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The aim of the current study is to explain the effect of leek extract against harmful effect induced by Arsenic. Sixty adult male rats were divided into 6 groups G1 control, G2 received orally daily sodium arsenate (40 ppm) by drinking water for six weeks then left another six weeks for recovery, G3 received orally daily sodium arsenate (40 ppm) by drinking water for six weeks then intubated orally with Leek in dose (200 mg/kg B.W) for six weeks, G4 received orally daily sodium arsenate (40 ppm) by drinking water for six weeks then intubated orally with Leek in dose (100 mg/kg B.W) for six weeks, G5 received Leek in dose (200 mg/kg B.W) for six weeks then left another six weeks for recovery, G6 received Leek in dose (100 mg/kg B.W) for six weeks then left another six weeks for recovery. The experiment continue for twelve weeks. The blood samples collection by heart puncture serum separated for biochemical analysis that include Urea, Creatinine and Uric acid and samples of brain for histopathological study. The biochemical study explained that there was significant increase (p<0.05) in urea in G2,G3,G4 as compared with control group (G1) after 6 weeks, after 12 weeks there was significant increase (p<0.05) in G2,G3,G4 as compared with control group (G1). There was significant decreased in urea in G3,G4,G6 between 6weeks and 12 weeks, after 12 weeks there was significant increase (p<0.05) in G2 as compared with control group (G1). There was significant increase in Creatinine in G2, G5 between 6 weeks and 12 weeks. There was significant increase (p<0.05) in Uric acid in G2, G3, G4 as compared with control group (G1) after 6 weeks, after 12 weeks there was significant increase (p<0.05) in G2, G3, G4, G5, G6 as compared with control group (G1). There was significant decreased in Uric acid in G3 between 6weeks and 12 weeks. Histopathological result explained that there was destruction of cerebral tissue, which characterized by cavitation with various size cavities within cerebral cortex. in the groups that received Leek in dose (100, 200 mg/kg B.W) for six weeks there was the sections of the cerebrum and cerebellum have showed normal appearance and were similar to the control group. After 12 weeks there was in G2 the sections of cerebellum have revealed marked degeneration of granular layer cells and purkinje layer cells. In G3 there was the sections of both cerebellum and cerebrum were similar those in control group, in G4 there was the sections of the cerebral internal pyramidal layer have showed moderate vacular changes of astrocytes with mild tissue depletion, while the section of cerebellum have showed normal appearance. In G5, G6 there was the section of cerebrum and cerebellum of both groups were similar those of control group. [ABSTRACT FROM AUTHOR]

Exposure of humans to Arsenic from groundwater drinking sources is an acute global public health problem, entailing the urgent need for highly efficient/low-cost Arsenite (AsIII) up-taking materials. Herein we present an innovative hybrid-material, ZrMOF@SFd operating like an "AsIII-sponge" with unprecedented efficiency of 1800 mg AsIII gr−1. ZrMOF@SFd consists of a neutral Zirconium Metal-Organic Framework [ZrMOF] covalently grafted on a natural silk-fiber (SFd). ZrMOF itself exhibits AsIII adsorption of 2200 mg gr−1, which supersedes any -so far- known AsΙΙΙ-sorbent. Using XPS, FTIR, BET-porosimetry data, together with theoretical Surface-Complexation-Modeling (SCM), we show that the high-AsΙΙΙ-uptake is due to a sequence of two phenomena:[i] at low AsIII-concentrations, surface-complexation of H3AsO3 results in AsIII-coated voids of ZrMOF, [ii] at increased AsIII-concentrations, the AsIII-coated voids of ZrMOF are filled-up by H3AsO3via a partitioning-like mechanism. In a more general context, the present research exemplifies a mind-changing concept, i.e. that a "partitioning-like" mechanism can be operating for adsorption of metalloids, such as H3AsO3, by metal oxide materials. So far, such a mechanism has been conceptualized only for the uptake of non-polar organics by natural organic matter or synthetic polymers. [ABSTRACT FROM AUTHOR]

Chronic exposure to inorganic arsenic (As)—As(III) + As(V)—is associated with type 2 diabetes, vascular diseases and various types of cancer. Although the oral route is the main way of exposure to inorganic As, the adverse gastrointestinal effects produced by chronic exposure are not well documented. The aim of the present study is to evaluate the effect of chronic exposure to As(III) on the intestinal epithelium. For this purpose, NCM460 cells, non‐transformed epithelial cells from the human colon, were exposed to As(III) (0.01‐0.2 mg/L) for 6 months and monitored for acquisition of a tumor‐like phenotype. Secretion of matrix metalloproteinases, histone modifications (H3 acetylation), hyperproliferation capacity, formation of floating spheres, anchorage‐independent growth, release of cytokine interleukin‐8 and expression of relevant genes in colon tumorigenesis were assessed. The results show a maintained proinflammatory response from the beginning, with an increase in interleukin‐8 secretion (≤570%). Downregulation of CDX1 and CDX2 was also observed. After 14 weeks of exposure, cells presented marked increases in matrix metalloproteinase‐2 secretion and histone modifications. As(III)‐treated cells were hyperproliferative, grew in low‐serum media and were able to form free‐floating spheres. Overall, these data suggest that exposure of human colon epithelial cells to As(III) facilitates acquisition of transformed cell characteristics. Chronic exposure to environmental relevant concentrations of As(III) facilitates acquisition of transformed cell characteristics in intestinal cells (marked increases in matrix metalloproteinase‐2 secretion, histone modifications, downregulation of CDX1 and CDX2, anchorage‐independent growth and free‐floating spheres formation, among others). The increase in cellular transformation characters is accompanied by a proinflammatory process that begins in the first weeks of exposure and that could be partly responsible for it. [ABSTRACT FROM AUTHOR]

Arsenic is a metalloid that contaminates drinking water supplies worldwide. Owing to concerns for human health, the World Health Organization and the US Environmental Protection Agency have established a safe level in drinking water of ≤10 ppb. Recently, arsenic exposure has also been linked to lower IQ values in children. The effect of arsenic on neurogenesis, specifically eye development, has not been widely explored. This study aimed to examine the effect of environmentally relevant concentrations of arsenic on early eye development by morphological and molecular analysis. The zebrafish, Danio rerio, was chosen to model the impact of arsenic on retinogenesis because of similarities to human eye development. Arsenic exposure to zebrafish embryos resulted in a significant increase in eye diameter at 14 days postfertilization. This was coupled with a trend in thinning of the retinal pigmented epithelium (RPE) layer in embryos exposed to 500 ppb arsenic. Reverse transcription‐quantitative polymerase chain reaction analysis of genes associated with eye development revealed differential expression of Pax6a, Pax2a, Ngn1, Sox2 and Shha relative to control. Pax6a, Pax2a and Sox2 are important in the formation of the RPE. Proper formation of the RPE is necessary for growth of the sclera, which, in turn, is responsible for maintaining the shape of the eye. This could potentially be explained by the disruption of gene expression under arsenic exposure during critical time points in early eye development. These results provide insight into the effects arsenic may be having on early eye development in children exposed to contaminated drinking water supplies. We investigated the effects of arsenic on eye development in the zebrafish, Danio rerio. Arsenic exposure during embryogenesis resulted in a larger eye size in 2‐week‐old larvae. Arsenic exposure also produced thinning of the retinal pigmented epithelium and differential expression of genes necessary for neural retina and retinal pigmented epithelium development. This gives insight into the effects arsenic may be having on retinogenesis and early eye development in children exposed to contaminated drinking supplies. [ABSTRACT FROM AUTHOR]

As a well-established human carcinogen, arsenic has increased the risk of lung cancer over the past decades. Wide exposure to arsenic in the environment has attracted the attention of scientists. Its carcinogenicity at early life stages has been observed in certain animal studies already, yet current evidence is insufficient to extrapolate this to humans. Although the mechanisms of lung cancer induced by arsenic remain unclear, most of them are related to the biotransformation of arsenic, which would further provide target sites for precaution and therapy. This review comprehensively summarizes current studies associated to arsenic exposure and lung cancer and the mechanism of its carcinogenesis in lung cancer in three sections, namely, epidemiological studies, experimental studies, and mechanistic studies. In addition, prevention and treatment strategies as well as directions for future studies are discussed. [ABSTRACT FROM AUTHOR]

