Arsenic-protein interactions as a mechanism of arsenic toxicity.

Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects.

Factors Affecting Arsenic Methylation in Contaminated Italian Areas.

Chronic arsenic (As) exposure is a critical public health issue. The As metabolism can be influenced by many factors. The objective of this study is to verify if these factors influence As metabolism in four Italian areas affected by As pollution. Descriptive analyses were conducted on 271 subjects aged 20-49 in order to assess the effect of each factor considered on As methylation. Percentages of metabolites of As in urine, primary and secondary methylation indexes were calculated as indicators for metabolic capacity. The results indicate that women have a better methylation capacity (MC) than men, and drinking As-contaminated water from public aqueducts is associated with poorer MC, especially in areas with natural As pollution. In areas with anthropogenic As pollution occupational exposure is associated with a higher MC while smoking with a poorer MC. Dietary habits and genetic characteristics are probably implicated in As metabolism. BMI, alcohol consumption and polymorphism of the AS3MT gene seem not to influence As MC. Arsenic metabolism may be affected by various factors and in order to achieve a comprehensive risk assessment of As-associated disease, it is crucial to understand how these factors contribute to differences in As metabolism.

Biotransformation of arsenic and toxicological implication of arsenic metabolites.

Arsenic is a well-known environmental carcinogen and chronic exposure to arsenic through drinking water has been reported to cause skin, bladder and lung cancers, with arsenic metabolites being implicated in the pathogenesis. In contrast, arsenic trioxide (As2O3) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, in which the binding of arsenite (iAsIII) to promyelocytic leukemia (PML) protein is the proposed initial step. These findings on the two-edged sword characteristics of arsenic suggest that after entry into cells, arsenic reaches the nucleus and triggers various nuclear events. Arsenic is reduced, conjugated with glutathione, and methylated in the cytosol. These biotransformations, including the production of reactive metabolic intermediates, appear to determine the intracellular dynamics, target organs, and biological functions of arsenic.

Arsenic Toxicity: Molecular Targets and Therapeutic Agents.

: High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.

Inorganic arsenic causes intestinal barrier disruption.

Inorganic arsenic (As) is the most toxic form of As found in food and water. Gastrointestinal disorders have been reported in populations chronically exposed to this arsenical form or to one of its metabolites; however, studies to determine the mechanisms of inorganic As toxicity at the intestinal level are scarce. The aim of this study is to determine the mechanisms of toxicity of inorganic As [As(iii) and As(v)] on intestinal epithelial cells. For this purpose, two human intestinal cell models were used: non-transformed colon epithelial cells (NCM460) and epithelial cells from a colorectal adenocarcinoma (Caco-2). Exposure to As(iii) and As(v) generates an increase in the release of the pro-inflammatory cytokine IL-8 (57-1135%) and an increase in the generation of reactive oxygen and/or nitrogen species (130-340%) in both cell lines. This pro-inflammatory and pro-oxidant response may be responsible for the structural and functional modifications demonstrated in the monolayers formed by both cell types. Treatments with As(iii) and As(v) produce a redistribution of zonula occludens 1 and a reduction in the expression of claudin 1, tight junction proteins that participate in maintaining the structure of the epithelium. All these toxic effects are finally translated into a loss of the barrier function of intestinal monolayers.

miR-145 via targeting ERCC2 is involved in arsenite-induced DNA damage in human hepatic cells.

Arsenic, an established human carcinogen, causes genetic toxicity. However, the molecular mechanisms involved remain unknown. MicroRNAs (miRNAs) are regulators that participate in fundamental cellular processes. In the present investigation, we selected, as research subjects, patients with arsenic poisoning caused by burning of coal in Guizhou Province, China. For these patients, the plasma levels of miR-145 were up-regulated. In L-02 cells, arsenite, an active form of arsenic, induced up-regulation of miR-145 and down-regulation of ERCC1 and ERCC2, and caused DNA damage. For L-02 cells, transfection with an miR-145 inhibitor prevented arsenite-induced DNA damage and decreased ERCC2 levels. Luciferase reporter assays showed that miR-145 regulated ERCC2 expression by targeting the 3'-UTR of ERCC2, but not that for ERCC1. The present results demonstrate that arsenite induces the over-expression of miR-145 and inhibits DNA repair via targeting ERCC2, thus promoting DNA damage. The information provides a new mechanism for arsenic-induced liver injury.

