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.

Associations between and risks of trace elements related to skin and liver damage induced by arsenic from coal burning.

Long-term exposure to high levels of arsenic has been documented to induce skin and liver damage, affecting hundreds of millions of people. While arsenic-induced skin and liver damage and trace element alterations have been studied, their correlations and risks have not been explained. Based on the above premise, this study included a total of 172 subjects from a coal-burning arsenic poisoning area. The levels of 18 trace elements in hair and six liver function indices in serum were detected, and the associations between and risks of trace elements related to skin and liver damage were analyzed. Finally, the receiver operating characteristic (ROC) curve and areas under the curve (AUC) were used to analyze the diagnostic values of certain trace elements for arsenic-induced skin and liver damage. The results found that a decrease in Se was a risk factor for arsenic-induced skin and liver damage (OR = 8.33 and 1.92, respectively). Furthermore, increases in Al and V were risk factors for arsenic-induced skin damage (OR = 1.05) and liver damage (OR = 13.16), respectively. In addition, the results found that Se and Al possessed certain diagnostic values for arsenic-induced skin damage (AUC = 0.93, 0.80), that Se possessed a diagnostic value for liver damage (AUC = 0.93), and that the combination of Se and Al increased the diagnostic value for skin damage (AUC = 0.96). This study provides an important research basis for further understanding the reasons for arsenic-induced skin and liver damage, for screening and identifying candidate diagnostic biomarkers, and for improving prevention and control strategies for arsenism.

Progress in the prevention and control of water-borne arsenicosis in China.

In this report, we provided an overview of the prevalence, control, and prevention of water-borne arsenicosis in China during 2001-2016. Random sampling was continuously performed during 2001-2010 to find villages having high levels of arsenic (>50 µg/L) in drinking water. The high-arsenic-exposure villages with more geographically dispersed water supplies were subsequently analyzed for characteristics of arsenic distribution, and villages with relatively large populations were investigated for arsenicosis. The results showed that among 32,673,677 inhabitants in 36,820 villages, 1,894,587 inhabitants in 2,476 villages were at risk of high arsenic exposure. Among the 33,318 drinking water sources surveyed in 625 high-arsenic-exposure villages, 9,807 drinking water sources that contained high levels of arsenic (>50 µg/L) were identified. The overall prevalence rate of arsenicosis was 1.93%. Further, some representative villages were chosen to monitor arsenicosis annually, showing that the prevalence rate of arsenicosis was lower in villages with arsenic-safe water supplies than in villages without arsenic-safe water supplies. To the best of our knowledge, this report provides the most comprehensive assessment of the distribution of high arsenic exposure and arsenicosis in China until now.

Comparative efficacy of Nano and Bulk Monoisoamyl DMSA against arsenic-induced neurotoxicity in rats.

Chelation therapy is considered as a safe and effective strategy to combat metal poisoning. Arsenic is known to cause neurological dysfunctions such as impaired memory, encephalopathy, and peripheral neuropathy as it easily crosses the blood-brain barrier. Oxidative stress is one of the mechanisms suggested for arsenic-induced neurotoxicity. We prepared Solid Lipid nanoparticles loaded with Monoisoamyl 2, 3-dimercaptosuccinic acid (Nano-MiADMSA), and compared their efficacy with bulk MiADMSA for treating arsenic-induced neurological and other biochemical effects. Solid lipid nanoparticles entrapping MiADMSA were synthesized and particle characterization was carried out by transmission electron microscopy (TEM) and dynamic light scattering (DLS). An in vivo study was planned to investigate the therapeutic efficacy of MiADMSA-encapsulated solid lipid nanoparticles (Nano-MiADMSA; 50 mg/kg orally for 5 days) and compared it with bulk MiADMSA against sodium meta-arsenite exposed rats (25 ppm in drinking water, for 12 weeks) in male rats. The results suggested the size of Nano-MiADMSA was between 100-120 nm ranges. We noted enhanced chelating properties of Nano-MiADMSA compared with bulk MiADMSA as evident by the reversal of oxidative stress variables like blood δ-aminolevulinic acid dehydratase (δ-ALAD), Reactive Oxygen Species (ROS), Catalase activity, Superoxide Dismutase (SOD), Thiobarbituric Acid Reactive Substances (TBARS), Reduced Glutathione (GSH) and Oxidized Glutathione (GSSG), Glutathione Peroxidase (GPx), Glutathione-S-transferase (GST) and efficient removal of arsenic from the blood and tissues. Recoveries in neurobehavioral parameters further confirmed nano-MiADMSA to be more effective than bulk MiADMSA. We conclude that treatment with Nano-MiADMSA is a better therapeutic strategy than bulk MiADMSA in reducing the effects of arsenic-induced oxidative stress and associated neurobehavioral changes.