It is known that either arsenic exposure or diabetes can impact renal function. However, it is unclear how these combined factors may influence kidney functions. Therefore, we evaluated morphological, functional, and oxidative parameters in the kidney of diabetic rats exposed to arsenic. Healthy male Wistar rats and streptozotocin-induced diabetic rats were exposed to 0 and 10 mg/L arsenate through drinking water for 40 days. Renal tissue was assessed using morphometry, mitosis and apoptosis markers, mineral proportion, oxidative stress markers, as well as the activity of antioxidant enzymes and membrane-bound adenosine triphosphatases. Arsenate intake altered glucose levels in healthy animals, but it did not reach hyperglycemic conditions. In diabetic animals, arsenate led to a remarkable increase of glycogen nephrosis in distal tubules. In these animals, additionally, the activity of catalase and glutathione S-transferase, besides the proportion of Fe, Cu, and K in renal tissue, was altered. Nevertheless, arsenate did not accumulate in the kidney and did not impact on other parameters previously altered by diabetes, including levels of malondialdehyde, Na, urea, creatinine, and apoptosis and mitosis markers. In conclusion, besides the intensification of glycogen nephrosis, the kidney was able to handle arsenate toxicity at this point, preventing arsenic deposition in the exposed groups and the impairment of renal function. [ABSTRACT FROM AUTHOR]

Abstract Arsenic poses a profound health risk including male reproductive dysfunction upon prolonged exposure. Histone methylation is an important epigenetic driver; however, its role in arsenic- induced steroidogenic pathogenesis remains obscure. In current study, we investigated the effect of histone H3K9 tri-methylation (H3K9me3) on expression pattern of steroidogenic genes in rat testis after long-term arsenic exposure. Our results revealed that arsenic exposure down-regulated the mRNA expressions of all studied steroidogenic genes (Lhr , Star, P450scc, Hsd3b, Cyp17a1, Hsd17b and Arom). Moreover, arsenic significantly increased the H3K9me3 level in rat testis. The plausible explanation of increased H3K9me3 was attributable to the up-regulation of histone H3K9me3 methyltransferase, Suv39h1 and down-regulation of demethylase, Jmjd2a. Since H3K9me3 activation leads to gene repression, we further investigated whether the down-regulation of steroidogenic genes was ascribed to the increased H3K9me3 level. To elucidate this, we determined the H3K9me3 levels in steroidogenic gene promoters, which also showed significant increase of H3K9me3 in the investigated regions after arsenic exposure. In conclusion, arsenic exposure suppressed the steroidogenic gene expression by activating H3K9me3 status, which contributed to steroidogenic inhibition in rat testis. Graphical abstract fx1 Highlights • Arsenic exposure causes various health risks including male reproductive dysfunction. • Arsenic significantly down-regulated steroidogenic gene expressions. • Histone H3K9 tri-methylation was enhanced by arsenic in rat testis. • Chronic arsenic exposure inhibits testicular steroidogenesis via activating H3K9me3. [ABSTRACT FROM AUTHOR]

Abstract Some studies suggest a positive association between arsenic exposure and risk of diabetes. However, the findings are inconsistent and inconclusive, particularly at a low to moderate arsenic exposure level, and longitudinal data are lacking. We examined toenail arsenic at low to moderate level in young adulthood in relation to incidence of diabetes later in life. This study included 4102 black and white participants aged 20–32 at baseline (1987–88) who completed up to 7 follow-up exams through 2015–16. Toenail arsenic was measured by collision-cell inductively-coupled-plasma mass-spectrometry. Incident diabetes was defined as fasting glucose ≥ 126 mg/dL, non-fasting glucose ≥ 200 mg/dL, 2-h postchallenge glucose ≥ 200 mg/dL, hemoglobin A1c ≥ 6.5%, or use of glucose-lowering medications. Cox proportional hazards model and generalized estimating equations (GEEs) were used to determine the associations of quintiles of toenail arsenic with incident diabetes and other metabolic parameters. The median (inter-quartile range) toenail arsenic level was 0.097 (0.065–0.150) ppm in this study. During the follow-up period, 599 incident cases of diabetes were identified. After adjustment for potential confounders, the hazards ratio (95% confidence interval) was 0.96 (0.73, 1.27) (P for linear trend= 0.85) comparing the highest to the lowest quintile of toenail arsenic levels. No significant association was observed between toenail arsenic and levels of fasting glucose, insulin, homeostatic model assessment of insulin resistance, homeostatic model assessment of beta cell function, or C-reactive protein. The null associations persisted across subgroups of age, sex, race, and body mass index. Findings from this longitudinal study do not support the hypothesis that low to moderate toenail arsenic levels in young adulthood is associated with diabetes risk later in life. Highlights • The median (inter-quatile range) toenail arsenic (As) level was 0.097 (0.065–0.150) ppm in this study. • No significant association was observed between toenail As and levels of metabolic parameters such as HOMA and CRP. • The study does not support toenail As at low to moderate levels at young adulthod is related to diabetes risk later in life. [ABSTRACT FROM AUTHOR]

Abstract Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant risk for human cancer and non-cancer diseases. It is now evident that arsenic contamination in food, especially rice and grains, presents a significant exposure to hundreds of millions of individuals worldwide. However, the disease risk from chronic exposure to the low amounts of arsenic found in food remains to be established. Thus, this research estimates the global burdens of disease expressed as Disability-Adjusted Life Years (DALYs) for lung, skin and bladder cancers, as well as coronary heart disease (CHD) attributable to inorganic arsenic in food. To determine foodborne inorganic arsenic exposures worldwide, we used the World Health Organization (WHO) estimates of food consumption in 17 country clusters, in conjunction with the reported measurements of total and inorganic arsenic in different foods. We estimated cancer potency factors for arsenic related bladder and lung cancers, and from US Environmental Protection Agency risk estimates for skin cancer to calculate the cancer incidence in males and females within each of the WHO member states. Summary relative risk estimates and population attributable fractions were developed to estimate the YLD, YLL, and DALYs for arsenic-induced CHD. The findings indicate that, globally, each year the combined DALYs for all cancers attributable to inorganic arsenic in food are approximately 1.4 million with variation in global distribution based on population and food consumption patterns. The global burden of CHD attributable to foodborne inorganic arsenic also varied with WHO region and may contribute as much as 49 million DALYs. However, in contrast to cancer burden, there is a threshold effect for arsenic-associated CHD with no increased risk of heart disease at the expected lower bound of arsenic consumption in food. These estimates indicate that foodborne arsenic exposure causes a significant yet avoidable global burden of human disease. Highlights • We assessed the global disease burden from dietary arsenic exposure. • We considered coronary heart disease (CHD) and skin, bladder and lung cancer. • In 2015, dietary arsenic exposure was associated with 240,000 cancer cases. • Dietary arsenic was associated with up to 4.3 million CHD cases in 2015. • The global disease burden was 50.5 million Disability-Adjusted Life Years. [ABSTRACT FROM AUTHOR]

Abstract Inefficient arsenic methylation capacity has been associated with developmental delay in preschool children. Selenium has antioxidant and anti-inflammatory properties that protect experimental animals from chemically induced neurotoxicity. The present study was designed to explore whether plasma selenium levels affects arsenic methylation capacity related to developmental delay in preschool children. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 178 children with a developmental delay and 88 children without a delay were recruited. High-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry were used to determine urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV). Plasma selenium levels were measured by inductively coupled plasma mass spectrometry. As results, plasma selenium concentration was significantly inversely associated with the odds ratio (OR) of developmental delay. Plasma selenium concentration was positively associated with arsenic methylation capacity [percentage of inorganic arsenic and percentage of MMAV (MMAV%) decreased, and percentage of DMAV (DMAV%) increased]. High plasma selenium concentration and high DMA% significantly and additively interacted to decrease the OR of developmental delay; the OR and 95% confidence interval were 0.40 (0.18–0.90). This is the first study to show a combined dose-response effect of plasma selenium concentration and that efficient arsenic methylation capacity decreased the OR of developmental delay in preschool children. Highlights • Plasma selenium concentration was significantly inversely associated with the odds ratio of developmental delay. • Increases in plasma selenium concentration increased the arsenic methylation capacity. • High plasma selenium concentration and high DMA% significantly and additively interacted to decrease the OR of developmental delay. [ABSTRACT FROM AUTHOR]