Metabolism and disposition of arsenic species after repeated oral dosing with sodium arsenite in drinking water. II. Measurements in pregnant and fetal CD-1 mice.

Arsenic is ubiquitous in the earth's crust, and human diseases are linked with exposures that are similar to dietary intake estimates. Metabolic methylation of inorganic arsenic facilitates excretion of pentavalent metabolites and decreases acute toxicity; however, tissue binding of trivalent arsenic intermediates is evidence for concomitant metabolic activation. Pregnant and fetal CD-1 mice comprise a key animal model for arsenic carcinogenesis since adult-only exposures have minimal effects. This study evaluated inorganic arsenic and its metabolites in pentavalent and trivalent states in blood and tissues from maternal and fetal CD-1 mice after repeated administration of arsenite through drinking water. After 8 days of exposure, DMA species were ubiquitous in dams and fetuses. Despite the presence of MMAIII in dams, none was observed in any fetal sample. This difference may be important in assessing fetal susceptibility to arsenic toxicity because MMA production has been linked with human disease. Binding of DMAIII in fetal tissues provided evidence for metabolic activation, although the role for such binding in arsenic toxicity is unclear. This study provides links between administered dose, metabolism, and internal exposures from a key animal model of arsenic toxicity to better understand risks from human exposure to environmental arsenic.

The history of arsenical pesticides and health risks related to the use of Agent Blue.

Arsenicals in agriculture. Beginning in the 1970s, the use of arsenic compounds for such purposes as wood preservatives, began to grow. By 1980, in the USA, 70% of arsenic had been consumed for the production of wood preservatives. This practice was later stopped, due to the US Environmental Protection Agency (EPA) ban of the arsenic-and chromium-based wood preservative chromated copper arsenate. In the past, arsenical herbicides containing cacodylic acid as an active ingredient have been used extensively in the USA, from golf courses to cotton fields, and drying-out the plants before harvesting. The original commercial form of Agent Blue was among 10 toxic insecticides, fungicides and herbicides partially deregulated by the US EPA in February 2004, and specific limits on toxic residues in meat, milk, poultry and eggs, were removed. Today, however, they are no longer used as weed-killers, with one exception - monosodium methanearsonate (MSMA), a broadleaf weed herbicide for use on cotton. Severe poisonings from cacodylic acid caused headache, dizziness, vomiting, profuse and watery diarrhea, followed by dehydration, gradual fall in blood pressure, stupor, convulsions, general paralysis and possible risk of death within 3-14 days.The relatively frequent use of arsenic and its compounds in both industry and agriculture points to a wide spectrum of opportunities for human exposure. This exposure can be via inhalation of airborne arsenic, contaminated drinking water, beverages, or from food and drugs. Today, acute organic arsenical poisonings are mostly accidental. Considerable concern has developed surrounding its delayed effects, for its genotoxic and carcinogenic potential, which has been demonstrated in epidemiological studies and subsequent animal experiments. Conclusions. There is substantial epidemiological evidence for an excessive risk, mostly for skin and lung cancer, among humans exposed to organic arsenicals in occupational and environmental settings. Furthermore, the genotoxic and carcinogenic effects have only been observed at relatively high exposure rates. Current epidemiological and experimental studies are attempting to elucidate the mechanism of this action, pointing to the question whether arsenic is actually a true genotoxic, or rather an epigenetic carcinogen. Due to the complexity of its effects, both options remain plausible. Its interactions with other toxic substances still represent another important field of interest.

A retrospective review of the dermatologic manifestations of chronic arsenic poisoning in the Philippines.

