the response of rat tissues to low level exposure of arsenic (III) for different time periods. Rats were exposed to 0 (Gr. I, healthy control, n=18) or 10 ppm arsenic (Gr. II, positive control, n=18) through drinking water ad lib for a maximum period of 12 weeks. Six rats were sacrificed from each group under light chloroform anesthesia at the end of 4, 8 and 12 weeks of arsenic exposure for collection of blood, liver and kidneys. Samples were processed for estimation of oxidative stress indices and biochemical variables indicative of hepatic and renal functions. Tissue arsenic burden was measured at the end of 12 weeks of exposure. Arsenic treated rats (Gr. II) had comparatively poor body weight gain over time, and the mean body weights of these rats were significantly (P<0.05) lower from 10th weeks onwards. Oral exposure to arsenic for a period of 12 weeks significantly (P<0.05) increased arsenic burden in blood, liver and kidney from arsenic treated rats. This was associated with exposure duration-dependent rise (P<0.05) in lipid peroxidation in these tissues. Superoxide dismutase (SOD) and catalase (CAT) activities increased initially (P<0.05) in all the tissues followed by a declining trend and at the end of 12 weeks, the activities were non-significantly (P>0.05) lower than respective controls. Alterations in most of the biochemical parameters did not reach statistical significance (P>0.05). It was concluded from the present study that low dose arsenic exposure for a shorter period caused activation of intrinsic antioxidant defense whereas a prolonged insult suppressed it. However, biochemical parameters indicative of hepatic and renal dysfunction remained well within the normal range.

Administration, Oral↗
PubMed2005

Massive acute arsenic poisonings.

Arsenic poisonings are still important in the field of toxicology, though they are not as frequent as about 20-30 years ago. In this paper, the arsenic concentrations in ante- and post-mortem materials, and also forensic and anatomo-pathological aspects in three cases of massive acute poisoning with arsenic(III) oxide (two of them with unexplained criminalistic background, in which arsenic was taken for amphetamine and one suicide), are presented. Ante-mortem blood and urine arsenic concentrations ranged from 2.3 to 6.7 microg/ml, respectively. Post-mortem tissue total arsenic concentrations were also detected in large concentrations. In case 3, the contents of the duodenum contained as much as 30.1% arsenic(III) oxide. The high concentrations of arsenic detected in blood and tissues in all presented cases are particularly noteworthy in that they are very rarely detected at these concentrations in fatal arsenic poisonings.

Adult↗
PubMed2006

Laboratory based approaches for arsenic remediation from contaminated water: recent developments.

Arsenic contamination in water has posed severe health problems around the world. In spite of the availability of some conventional techniques for arsenic removal from contaminated water, development of new laboratory based techniques along with enhancement and cost reduction of conventional techniques are essential for the benefit of common people. This paper provides an overview of the arsenic issue in water such as modes of contamination of ground water as well as surface water by arsenic, its metabolism and health impacts, factors influencing arsenic poisoning, fundamentals of arsenic poisoning mechanism and world scenario of arsenic poisoning. It discusses and compares the conventional laboratory based techniques, like precipitation with alum, iron, Fe/Mn, lime softening, reverse osmosis, electro dialysis, ion exchanges, adsorption on activated alumina/carbon, etc., for arsenic removal from contaminated water. It also discusses the best available techniques and mentions the cost comparison among these techniques too. Recent developments in the research on the laboratory based arsenic removal techniques, like improvement of conventional techniques and advances in removal technology along with its scopes and limitations have also been reviewed.

Adsorption↗
PubMed2006

Comparative investigations of sodium arsenite, arsenic trioxide and cadmium sulphate in combination with gamma-radiation on apoptosis, micronuclei induction and DNA damage in a human lymphoblastoid cell line.

In the field of radiation protection the combined exposure to radiation and other toxic agents is recognised as an important research area. To elucidate the basic mechanisms of simultaneous exposure, the interaction of the carcinogens and environmental toxicants cadmium and two arsenic compounds, arsenite and arsenic trioxide, in combination with gamma-radiation in human lymphoblastoid cells (TK6) were investigated. Gamma-radiation induced significant genotoxic effects such as micronuclei formation, DNA damage and apoptosis, whereas arsenic and cadmium had no significant effect on these indicators of cellular damage at non-toxic concentrations. However, in combination with gamma-radiation arsenic trioxide induced a more than additive apoptotic rate compared to the sum of the single effects. Here, the level of apoptotic cells was increased, in a dose-dependent way, up to two-fold compared to the irradiated control cells. Arsenite did not induce a significant additive effect at any of the concentrations or radiation doses tested. On the other hand, arsenic trioxide was less effective than arsenite in the induction of DNA protein cross-links. These data indicate that the two arsenic compounds interact through different pathways in the cell. Cadmium sulphate, like arsenite, had no significant effect on apoptosis in combination with gamma-radiation at low concentrations and, at high concentrations, even reduced the radiation-induced apoptosis. An additive effect on micronuclei induction was observed with 1muM cadmium sulphate with an increase of up to 80% compared to the irradiated control cells. Toxic concentrations of cadmium and arsenic trioxide seemed to reduce micronuclei induction. The results presented here indicate that relatively low concentrations of arsenic and cadmium, close to those occuring in nature, may interfere with radiation effects. Differences in action of the two arsenic compounds were identified.

Apoptosis↗
PubMed2006

Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis.

Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA(V)) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA(V) (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMA(V), and dimethylarsinic acid (DMA(V)). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% (> or =16.5%) and high homocysteine levels (> or =12.7 micromol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 micromol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.

Age Factors↗
PubMed2005

Assessment of DNA damage in peripheral blood lymphocytes of individuals susceptible to arsenic induced toxicity in West Bengal, India.

Assessment of DNA damage was carried out using alkaline comet assay in lymphocytes of 30 individuals exposed to high levels of arsenic (247.12+/-18.93 microg/l) through contaminated groundwater in North 24 Parganas district, West Bengal, India. All of them exhibited high arsenic contents in nail (4.20+/-0.67 microg/g), hair (2.06+/-0.20 microg/g) and urine (259.75+/-33.89 microg/l) samples and manifested various arsenical skin lesions. Unexposed samples were collected from 30 residents of the unaffected East Midnapur district with very little or no exposure to arsenic (7.69+/-0.49 microg/l) in drinking water. The results were evaluated principally by manual analysis of comets and partly by computerized image analysis. Both the analytical methods exhibited a high degree of agreement in results. The exposed participants expressed significantly higher DNA damage (p < 0.01) in their lymphocytes than the unexposed participants. Alkaline comet assay was also combined with formamidopyrimidine-DNA glycosylase enzyme digestion to confirm that arsenic induced oxidative base damage in the lymphocytes. Significant positive trend effects of comet lengths in relation to arsenic levels in water prove that DNA damage can be used as a sensitive biomarker of arsenic exposure. This study demonstrates that arsenic induced significant DNA damage in the exposed participants, which could correspond to a higher susceptibility to arsenic induced toxicity and carcinogenicity.

Adult↗