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.

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic-induced DNA damage and repair in normal human liver cells.

Long-term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L-02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic-induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N-methylpurine-DNA glycosylase [MPG], XRCC1 and poly(ADP-ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic-induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.

Arsenic intoxication: general aspects and chelating agents.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.

Global threat of arsenic in groundwater.

Naturally occurring arsenic in groundwater affects millions of people worldwide. We created a global prediction map of groundwater arsenic exceeding 10 micrograms per liter using a random forest machine-learning model based on 11 geospatial environmental parameters and more than 50,000 aggregated data points of measured groundwater arsenic concentration. Our global prediction map includes known arsenic-affected areas and previously undocumented areas of concern. By combining the global arsenic prediction model with household groundwater-usage statistics, we estimate that 94 million to 220 million people are potentially exposed to high arsenic concentrations in groundwater, the vast majority (94%) being in Asia. Because groundwater is increasingly used to support growing populations and buffer against water scarcity due to changing climate, this work is important to raise awareness, identify areas for safe wells, and help prioritize testing.

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.

Arsenic-induced neurotoxicity: a mechanistic appraisal.

Arsenic is a metalloid found in groundwater as a byproduct of soil/rock erosion and industrial and agricultural processes. This xenobiotic elicits its toxicity through different mechanisms, and it has been identified as a toxicant that affects virtually every organ or tissue in the body. In the central nervous system, exposure to arsenic can induce cognitive dysfunction. Furthermore, iAs has been linked to several neurological disorders, including neurodevelopmental alterations, and is considered a risk factor for neurodegenerative disorders. However, the exact mechanisms involved are still unclear. In this review, we aim to appraise the neurotoxic effects of arsenic and the molecular mechanisms involved. First, we discuss the epidemiological studies reporting on the effects of arsenic in intellectual and cognitive function during development as well as studies showing the correlation between arsenic exposure and altered cognition and mental health in adults. The neurotoxic effects of arsenic and the potential mechanisms associated with neurodegeneration are also reviewed including data from experimental models supporting epidemiological evidence of arsenic as a neurotoxicant. Next, we focused on recent literature regarding arsenic metabolism and the molecular mechanisms that begin to explain how arsenic damages the central nervous system including, oxidative stress, energy failure and mitochondrial dysfunction, epigenetics, alterations in neurotransmitter homeostasis and synaptic transmission, cell death pathways, and inflammation. Outlining the specific mechanisms by which arsenic alters the cell function is key to understand the neurotoxic effects that convey cognitive dysfunction, neurodevelopmental alterations, and neurodegenerative disorders.

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.

Association of Arsenic Exposure With Cardiac Geometry and Left Ventricular Function in Young Adults.

BACKGROUND: Arsenic exposure has been related to numerous adverse cardiovascular outcomes. The aim of this study was to investigate the cross-sectional and prospective association between arsenic exposure with echocardiographic measures of left ventricular (LV) geometry and functioning. METHODS: A total of 1337 young adult participants free of diabetes mellitus and cardiovascular disease were recruited from the SHFS (Strong Heart Family Study). The sum of inorganic and methylated arsenic concentrations in urine (ΣAs) at baseline was used as a biomarker of arsenic exposure. LV geometry and functioning were assessed using transthoracic echocardiography at baseline and follow-up. RESULTS: Mean follow-up was 5.6 years, and median (interquartile range) of ΣAs was 4.2 (2.8-6.9) µg/g creatinine. Increased arsenic exposure was associated with prevalent LV hypertrophy, with an odds ratio (95% CI) per a 2-fold increase in ΣAs of 1.47 (1.05-2.08) in all participants and of 1.58 (1.04-2.41) among prehypertensive or hypertensive individuals. Measures of LV geometry, including LV mass index, left atrial systolic diameter, interventricular septum, and LV posterior wall thickness, were positively and significantly related to arsenic exposure. Among measures of LV functioning, stroke volume, and ejection fraction were associated with arsenic exposure. CONCLUSIONS: Arsenic exposure was related to an increase in LV wall thickness and LV hypertrophy in young American Indians with a low burden of cardiovascular risk factors. The relationship was stronger in participants with prehypertension or hypertension, suggesting that potential cardiotoxic effects of arsenic might be more pronounced in individuals already undergoing cardiovascular adaptive mechanisms following elevated systemic blood pressure.