Summary: Ectomycorrhizal fungi play an important role in protecting their host plant from metal(loid) stresses by synthesizing various thiol rich compounds like metallothioneins and glutathione. We investigated the effect of cadmium (Cd) and arsenic (As) stress with a specific interest on glutathione (GSH) in the ectomycorrhizal fungus Laccaria bicolor. The total GSH levels inside the cell were significantly increased with increase in external metal(loid) stress. An analysis of the transcript levels of genes responsible for GSH synthesis, γ‐glutamylcysteine synthetase (Lbγ‐GCS) and glutathione synthetase (LbGS), using qPCR revealed that expression of both genes increased as a function of external metal(loid) concentration. The enzyme activity of both Lbγ‐GCS and LbGS were increased with increase in external Cd and As concentration. Further, the functional role of Lbγ‐GCS and LbGS genes in response to Cd and As stress was studied using their respective yeast mutant strains gsh1Δ and gsh2Δ. The mutant strains successfully expressed the two genes resulting in wild‐type phenotype restoration of Cd and As tolerance. From these results, it was concluded that GSH act as a core component in the mycorrhizal defence system under Cd and As stress for metal(loid) homeostasis and detoxification. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (iAs) is reportedly associated with the increased incidence of type 2 diabetes in the population. Here, we found that iAs exposure significantly decreased the expression of glycolytic genes and glycogen content and increased gluconeogenesis gene levels in C57/BL6J mice. The expression of peroxisome proliferator‐activated receptor γ (PPARγ), and mechanistic target of rapamycin complex 2 (mTORC2) were decreased in the livers of iAs‐treated mice. Furthermore, in iAs‐treated HepG2 cells, we found that PPARγ agonist rosiglitazone (RGS) increased the expression of mTORC2, inhibited autophagy, and improved glucose metabolism. mTORC2 agonist palmitic acid inhibited autophagy and improved glucose metabolism as well as the autophagosome formation inhibitor 3‐methyladenine. Taurine, a natural compound, reversed impaired glucose metabolism and decreased expression of PPARγ and mTORC2 induced by iAs in mice liver and HepG2 cells. These data indicated that taurine administration could ameliorate iAs‐induced insulin resistance through activating PPARγ‐mTORC2 signalling and subsequently inhibiting hepatic autophagy. iAs‐inhibited peroxisome proliferator‐activated receptor γ (PPARγ)‐ mechanistic target of rapamycin complex 2 (mTORC2) signalling and induced autophagy. Activating PPARγ or inhibiting autophagy could rectify insulin resistance (IR) induced by iAs. Taurine improved iAs‐induced IR through activating PPARγ‐mTORC2 signalling and inhibiting autophagy. [ABSTRACT FROM AUTHOR]

Arsenic contamination is a significant public health issue, and kidney is one of the target organ for arsenic‐induced adverse effects. Renal fibrosis is a well‐known pathological stage frequently observed in progressive chronic kidney disease (CKD). Epidemiological studies implicate arsenic exposure to CKD, but the role of arsenic in kidney fibrosis and the underlying mechanism is still unclear. It is in this context that the current study evaluated the effects of long‐term arsenic exposure on the cellular response in morphology, and marker genes expression with respect to fibrosis using human kidney 2 (HK‐2) epithelial cells. Results of this study revealed that in addition to increased growth, HK‐2 cells underwent phenotypic, biochemical and molecular changes indicative of epithelial–mesenchymal transition (EMT) in response to the exposure to arsenic. Most importantly, the arsenic‐exposed cells acquired the pathogenic features of fibrosis as supported by increased expression of markers for fibrosis, such as Collagen I, Fibronectin, transforming growth factor β, and α‐smooth muscle actin. Upregulation of fibrosis associated signaling molecules such as tissue inhibitor of metalloproteinases‐3 and matrix metalloproteinase‐2 as well as activation of AKT was also observed. Additionally, the expression of epigenetic genes (DNA methyltransferases 3a and 3b; methyl‐CpG binding domain 4) was increased in arsenic‐exposed cells. Treatment with DNA methylation inhibitor 5‐Aza‐2′‐dC reversed the EMT properties and restored the level of phospho‐AKT. Together, these data for the first time suggest that long‐term exposure to arsenic can increase the risk of kidney fibrosis. Additionally, our data suggest that the arsenic‐induced fibrotic changes are, at least in part, mediated by DNA methylation and therefore potentially can be reversed by epigenetic therapeutics. Although the epidemiological evidence implicates arsenic exposure to chronic kidney disease, the role of arsenic in kidney fibrosis is still unclear. In this context, the findings of this study, for the first time, revealed that chronic exposure to arsenic can increase the risk of kidney fibrosis. Our data also suggest that the arsenic‐induced fibrotic changes in kidney epithelial cells are, at least in part, mediated by epigenetic mechanism of DNA methylation and therefore potentially can be reversed by epigenetic therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Arsenic is a confirmed human lung carcinogen with estrogenic activity. There are gender differences in the incidence of lung cancer. Estrogen receptors (ER) play an important role in the process of the development of lung cancer. In order to understand the gender difference effects of ER during carcinogenesis of lung induced by arsenic, the effects of arsenic and estrogen receptor antagonist (ICI182780) on expression levels of estrogen receptor beta (ERβ), extracellular regulated protein kinase (ERK1/2) and nuclear factor κB (NF-κB/P65) in type II alveolar epithelial cells (AECII) from different sex ICR fetal mice lung were detected. Results showed that arsenic increased the expression levels of mRNA and protein of ERβ, ERK1/2 and NF-κB/P65, and ICI182780 inhibited the increase. Furthermore, there remains a gender difference in these changes. To summarize, the observations here strongly suggested that estrogen receptor and its mediated signal pathway molecules might have critical roles of the gender difference of incidence of lung cancer in arsenic induced. Highlights • Arsenic induced gender differences of estrogen receptor and its mediated signal pathway in AECII cells from ICR fetal mouse. • The expression of estrogen receptor beta induced by arsenic could be inhibited by estrogen receptor antagonist (ICI 182780). • AECII cells from male and female ICR fetal mouse was used in this study, respectively. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity. [ABSTRACT FROM AUTHOR]

Arsenic (As) contaminates drinking water worldwide and its potential impact on human health has been studied for decades. A number of traditional medicinal plants are used to counteract arsenic's deleterious effects on humans. Phytochemical screening of Caryopteris grata revealed the presence of Quercetin, myricetin, sesquiterpenoids, and spathulenol. The present study was designed to evaluate whether the crude extract of leaves of C. grata inhibited arsenic-induced testicular toxicity in albino BALB/c mice. To examine the effects, mice were divided into five groups (A-E) of 6 mice each: Group A was provided with distilled water and served as a control. Group B mice were given sodium arsenite (NaAsO2 ) at a dose of 10 mg/kg body weight (bw) for 10 days orally. Groups C, D, and E were treated with NaAsO2 plus graded doses of C. grata extract (150, 300, 400 mg/kg bw), respectively. Testicular activities of antioxidant enzymes such as CAT, POD, SOD, GSH, GSR, and serum testosterone levels were significantly (P<0.05) decreased in Group B compared to Group A. C. grata markedly normalized (P<0.05) levels of CAT (0.72 and 0.46 U/mint), POD (0.311 and 0.126 U/mint), SOD (2.11 and 1.33 U/mg protein), GSH (0.679 and 0.284 μmol/g), and GSR (216.11 and 172.25 nmol/min/mg protein), along with testosterone levels (1.18±0.017 and 0.38±0.021 ng/ml) at the tested doses, respectively. Conclusively, the crude extract of C. grata leaves may inhibit both arsenic's adverse effect on male reproductive hormones and testicular oxidative damage in mice. [ABSTRACT FROM AUTHOR]