BACKGROUND: The Section of Dermatology of the University of the Philippines, Philippine General Hospital, reported a case of chronic arsenic poisoning from a community in Luzon island to the Department of Health resulting in the conduct of two health and environmental assessment missions in December 2014. OBJECTIVE: To describe the demographic profile and cutaneous manifestations of chronic arsenic poisoning among affected residents in Luzon, Philippines. METHODS: A review of the medical records of 116 residents screened during the health assessment missions in December 2014 was conducted. RESULTS: Among the 116 residents screened, 81 (70%) had clinically confirmed arsenic keratoses and hyperpigmentation. Among them, 52 were males and 29 were females with age range of 4-82 years. Two cases of squamous cell carcinoma in situ were detected through skin biopsy. High levels of arsenic in the tap water and topsoil supported the occurrence of an epidemic of chronic arsenic poisoning. CONCLUSION: Specific dermatologic findings of arsenic keratoses and pigmentation were common among the residents screened. Significantly higher occurrence of arsenic keratoses was seen in adults.

Metabolism, toxicity and anticancer activities of arsenic compounds.

A variety of studies indicated that inorganic arsenic and its methylated metabolites have paradoxical effects, namely, carcinogenic and anticancer effects. Epidemiological studies have shown that long term exposure to arsenic can increase the risk of cancers of lung, skin or bladder in man, which is probably associated with the arsenic metabolism. In fact, the enzymatic conversion of inorganic arsenic by Arsenic (+3 oxidation state) methyltransferase (AS3MT) to mono- and dimethylated arsenic species has long been considered as a major route for detoxification. However, several studies have also indicated that biomethylation of inorganic arsenic, particularly the production of trivalent methylated metabolites, is a process that activates arsenic as a toxin and a carcinogen. On the other hand, arsenic trioxide (As2O3) has recently been recognized as one of the most effective drugs for the treatment of APL. However, elaboration of the cytotoxic mechanisms of arsenic and its methylated metabolites in eradicating cancer is sorely lacking. To provide a deeper understanding of the toxicity and carcinogenicity along with them use of arsenic in chemotherapy, caution is required considering the poor understanding of its various mechanisms of exerting toxicity. Thereby, in this review, we have focused on arsenic metabolic pathway, the roles of the methylated arsenic metabolites in toxicity and in the therapeutic efficacy for the treatments of solid tumors, APL and/or non-APL malignancies.

Does arsenic increase the risk of neural tube defects among a highly exposed population? A new case-control study in Bangladesh.

BACKGROUND: Neural tube defects are debilitating birth defects that occur when the developing neural plate fails to close in early gestation. Arsenic induces neural tube defects in animal models, but whether environmental arsenic exposure increases risk of neural tube defects in humans is unknown. METHODS: We describe a new case-control study in Bangladesh, a country currently experiencing an epidemic of arsenic poisoning through contaminated drinking water. We plan to understand how arsenic influences risk of neural tube defects in humans through mechanisms that include disruption of maternal glucose and folate metabolism, as well as epigenetic effects. We also investigate whether sweat chloride concentration, a potential new biomarker for arsenic toxicity, can be used to identify women at higher risk for having a child affected by neural tube defect. We will collect dural tissue from cases, obtained at the time of surgical closure of the defect, and believe investigation of these samples will provide insight into the epigenetic mechanisms by which prenatal arsenic exposure affects the developing nervous system. CONCLUSION: These studies explore mechanisms by which arsenic may increase risk of neural tube defects in humans and use a unique population with high arsenic exposure to test hypotheses. If successful, these studies may assist countries with high arsenic exposure such as Bangladesh to identify populations at high risk of neural tube defects, as well as direct development of novel screening strategies for maternal risk.Birth Defects Research 109:92-98, 2017.© 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.

Risk of ingesting As, Cd, and Pb in animal products in north Rio de Janeiro state, Brazil.