Fatal acute arsenic poisoning by external use of realgar: Case report and 30 years literature retrospective study in China.

Realgar (arsenic sulfide) is widely used in combination with other herbs as Chinese patent medicine to treat a variety of diseases in China. As a mineral arsenic, its mild toxicity was also well known. Longtime over-dose usage or wrongly oral intake of realgar can cause chronic arsenic poisoning and/or death, but acute fatal arsenic poisoning resulted from short-term dermal use of realgar-containing medicine was very rare. Here, we present the case of a 35-year-old Chinese man, who was diagnosed with severe psoriasis and died of fatal acute arsenic poisoning after he applied a local folk prescription ointment containing mainly the realgar to the affected skin for about 4 days. The autopsy showed multiple punctate hemorrhages over the limbs, pleural effusion, edematous lungs with consolidation, mild myocardial hypertrophy and normal-looking kidneys. The histopathological examination of renal tissue showed severe degeneration, necrosis and desquamation of renal tubular epithelial cells, presence of protein cast and a widened edematous interstitium with interstitial fibrosis. The presence of arsenic in large amount in the ointment (about 6%), in blood (1.76 µg/mL), and in skin (4.71 µg/g), were confirmed analytically. We also provide the clinical records of the deceased and briefly reviewed 7 similar cases in literature (6 in Chinese and 1 in English) in the past 30 years in China.

A curious association of chronic homeopathic arsenic ingestion with nonspecific symptoms in a Swiss teenager.

Arsenic is a toxicant that has no dose threshold below which exposures are not harmful. Here I report a curious association of chronic homeopathic arsenic ingestion with nonspecific symptoms in a Swiss teenager. For about 4 years she had taken globules of a freely purchasable homeopathic remedy containing inorganic arsenic (iAs), infinitesimally diluted to D6 (average arsenic content per single globule: 0.85 ± 0.08 ng). In the previous 7 months she had taken 20 to 50 globules daily (average 30 ng arsenic daily). She complained of nausea, stomach and abdominal cramps, diarrhoea and flatulence, headache, dizziness, anxiety, difficulty concentrating, insomnia, snoring, leg cramps and fatigue, loss of appetite, increased thirst and sweating, reduced diuresis, weight gain, paleness and coolness of both hands with a furry feeling of the hands, eczema of the hands, arms and legs, conjunctivitis and irregular menstruation. The physical and laboratory examinations showed a body mass index of 30 kg/m2, acne vulgaris, bilateral spotted leukonychia, eczema of hands, arms and legs, non-pitting oedema of the legs, elevated plasma alkaline phosphatase activity, folate deficiency and severe vitamin D3 insufficiency. The arsenic concentration in her blood was <0.013 µmol/l, and arsenic was undetectable in her scalp hair. The total iAs concentration was 116 nmol/l in the morning urine and 47 nmol/l in the afternoon urine. The urinary arsenic concentration decreased and the patient’s complaints improved upon interruption of the arsenic globules, vitamin D3, thiamine and folic acid supplementation, and symptomatic therapy. It is concluded that an avoidable toxicant such as inorganic arsenic, for which no scientific safe dose threshold exists, should be avoided and not be found in over-the-counter medications.

[Pollution and Chronic Arsenic Poisoning Associated with the Operation of Former Toroku Mine in Takachiho Town, Miyazaki Prefecture].

Japan has laws in place that are intended to reduce health risks from environmental pollution, including air pollution. On the basis of the "polluters pay" principle, these laws are designed to support pollution victims. In Miyazaki Prefecture, people were chronically exposed to arsenic in Takachiho Town as a result of the operation of Toroku Mine. As a result of this pollution, the Miyazaki Prefectural Government has provided annual health checkups for residents since 1973. The examination consists of the following: blood test, urine test, body measurement, CT scan, respiratory test, hearing test, taste test, olfactory test, eye exam, neurological exam, internal exam, and skin exam. Test results are entered into the electronic database for chronic arsenic poisoning. In order to maintain public awareness of the danger of environmental pollution, we are engaging in a project to inform the public of our history of pollution and environmental restoration efforts. We also hope to help other Asian countries that are suffering from arsenic contamination of groundwater by providing support for trainees that are participating in JICA projects.