Although exposure to inorganic arsenic is a health concern, especially in developing foetuses and children, dietary exposure levels among pregnant women and children have not been extensively studied in Japan. To address this shortcoming, we completed a 3-day duplicate diet study for 104 children and 101 pregnant women in two cities, Shimotsuke, Tochigi and Asahikawa, Hokkaido. The levels of intake of total and inorganic arsenic were estimated using the concentrations of total and inorganic arsenic in food and drinking water measured by inductively coupled plasma-mass spectrometry. Estimated intakes of total and inorganic arsenic were 8.46 ± 3.02 [µg/kg BW/week] and 1.74 ± 1.07 [µg/kg BW/week] in pregnant women and 20.07 ± 3.53 [µg/kg BW/week] and 8.46 ± 3.02 [µg/kg BW/week] in children, respectively. Weekly arsenic exposure per kg body weight was significantly higher in children than in pregnant women. Concentrations of total arsenic were generally very low in collected drinking water samples with a small number of exceptions, and drinking water was not considered as a major source of inorganic arsenic exposure in Japan. We found that total and inorganic arsenic intake were higher among frequent consumers of hijiki seaweed, in both pregnant women and children. Although rice and rice products that are staple foods of the Japanese have been reported to be major sources of inorganic arsenic exposure in Japan, our results indicate that hijiki consumption elevates levels of inorganic arsenic in Japanese children and pregnant women. More efforts are necessary to reduce the risk of exposure to inorganic arsenic in populations highly sensitive to environmental pollutants. [ABSTRACT FROM AUTHOR]

Abstract The Wiśniówka rock strip mining area (south-central Poland) with quartzite quarries, acid water bodies and tailings piles is one of the most unique acid mine drainage (AMD) sites throughout the world. This is due to the occurrence of enormous amounts of pyrite unknown in sedimentary formations worldwide. Of the two mineralization zones, one that is the most abundant in arsenical pyrite occurs in the lowermost Upper Cambrian formation of the Podwiśniówka quarry. The As-rich pyritiferous clastic rocks are exposed as a result of deep quartzite extraction during 2013–2014. In addition, the clayey-silty shale interbeds are enriched in rare earth element (REE) minerals. The mining operation left an acidic lake with a pH of about 2.4–2.6 and increased contents of sulfates, metal(loid)s and REE. The Podwiśniówka pyrite-rich waste material was stacked up in many places of the mining area giving rise to strongly acidic spills that jeopardized the neighboring environment. One of these unexplored tailings piles was a source of extremely sulfate- and metal(loid)-rich pools with unusual enrichments in As (up to 1548 mg L−1) and REE (up to 24.84 mg L−1). These distinctly exceeded those previously reported in the Wiśniówka area. A broad scope of geochemical, mineralogical and petrographic methods was used to document these specific textural and mineralogical properties of pyrite facilitating its rapid oxidation. The pyrite oxidation products reacted with REE-bearing minerals releasing these elements into acid water bodies. Statistical methods were employed to connect the obtained tailings pool hydrogeochemical data with those derived from this and the previous studies of the Podwiśniówka and Wiśniówka Duża acid pit lakes. In contrast to metal(loid) profiles, the characteristic shale-normalized REE concentration patterns turned out to be more suitable for solving different AMD issues including provenance of mine waste material in the tailings pile examined. Graphical abstract Image 1 Highlights • Oxidation of pyrite generates highly acidic and metal(loid) enriched waters. • Maximum As concentration determined in water is 1548 mg L−1. • Mining waters contain total rare earth element concentrations up to 24.84 mg L−1. • Tailings pile material influences normalized rare earth element patterns in water. • Weathering of pyrite releases As, Co, Cr, Cu, Ni, and U to waters. Statistical methods were used to link the pollution sources with their receptors. [ABSTRACT FROM AUTHOR]

Abstract In this work, simultaneous biosorption of As(III) and As(V) by Sargassum glaucescens was optimized using multiple response optimizations and Doehlert experimental design. The optimum condition for simultaneous biosorption of As(III) and As(V) were: biosorbent dosage 0.47 g L−1, pH 5.9 and initial concentration 120.34 mg L−1 with maximum overall desirability of 0.94. Different isotherms were fitted to biosorption equilibrium data and the Freundlich isotherm was the most suitable model. Based on thermodynamic study, the biosorption of arsenic species onto alga was endothermic and spontaneous. Kinetic results indicated that intraparticle diffusion model was the best kinetic model. Biosorption capacity of S. glaucescens and other biosorbents were also compared. Graphical abstract fx1 Highlights • Sargassum glaucescens was used for the simultaneous biosorption of As(III) and As(V). • Experimental parameters were optimized using multiple response optimization. • Biosorption capacities were 116.6 and 207.3 mg/g for As(III) and As(V), respectively. • Alga is an eco-friendly biosorbent due to its availability and low operating costs. [ABSTRACT FROM AUTHOR]

Highlights • Arsenic and iron concentrations were removed in microbial fuel cell systems. • Biofilms on electrodes were tolerant to low pH and high concentrations of metals. • pH neutralization favored the formation of Fe minerals, and subsequent As removal. • XRD analysis suggests the precipitation of Amorphous Fe minerals. [ABSTRACT FROM AUTHOR]

Highlights • Bats from WWTW accumulate arsenic in their hair and brain tissue. • Bats from WWTW have low non-enzymatic antioxidant capacity. Abstract Increasing rates of urbanisation cause ubiquitous infrastructures that remove anthropogenic contaminants – particularly Wastewater Treatment Works (WWTWs) – to become stressed, and hence pollute surrounding water systems. Neoromicia nana bats are suitable models to study the effects of pollution in these environments because they exploit abundant pollutant-tolerant chironomid midges that breed at WWTWs, and consequently accumulate metals such as iron, copper and zinc in their livers and kidneys. If these metals persist in their circulatory systems, and cross the blood brain barrier (BBB) they can have adverse effects on critical functions such as flight and echolocation. The aim of this study was to investigate the potential neurological effects on N. nana foraging at WWTWs versus bats at reference sites in Durban, South Africa. Our objectives were to 1) compare trace metal levels in brain and hair samples (as a proxy for circulating metals) between N. nana foraging at WWTWs and reference sites to determine if excess metals pass through the BBB via the circulatory system; and 2) compare biomarkers of neuron function (acetylcholinesterase activity), protection (antioxidant capacity), DNA integrity (DNA fragmentation), lipid integrity (lipid peroxidation) and cell viability (caspase-3 activity) between N. nana foraging at WWTW and reference sites. We found a significantly higher concentration of arsenic in hair (p < 0.05) and brain tissue (p < 0.1) of WWTW bats compared to bats at reference sites. By contrast, acetylcholinesterase activity did not differ in bats among sites and there was no evidence of significant differences in lipid peroxidation, compromised DNA integrity or apoptosis in the brains between WWTW bats and reference site bats. However, total antioxidant capacity was significantly lower in brains of WWTW bats than bats at reference sites suggesting that antioxidant protection may be compromised. Long-term exposure to environmental pollutants at WWTWs may therefore affect cellular processes and protection mechanisms in brains of N. nana bats. It may also affect other mechanisms and functions in the brain such as mitochondrial efficiency and other neurotransmitters but that remains to be tested. [ABSTRACT FROM AUTHOR]

The present study of 28 days was carried out to assess the effect of arsenic and chromium on biomass gain and reproduction parameters (cocoon and hatchling production) of E. eugeniae. The worms were cultured in substrate having different concentrations of arsenic and chromium alongwith control in triplicates. Dose and time dependent decreased in number of adults, cocoon production and hatchling emergence and reduction in growth was observed. In worms exposed to Cr (0.1 ppm), reduction in population (24.66%), body weight (2.44%), cocoon production (47.14%) and hatchling emergence (39.99%) was observed. While As (0.1 ppm) exposure resulted in reduction of adult population (10.66%), body weight (0.24%), cocoon production (37.05%) and hatchling emergence (28.53%) was observed. Cocoon production was observed to be the most sensitive parameter for heavy metal exposure in all treatments. Chromium was observed to be more detrimental to earthworms when compared with arsenic. [ABSTRACT FROM AUTHOR]