This study evaluated the levels of As, Cd, and Pb in muscle and liver the cattle and chicken. The risk was estimated for the adult population of a midsized city in southeast Brazil, concerning the tolerable ingestion and cancer risk. Samples of muscle and liver (cattle and chicken) were collected (n = 250). Samples of mineral supplements for cattle (n = 4) and chicken feed samples (n = 4) were evaluated as one of many potential source of contamination. Muscle, liver, mineral supplement, and feed samples were dissolved in acid medium and analyzed by ICP-OES. Daily muscle and liver intake was estimated using a questionnaire (N = 427). Daily intake of trace elements by the population based on the consumption of cattle muscle, cattle liver, chicken muscle, and chicken liver was low, corresponding to 2.76%, 0.33%, 2.12%, and 0.22% of the Tolerable Intake defined by the WHO for As; 0.54%, 0.29% 0.55%, 0.01%, for Cd; and 0.80%, 0.07%, 0.62%, 0.02%, for Pb. The mean of total ingestion of As, Cd and Pb was 5.43%, 1.18% and 1.51%, respectively of Tolerable Intake defined by WHO. Cancer risk was lower than 5 × 10-5 year-1. The results indicate that the muscle and liver consumption is a source of As, Cd, and Pb. Consumers that ingest cattle and chicken muscle need attention in terms the risk of cancer related to intake of As and Cd. Feed and mineral supplementation remain as one of many sources of exposure of As, Cd, and Pb.

Induction of Aneuploidy, Centrosome Abnormality, Multipolar Spindle, and Multipolar Division in Cultured Mammalian Cells Exposed to an Arsenic Metabolite, Dimethylarsinate.

Toxicological studies of arsenic compounds were conducted in cultured mammalian cells to investigate the effects of glutathione (GSH) depletion. Dimethylarsinate DMA(V) was not cytotoxic in cells depleted of GSH, but was found to be cytotoxic when GSH was present outside the cells. The results suggested that a reactive form of DMA(V) was generated through interaction with GSH. Dimethylarsine iodide DMI(III) was used as a model compound of DMA(III), and the biological effects were investigated. DMI(III) was about 10000 times more toxic to the cells than DMA(V). Chromosome structural aberrations and numerical changes, such as aneuploidy, were induced by DMI(III). DMA(V) induced multiple foci of the centrosome protein, γ-tubulin, which were colocalized with multipolar spindles in mitotic cells. The multiple foci coalesced into a single dot on disruption of the microtubules (MT). However, reorganization of the MT caused multiple foci of γ-tubulin, suggesting that the induction of centrosome abnormalities by DMA(V) required intact MT. Inhibition of the MT-dependent motor, kinesin, prevented formation of multiple foci of γ-tubulin, which pointed to the involvement of the MT-dependent mitotic motor, kinesin, in the maintenance of centrosome abnormalities. DMI(III) caused abnormal cytokinesis (multipolar division). In addition, DMI(III) caused morphological transformation in Syrian hamster embryo cells. Consideration of the overall process following the centrosome abnormalities caused by DMA(V) suggested a mode of cytotoxicity in which the mitotic centrosome is a critical target.

Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension.

BACKGROUND AND AIMS: Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality. METHODS: Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty-four percent to 96 % of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry. RESULTS: Nail arsenic levels were raised in five (10 %) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11 %) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5 µg/L). CONCLUSIONS: Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'.

A cross sectional study of anemia and iron deficiency as risk factors for arsenic-induced skin lesions in Bangladeshi women.

BACKGROUND: In the Ganges Delta, chronic arsenic poisoning is a health concern affecting millions of people who rely on groundwater as their potable water source. The prevalence of anemia is also high in this region, particularly among women. Moreover, arsenic is known to affect heme synthesis and erythrocytes and the risk of arsenic-induced skin lesions appears to differ by sex. METHODS: We conducted a case-control study in 147 arsenic-exposed Bangladeshi women to assess the association between anemia and arsenic-induced skin lesions. RESULTS: We observed that the odds of arsenic-related skin lesions were approximately three times higher among women who were anemic (hemoglobin < 120 g/L) compared to women with normal hemoglobin levels [Odds Ratio (OR) = 3.32, 95% Confidence Intervals (CI): 1.29, 8.52] after adjusting for arsenic levels in drinking water and other covariates. Furthermore, 75% of the women with anemia had adequate iron stores (serum ferritin ≥ 12 µg/L), suggesting that the majority of anemia detected in this population was unrelated to iron depletion. CONCLUSIONS: Considering the magnitude of arsenic exposure and prevalence of anemia in Bangladeshi women, additional research is warranted that identifies the causes of anemia so that effective interventions can be implemented while arsenic remediation efforts continue.