Exposure to environmental stressors during susceptible windows of development can result in negative health outcomes later in life, a concept known as the Developmental Origins of Health and Disease (DOHaD). There is a growing body of evidence that exposures to metals early in life (in utero and postnatal) increase the risk of developing adult diseases such as cancer, cardiovascular disease, non-alcoholic fatty liver disease, and diabetes. Of particular concern is exposure to the metalloid arsenic, a drinking water contaminant and worldwide health concern. Epidemiological studies of areas with high levels of arsenic in the drinking water, such as some regions in Chile and Bangladesh, indicate an association between in utero arsenic exposure and the development of adult diseases. Therefore, the need for experimental models to address the mechanism underlining early onset of adult diseases have emerged including the in utero and whole-life exposure models. This review will highlight the epidemiological events and subsequent novel experimental models implemented to study the impact of early life exposure to arsenic on the development of adult diseases. In addition, current research using these models will be discussed as well as possible underlying mechanism for the early onset of disease. Abbreviations: ALT: alanine aminotransferase; AMI: acute myocardial infarction; AST: aspartate aminotransferase; ATSDR: Agency for Toxic Substances and Disease Registry; CVD: cardiovascular disease; DMA: dimethylarsinate; DOHaD: Developmental Origins of Health and Disease; EPA: U.S. Environmental Protection Agency; ER-α: estrogen receptor alpha; HDL: high-density lipoprotein; HOMA-IR: homeostatic model assessment of insulin resistance; iAs: inorganic arsenic; LDL: low-density lipoprotein; MetS: metabolic syndrome; MMA: monomethylarsonate; NAFLD: non-alcoholic fatty liver disease; PND: postnatal day; ppb: parts per billion; ppm: parts per million; SAM: S-adenosylmethionine; USFDA: United States Food and Drug Administration [ABSTRACT FROM AUTHOR]

Abstract Chronic exposure of humans to inorganic arsenic as a potential risk for the incidence of diabetes has received wide attention. However, the biological mechanism through which arsenic plays a role in the development of diabetes is still being evaluated. One of the hallmark of diabetes is the β-cell dysfunction followed by the changes in the insulin secretion. Pancreatic duodenal homeobox 1 (PDX1) has been widely recognized to play crucial role in the β-cell development, survival and its regulation of insulin gene expression. Many of the arsenic mediated cellular affects have been shown to be regulated by miR-2909 in vitro. Our present study provides evidence to reveal that arsenic affects miR-2909 expression in the pancreatic β-cell and this novel miRNA regulates PDX1 transcriptional expression indirectly through genes coding for c-Jun, MafA, PI3K and directly at the translational level by targeting the PDX1 mRNA. We provide further evidence for this miR-2909 RNomics in pancreatic tissue obtained from NOD mice where the expression of miR-2909 was high compared to the control mice. Keeping in view the fact that arsenic is known to cause β-cell dysfunction and most of the cellular effects of arsenic have been shown to be mediated through miR-2909 RNomics, our study revealed that arsenic employs miR-2909 (at low doses) and c-Jun (at high doses) to down regulate PDX1 in order to cause β-cell dysfunction leading to diabetic state. [ABSTRACT FROM AUTHOR]

Background: Studies on low-level As exposure have not found an association with cancer, while increased risks were reported for skin lesions, respiratory and cardiovascular diseases and reproductive outcomes. Prospective observational studies with individual exposure measures are needed to study low-level As exposure effects. In a geothermal area in Southern Tuscany (Italy), characterized by a natural presence of As in drinking water (< 50 µg/l), As urinary concentrations were measured in a survey in 1998 and cohort members were followed to evaluate the effects on health.Methods: Around 900 subjects (20-55 years old) randomly sampled in 4 municipalities of the area (Monte Amiata), have been followed from 1999 to 2015, by hospitalisation and mortality registries. Standardized Hospitalisation Ratios (SHRs) were performed, compared to a reference area. Competing-risks regression models were performed to test the association between As urinary concentration and risk of first hospitalisation.Results: SHRs show various increased risks, more frequently among males. Internal analyses show a positive association between As and skin diseases in the general population, the Hazard Ratio (HR) for 1 µg/l increase of As urinary concentration is 1.06 (90%CI 1.01-1.11) and in males, HR 1.08 (90%CI 1.02-1.14), between As and circulatory system diseases in males, HR 1.03 (90%CI 1.01-1.05).Conclusions: The results suggest an effect on skin diseases and circulatory system diseases and, considering the relative young age of cohort members, they could be considered also as predictive of future severer diseases. [ABSTRACT FROM AUTHOR]

Abstract Background The prevalence of type 2 diabetes (T2D) has nearly doubled since 1980. Elevated body mass index (BMI) is the leading risk factor for T2D, mediated by inflammation and oxidative stress. Arsenic shares similar pathogenic processes, and may contribute to hyperglycemia and β-cell dysfunction. Objectives We assessed a unique situation of individuals living in Northern Chile with data on lifetime arsenic exposure to evaluate the relationship between arsenic and T2D, and investigate possible interactions with BMI. Methods We analyzed data collected from October 2007-December 2010 from an arsenic-cancer case-control study. Information on self-reported weight, height, smoking, diet, and other factors were obtained. Diabetes was defined by self-reported physician-diagnoses or use of hypoglycemic medication. A total of 1053 individuals, 234 diabetics and 819 without known diabetes were included. Results The T2D odds ratio (OR) for cumulative arsenic exposures of 610–5279 and ≥ 5280 μg/L-years occurring 40 years or more before interview were 0.97 (95% CI: 0.66–1.43) and 1.53 (95% CI: 1.05–2.23), respectively. Arsenic-associated T2D ORs were greater in subjects with increased BMIs. For example, the ORs for past cumulative exposures ≥ 5280 μg/L-years was 1.45 (95% CI: 0.74–2.84) in participants with BMIs < 25 kg/m2 but 2.64 (95% CI: 1.14–6.11) in those with BMIs ≥ 30 kg/m2 (synergy index = 2.49, 95% CI: 0.87–7.09). Results were similar when people with cancer were excluded. Conclusions These findings identify increased odds of T2D with arsenic exposure, which are significantly increased in individuals with excess BMI. Highlights • Northern Chile is one of the driest places on earth. • Historical arsenic water measurements allow for estimation of lifetime exposure. • Increased odds of type 2 diabetes with arsenic exposure observed. • Synergistic relationship between arsenic and obesity on type 2 diabetes identified. [ABSTRACT FROM AUTHOR]

Abstract As a nonmutagenic human carcinogen, arsenic (As)'s carcinogenic activity is likely the result of epigenetic changes, particularly alterations in DNA methylation. While increasing studies indicate a potentially important role for timing of As exposure on DNA methylation patterns and the subsequent differential risks for As toxicity and carcinogenesis, there is a lack of research that tackles these critical questions, particularly in human based populations. Here we reported a family-based study including three generations, in which each generation living in the same household had a distinctive timing of As exposure: in adulthood, in utero and during early childhood, and in germlines exposure for grandparents, parents, and grandchildren, respectively. We generated genome-wide DNA methylation data for 18 As-exposed families, nine control families, as well as 18 arsenical skin lesion patients. Our analysis showed that As exposure may leave detectable DNA methylation changes even though exposure occurred decades ago, and the most significant changes of global DNA methylation were observed among patients afflicted with arsenical skin lesions. As exposure across generations shared common differentially methylated DNA loci and regions (744 DML and 15 DMRs) despite the distinctive exposure timing in each generation. Importantly, based on these DML, clustering analysis grouped skin lesion patients together with grandparents in exposed families in the same cluster, separated from grandparents in control families. Further analysis identified a number of DML and several molecular pathways that were significantly distinguished between controls, exposed populations, as well as skin lesion patients. Finally, our exploratory analysis suggested that some of these DML altered by As exposure, may have the potential to be inherited affecting not only those directly exposed but also later generations. Together, our results suggest that common DML and/or DMRs associated with an increased risk for disease development could be identified regardless of when exposure to As occurred during their life span, and thus may be able to serve as biomarkers for identifying individuals at risk for As-induced skin lesions and possible cancers. Highlights • Historical arsenic exposure could leave detectable DNA methylation changes. • Arsenic exposure induces common DNA methylation changes across multiple generations. • Aberrant DNA methylations are enriched in patients with arsenic-induced skin lesions. • Potential for the transgenerational epigenetic impact of arsenic exposure is explored. [ABSTRACT FROM AUTHOR]

Abstract Arsenic is associated with several adverse health outcomes, and people with diabetes may be more susceptible to arsenic. In this study, we found that arsenic levels in some tissues such as liver, kidney, and heart but not lung of type 1 diabetes mellitus (T1DM) mice were higher than in those of normal mice after a single oral dose of arsenic trioxide for 2 h. However, little is known about the molecular mechanism of the increased tissue uptake of trivalent inorganic arsenic in mice with T1DM. This study aimed to investigate the expression of the mammalian arsenic transporters aquaglyceroporins (AQPs) and glucose transporter 1 (GLUT1) in T1DM mice and compare them with those in normal mice. Results showed that the levels of AQP9 and GLUT1 mRNA and protein were higher in T1DM mouse liver than in the normal one. The levels of AQP7 mRNA and protein were higher in T1DM mouse kidney. In the heart, we observed that the levels of AQP7 and GLUT1 mRNA and protein were higher in T1DM mice, but the levels of AQP9 mRNA and protein in the lung had no significant difference between both mice. These results suggested that T1DM may increase the expression of transporters of trivalent inorganic arsenic and thus increase the arsenic uptake in specific tissues. [ABSTRACT FROM AUTHOR]

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org) is a public resource that manually curates the scientific literature to provide content that illuminates the molecular mechanisms by which environmental exposures affect human health. We introduce our new chemical-phenotype module that describes how chemicals can affect molecular, cellular, and physiological phenotypes. At CTD, we operationally distinguish between phenotypes and diseases, wherein a phenotype refers to a nondisease biological event: eg, decreased cell cycle arrest (phenotype) versus liver cancer (disease), increased fat cell proliferation (phenotype) versus morbid obesity (disease), etc. Chemical-phenotype interactions are expressed in a formal structured notation using controlled terms for chemicals, phenotypes, taxon, and anatomical descriptors. Combining this information with CTD’s chemical-disease module allows inferences to be made between phenotypes and diseases, yielding potential insight into the predisease state. Integration of all 4 CTD modules furnishes unique opportunities for toxicologists to generate computationally predictive adverse outcome pathways, linking chemical-gene molecular initiating events with phenotypic key events, adverse diseases, and population-level health outcomes. As examples, we present 3 diverse case studies discerning the effect of vehicle emissions on altered leukocyte migration, the role of cadmium in influencing phenotypes preceding Alzheimer disease, and the connection of arsenic-induced glucose metabolic phenotypes with diabetes. To date, CTD contains over 165 000 interactions that connect more than 6400 chemicals to 3900 phenotypes for 760 anatomical terms in 215 species, from over 19 000 scientific articles. To our knowledge, this is the first comprehensive set of manually curated, literature-based, contextualized, chemical-induced, nondisease phenotype data provided to the public. [ABSTRACT FROM AUTHOR]

Inorganic arsenic is a human carcinogen that can target the prostate. Accumulating evidence suggests arsenic can disrupt stem cell (SC) dynamics during the carcinogenic process. Previous work demonstrated arsenic-transformed prostate epithelial (CAsE-PE) cells can recruit prostate SCs into rapidly acquiring a cancer SC (CSC) phenotype via the secretion of soluble factors. Exosomes are small, membrane-derived vesicles that contain lipids, RNA, and proteins, and actively contribute to cancer initiation and progression when taken up by target cells. Here we hypothesized that CAsE-PE cells are recruiting SCs to a CSC-like phenotype via exosomal signaling. CAsE-PE cells secreted 700% more exosomes than parental RWPE-1 cells. CAsE-PE exosomes were enriched with oncogenic factors, including oncogenes (KRAS, NRAS, VEFGA, MYB, and EGFR), inflammation-related (cyclooxygenase-2, interleukin 1B (IL1B), IL6, transforming growth factor-β, and tumor necrosis factor-A), and apoptosis-related (CASP7, CASP9, and BCL2) transcripts, and oncogenesis-associated microRNAs. When compared with SCs cultured in exosome-depleted conditioned medium (CM), SCs cultured in CM containing CAsE-PE-derived exosomes showed increased (198%) matrix metalloproteinase activity and underwent an epithelial-to-mesenchymal transition in morphology, suggesting an exosome-mediated transformation. KRAS plays an important role in arsenic carcinogenesis. Although KRAS transcript (>24 000%) and protein (866%) levels were elevated in CAsE-PE exosomes, knock-down of KRAS in these cells only partially mitigated the CSC-like phenotype in cocultured SCs. Collectively, these results suggest arsenic impacts both exosomal quantity and cargo. Exosomal KRAS is only minimally involved in this recruitment, and additional factors (eg, cancer-associated miRNAs) likely also play a role. This work furthers our mechanistic understanding of how arsenic disrupts SC dynamics and influences the tumor microenvironment during carcinogenesis. [ABSTRACT FROM AUTHOR]

Arsenic concentrations above 10 μg L −1 were previously found in 89% of ground water sources in six villages of Pakistan. The present study has ascertained the health risks associated with exposure to total arsenic (tAs) and its species in most frequently consumed foods. Inorganic arsenic (iAs) concentrations were found to be 92.5 ± 41.88 μg kg −1 , 79.21 ± 76.42 μg kg −1 , and 116.38 ± 51.38 μg kg −1 for raw rice, cooked rice and wheat respectively. The mean tAs concentrations were 47.47 ± 30.72 μg kg −1 , 71.65 ± 74.7 μg kg −1 , 105 ± 61.47 μg kg −1 . Wheat is therefore demonstrated to be a significant source of arsenic exposure. Dimethylarsinic acid was the main organic species detected in rice, whilst monomethylarsonic acid was only found at trace levels. Total daily intake of iAs exceeded the provisional tolerable daily intake of 2.1 μg kg −1 day −1 body weight in 74% of study participants due to concurrent intake from water (94%), wheat (5%) and raw rice (1%). A significant association between tAs in cooked rice and cooking water resulted in tAs intake 43% higher in cooked rice compared to raw rice. The study suggests that arsenic intake from food, particularly from wheat consumption, holds particular significance where iAs is relatively low in water. Chronic health risks were found to be significantly higher from wheat intake than rice, whilst the risk in terms of acute effects was below the USEPA's limit of 1.0. Children were at significantly higher health risk than adults due to iAs exposure from rice and/or wheat. The dietary exposure of participants to tAs was attributable to staple food intake with ground water iAs <10 μg L −1 , however the preliminary advisory level (200 μg kg −1 ) was achievable with rice consumption of ≤200 g day −1 and compliance with ≤10 μg L −1 iAs in drinking water. Although the daily iAs intake from food was lower than total water intake, the potential health risk from exposure to arsenic and its species still exists and requires exposure control measures. [ABSTRACT FROM AUTHOR]

An arsenic-resistant fungal strain, designated WKC-1, was isolated from a waste roaster pile in a historical tin mine in Cornwall, UK and successfully identified to be Acidomyces acidophilus using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS) proteomic-based biotyping approach. WKC-1 showed considerable resistance to As5+ and Sb5+ where the minimal inhibitory concentration (MIC) were 22500 and 100 mg L−1, respectively, on Czapex-Dox Agar (CDA) medium; it was substantially more resistant to As5+ than the reference strains CBS 335.97 and CCF 4251. In a modified CDA medium containing 0.02 mg L−1 phosphate, WKC-1 was able to remove 70.30% of As5+ (100 mg L−1). Sorption experiment showed that the maximum capacity of As5+ uptake was 170.82 mg g−1 dry biomass as predicted by the Langmuir model. The presence of Sb5+ reduced the As5+ uptake by nearly 40%. Based on the Fourier-transform infrared spectroscopy (FT-IR) analysis, we propose that Sb is competing with As for these sorption sites: OH, NH, CH, SO3 and PO4 on the fungal cell surface. To our knowledge, this is the first report on the impact of other Group 15 elements on the biosorption of As5+ in Acidomyces acidophilus. [ABSTRACT FROM AUTHOR]