Chronic Arsenic Poisoning Probably Caused by Arsenic-Based Pesticides: Findings from an Investigation Study of a Household.

In addition to naturally occurring arsenic, man-made arsenic-based compounds are other sources of arsenic exposure. In 2013, our group identified 12 suspected arsenicosis patients in a household (32 living members). Of them, eight members were diagnosed with skin cancer. Interestingly, all of these patients had lived in the household prior to 1989. An investigation revealed that approximately 2 tons of arsenic-based pesticides had been previously placed near a well that had supplied drinking water to the family from 1973 to 1989. The current arsenic level in the well water was 620 µg/L. No other high arsenic wells were found near the family's residence. Based on these findings, it is possible to infer that the skin lesions exhibited by these family members were caused by long-term exposure to well water contaminated with arsenic-based pesticides. Additionally, biochemical analysis showed that the individuals exposed to arsenic had higher levels of aspartate aminotransferase and γ-glutamyl transpeptidase than those who were not exposed. These findings might indicate the presence of liver dysfunction in the arsenic-exposed individuals. This report elucidates the effects of arsenical compounds on the occurrence of high levels of arsenic in the environment and emphasizes the severe human health impact of arsenic exposure.

Assessment of arsenic levels in body samples and chronic exposure in people using water with a high concentration of arsenic: a field study in Kutahya.

OBJECTIVE: This study aimed to evaluate the prevalence of skin lesions, which is a health effect of chronic arsenic (As) exposure, and determine the hair/blood arsenic concentrations of people living in Kutahya villages who are using and drinking tap water with a high concentration of arsenic. MATERIALS AND METHODS: A total of 303 people were included in the present cross-sectional study. A prepared questionnaire form was used to collect the participants' information and environmental history. Skin examination was performed on all participants. Hair, blood and water samples were analyzed using atomic absorption spectroscopy. The cumulative arsenic index (CAI) was calculated for all participants. RESULTS: Villages were divided into two groups according to the arsenic level (<20 µg/L, Group I; >20 µg/L, Group II) in their water. The prevalence of skin lesions, hair and blood arsenic level, and CAI were found to be higher in the Group II participants. There was a positive association between body arsenic levels and CAI in the participants of each group. CONCLUSIONS: The number of skin lesions and arsenic concentrations in body samples were found to increase with the water arsenic level and exposure time. We hope that sharing this study's results with local administrators will help accelerate the rehabilitation of water sources in Kutahya.

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment.

The possibility of an association between inorganic arsenic (iAs) exposure and cardiovascular outcomes has received increasing attention in the literature over the past decade. The United States Environmental Protection Agency (US EPA) is currently revising its Integrated Risk Assessment System (IRIS) review of iAs, and one of the non-cancer endpoints of interest is cardiovascular disease (CVD). Despite the increased interest in this area, substantial gaps remain in the available information, particularly regarding the mechanism of action (MOA) by which iAs could cause or exacerbate CVD. Few studies specifically address the plausibility of an association between iAs and CVD at the low exposure levels which are typical in the United States (i.e., below 100 µg As/L in drinking water). We have conducted a review and evaluation of the animal, mechanistic, and human data relevant to the potential MOAs of iAs and CVD. Specifically, we evaluated the most common proposed MOAs, which include disturbance of endothelial function and hepatic dysfunction. Our analysis of the available evidence indicates that there is not a well-established MOA for iAs in the development or progression of CVD. Few human studies of the potential MOAs have addressed plausibility at low doses and the applicability of extrapolation from animal studies to humans is questionable. However, the available evidence indicates that regardless of the specific MOA, the effects of iAs on physiological processes at the cellular level appear to operate via a threshold mechanism. This finding is consistent with the lack of association of CVD with iAs exposure in humans at levels below 100 µg/L, particularly when considering important exposure and risk modifiers such as nutrition and genetics. Based on this analysis, we conclude that there are no data supporting a linear dose-response relationship between iAs and CVD, indicating this relationship has a threshold.