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59–172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors. [ABSTRACT FROM AUTHOR]

The carcinogenicity of arsenic has been confirmed in many studies, but its mechanism of action is still unclear. A lymphocyte component of the innate immune system, natural killer (NK) cells are responsible for killing cancer cells. Although inorganic arsenical species are the prevalent forms of arsenic in the environment, monomethylarsonous acid (MMA +3 ) is the major arsenical species found in immune-system cells, in this 30 d drinking-water-exposure study in mice. Therefore, the effect of MMA +3 on NK cells should be studied as a possible contributor to arsenic-induced toxicity at environmental exposure levels. In the mouse drinking-water-exposure model, As +3 induces dose-dependent DNA damage in NK cells. In in vitro studies, MMA +3 inhibited cell growth and induced DNA damage and oxidative stress at low concentration (20 and 50 nM) in isolated mouse NK cells. Strong correlations were found between DNA damage and oxidative stress in MMA +3 -treated mouse NK cells. Even at low concentrations relevant to environmental arsenic exposures, MMA +3 is genotoxic to primary mouse NK cells. [ABSTRACT FROM AUTHOR]

Arsenic (As) pollution in drinking water is a worldwide health risk for humans. We previously showed hearing loss in young people who live in areas of As-polluted drinking water and in young mice orally treated with As. In this study, we epidemiologically examined associations between As levels in toenails and hearing in 145 Bangladeshi aged 12–55 years in 2014. Levels of As in toenails, but not those in urine, were shown to be significantly correlated with hearing loss at 4 kHz [odds ratio (OR) = 4.27; 95% confidence interval (CI): 1.51, 12.05], 8 kHz (OR = 3.91; 95% CI: 1.47, 10.38) and 12 kHz (OR = 4.15; 95% CI: 1.55, 11.09) by multivariate analysis with adjustments for age, sex, smoking and BMI. Our experimental study further showed a significant association between As levels in inner ears and nails (r = 0.8113, p = 0.0014) in mice orally exposed to As, suggesting that As level in nails is a suitable index to assess As level in inner ears. Taken together, the results of our study suggest that As level in nails could be a convenient and non-invasive biomarker for As-mediated hearing loss in humans. [ABSTRACT FROM AUTHOR]

Arsenic and copper, two ubiquitous pollutants, can be oxidative stress inducers when organisms are heavy or chronically exposed, causing adverse effects on digestion and absorption function, resulting in potential losses to poultry husbandry. The present study examined the effects of arsenic trioxide (30 mg/kg)- and copper sulfate (300 mg/kg)-mixed foods, administered alone or in combination for 12 weeks, on various biochemical indices of oxidative stress and immunity in the small intestines of Hy-line chickens. The results showed that for the first four weeks of exposure, both the redox and immune systems were unaffected. Subsequently, exposure to arsenic or copper significantly increased the level of lipid peroxidation (malondialdehyde and ability of anti-hydroxy radical) concomitant with a collapse of the antioxidant system (catalase and glutathione peroxidase), in a time-dependent manner. An increase in the mRNA and protein levels of pro-inflammatory indicators (nuclear factor kappa B, cyclooxygenases-2, tumor necrosis factor-α and prostaglandin E2 synthases) with a definite tendency toward Th1 (Th, helper T cell) cytokines was observed in both arsenic and copper treated chickens. Histologically, the destruction of the biofilm structure and inflammatory infiltrates was observed. Thus, in the intestine, heat shock proteins play protective roles against tissue damage. In some cases, we observed that the tissues of the small intestine were more sensitive to arsenic than to copper. Moreover, co-exposure induced more serious intestinal toxicity than single treatment group, and this mechanism needs further exploration. [ABSTRACT FROM AUTHOR]

Chronic exposure to arsenic, an inducer of oxidative stress, is one of the major causes of male infertility. Therefore, the present study investigated the protective role of Ellagic acid (EA), as a natural antioxidant, against testicular toxicity evoked by arsenic. Thirty-five male Wistar rats were divided into 5 treatment groups. Group 1 served as control, group 2 were orally exposed to sodium arsenite (SA, 10 mg/kg; 21 days), groups 3 and 4 were initially exposed to SA for 7 days and then were treated with both EA (10 and 30 mg/kg) and SA up to 21 days, and group 5 was treated with EA for 14 days. After this period, biochemical and histopathological parameters were evaluated in serum samples and testicular tissue. SA markedly reduced levels of serum testosterone, total antioxidant capacity, reduced glutathione as well as the activity of antioxidant enzymes. Furthermore, SA enhanced levels of malondialdehyde, tumor necrosis factor-α, interleukin-1β and nitric oxide in testes. Treatment with EA was found to reduce testicular arsenic accumulation and oxidative stress parameters. In addition, EA improved the serum testosterone level, testicular antioxidant markers and histological parameters after exposure to SA. EA may emerge as a promising therapeutic option to protect testes from arsenic-induced toxicity through reducing oxidative stress and inflammatory responses. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine arsenic and heavy metal concentrations (lead, mercury, copper, cadmium, zinc, iron and manganese) in snail tissues (foot and digestive gland) obtained from snail farms in Serbia (near urban areas). Snail samples were analysed using atomic absorption spectrophotometry. A total of 730 individual snail samples were included in this study. Snails were packed into plastic bags and transported to the laboratory at the Faculty of Veterinary Medicine, University of Belgrade. The levels of arsenic and mercury in the examined snail tissues were below the detection limit of the analytical method. Concentrations of heavy metals were higher in digestive gland tissues than in foot tissues. [ABSTRACT FROM AUTHOR]

Background Nutrients and genetic polymorphisms participating in one-carbon metabolism may explain interindividual differences in inorganic arsenic (iAs) methylation capacity, which in turn may account for variations in susceptibility to iAs-induced diseases. Objectives 1) To evaluate the association between polymorphisms in five one-carbon metabolism genes ( FOLH1 c.223 T > C, MTHFD1 c.1958 G > A, MTHFR c.665 C > T, MTR c.2756 A > G, and MTRR c.66 A > G) and iAs methylation capacity; 2) To assess if previously reported associations between nutrient intake and iAs methylation capacity are modified by those polymorphisms. Methods Women (n = 1027) exposed to iAs in Northern Mexico were interviewed. Blood and urine samples were collected. Nutrient dietary intake was estimated using a validated food frequency questionnaire. iAs methylation capacity was calculated from urinary iAs species (iAs, monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) measured by high performance liquid chromatography (HPLC-ICP-MS). One polymorphism in each of the five genes evaluated was genotyped by allelic discrimination. Multivariable linear regression models were used to evaluate if genetic polymorphisms modified the associations between iAs methylation capacity parameters and nutrient intake. Results The median (min-max) concentration of total arsenic (TAs) was 20.2 (1.3–2776.0) µg/g creatinine in the study population. Significant interactions for iAs metabolism were only found with FOLH1 c.223 T > C polymorphism and vitamin B12 intake, so that CT and CC genotype carriers had significantly lower %iAs, and higher DMA/iAs with an increased vitamin B12 intake, as compared to carriers of wild-type TT. Conclusion Differences in dietary nutrient intake and genetic variants in one-carbon metabolism may jointly influence iAs methylation capacity. Confirmation of these interactions in other populations is warranted. [ABSTRACT FROM AUTHOR]

Our recent study found that high urinary total arsenic levels were associated with renal cell carcinoma (RCC). Recent studies demonstrated that low circulating adiponectin was related to RCC. The aim of the present study was to explore the relationship between adiponectin gene ( ADIPOQ ) polymorphisms and RCC and investigate whether individuals with an ADIPOQ risk genotype, obesity, and high urinary total arsenic levels have a modified odds ratio (OR) of RCC. A total of 389 RCC patients and 389 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Image-guided biopsy or surgical resection of renal tumors was performed to pathologically verify RCC. Genomic DNA was used to examine the genotypes of the ADIPOQ rs182052, ADIPOQ rs2241766, ADIPOQ rs1501299, and ADIPOQ rs1063539 SNPs by PCR-RFLP. HPLC-HG-AAS was used to measure the concentrations of urinary arsenic species. Participants with the ADIPOQ rs182052 G/A+A/A genotype had a significantly higher OR of RCC compared with those with the ADIPOQ rs182052 G/G genotype. The OR (95% confidence interval [CI]) was 1.70 (1.23–2.36). The OR of RCC for the combined effect of high urinary total arsenic levels and obesity, which was dose-dependent, in individuals with the ADIPOQ rs182052 G/A+A/A genotype was 9.33 (3.85–22.62). The present study found significant combined effects of obesity and the ADIPOQ rs182052 G/A+A/A genotype on the arsenic-related risk of RCC in a population with low arsenic exposure. Arsenic exposure, obesity, and the ADIPOQ rs182052 polymorphism could be predictors of a higher OR of RCC. [ABSTRACT FROM AUTHOR]

Human exposure to trace elements has been a large concern due to the potential health issues. Accordingly, this study aimed to compare the concentrations of arsenic, copper, and zinc in the edible parts of vegetables grown in a mining-agricultural area and in an exclusively agricultural area and to compare the potential human health risks of consuming vegetables from both areas. The consumption habits of the studied population were extracted from the 2010 National Alimentary Survey of Chile. In most cases, the concentrations of trace elements in the edible tissues of vegetables (lettuce, spinach, garlic, onion, carrot, potato, sweet corn, and tomato) were higher in the mining-agricultural area than those in the control area. This difference was most pronounced for leafy vegetables, with arsenic being the trace element of concern. Specifically, the arsenic concentrations in the edible tissues of lettuce and spinach were 8.2- and 5.4-fold higher, respectively, in the mining-agricultural area than in the control area. Lettuce was the vegetable of concern due to its relatively high consumption and relatively high concentration of trace elements. Nevertheless, there was no health risk associated with vegetable consumption in either the mining area or the control area because none of the HQ values surpassed 1.0. [ABSTRACT FROM AUTHOR]

Environmental exposure to arsenic is linked to adverse health effects, including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation-defective, but not wild-type, SNAP29 into clustered regularly interspaced short palindromic repeat (CRISPR)-mediated SNAP29 knockout cells abolishes arsenicmediated autophagy inhibition. These findings reveal a mechanism by which low levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic. [ABSTRACT FROM AUTHOR]

In this study, we sought to investigate the effects of sub-chronic exposure of arsenic (As) and copper (Cu) on oxidative stress, inflammatory response, and mitochondria and death receptor apoptosis pathways in chicken liver. Seventy-two 1-day-old male Hy-line chickens were treated with basal diet, 30 mg/kg arsenic trioxide (As2O3), or/and 300 mg/kg copper sulfate (CuSO4) for 4, 8, and 12 weeks. Study revealed that exposure to As or/and Cu undermined the antioxidant function and increased lipid peroxidation. Worse yet, liver cell swollen, vacuolar degeneration, and inflammatory cell infiltration were accompanied by an increase of the nuclear factor-κB (NF-κB) and its downstream inflammation-related genes after exposure to As or/and Cu. Furthermore, mitochondria swollen and chromatin condensation were found in As and Cu groups, and hepatocyte nuclear membrane rupture and markedly increased (P < 0.01) apoptosis index were observed in As combined with Cu group. Meanwhile, the transcription and protein expression levels of Bcl-2-associated X protein (Bax), p53, cytochrome c (Cyt c), and caspase-3, 8, 9 were upregulated and B cell lymphoma-2 (Bcl-2) was downregulated in As, Cu, and As + Cu groups in the liver tissues (P < 0.05, P < 0.01). Our results indicated that exposure to As or/and Cu could lead to oxidative stress, inflammatory response, and tissue damage and aggravate hepatocellular apoptosis through mitochondrial and death receptor-dependent pathways in chicken liver. And As and Cu showed a possible synergistic relationship in liver damage. [ABSTRACT FROM AUTHOR]

Background: Chronic exposure to inorganic arsenic is an important public health problem and leads to hyperpigmentation, hyperkeratosis, Bowen’s disease and non-melanoma skin cancers in humans. Arsenic keratosis is the most common skin change that is associated with arsenic exposure. It may be an indicator of arsenic induced health hazards. Objective: To determine the needs of patients with arsenic keratosis by evaluating the impact of disease on the quality of life with respect to treatment and provide rehabilitation services. Methods: A total of 47 subjects with arsenic hyperkeratosis, were enrolled in this crossover study. The demographics, smoking status and the presence of chronic diseases diagnosed by the physician were recorded. Weight and height of the subjects were measured and BMI was calculated. The patients were asked to respond the visual analogue scale and EuroQoL-5D scales for assessing the pain and quality of life impairment associated with arsenic hyperkeratosis. Results: In the study group, moderate to severe problems were reported in 78.7% of patients for pain/uncomfortable condition domains and in 91.5% in anxiety/depression domains. Lower quality of life was reported in those with associated chronic disorders, at an advanced age, in thin patients and in those with severe lesions. Conclusion: According to our knowledge, our study is the first one measuring the quality of life in patients with arsenic keratosis in the literature. By this study, we tried to underline the guidance of health services to be developed towards the needs of patients and the need for the development of new health policies by determining the requirements of these patients. [ABSTRACT FROM AUTHOR]

High levels of heavy metals in soils may impose serious impacts on terrestrial organisms. In Brazil, the prevention values for evaluating the ecological risk of these elements are based only on soil chemical analyses and/or on data from ecotoxicological assays performed in soils of temperate regions. However, the attributes of the Brazilian highly-weathered tropical soils can influence the availability of heavy metals for soil fauna, resulting in different toxic values. To provide more accurate ecotoxicological risk values for arsenic (As) in tropical soils, we assessed the impacts of sodium arsenate (Na2HAsO4·7H2O) on the reproduction of earthworms (Eisenia andrei) and collembolans (Folsomia candida), as well as on As bioaccumulation and growth (weight loss) of E. andrei in a tropical artificial soil (TAS) and in an Oxisol. In TAS, As doses reduced the reproduction of the species and promoted weight loss of earthworms. On the other hand, the reproductions of the species as well as the earthworm growth were not altered by As in the Oxisol. The effective concentrations that reduce the reproduction of E. andrei and F. candida by 50 % (EC50) obtained in TAS (22.7 and 26.1 mg of As kg−1 of dry soil, respectively) were lower than those in the Oxisol (>135 mg kg−1, for both species). Although there was As bioaccumulation in earthworms in both soils, the internal concentrations in the earthworms were much higher in the oligochaetes exposed to arsenic in TAS. All these differences were attributed to the higher availability of As in the TAS, compared to the Oxisol, which increased the exposure of the species to the metal. The lower availability in the Oxisol was related to higher contents of type 1:1 silicate minerals and Fe and Al oxides and hydroxides, which strongly bind to As. These results highlight the importance of using tropical soils of humid regions to derive the Brazilian ecological risk prevention values for heavy metals, since the toxicity values are specific for these soils. [ABSTRACT FROM AUTHOR]

Marine and estuarine macroalgae are increasingly used for direct consumption, due to its high content of essential nutrients. However, the toxicity of chemical forms of arsenic (As) present in macroalgae are becoming of great concern and an important research topic. This review will discuss the sophisticated analytical methodologies used for arsenic speciation, as well the investigation of cheaper and fit for purpose methods able to inform about the safety of macroalgae consumption. Furthermore, we will also discuss relevant speciation studies performed by various authors highlighting the methodologies and respective figures of merit for all components of As in macroalgae, not only inorganic As (iAs). Focusing on the steps prior to speciation, such as sample extraction and clean-up, it will be stressed the need to develop certified reference materials (CRMs) in order to assist in the validation of analytical methodologies for As speciation in macroalgae. [ABSTRACT FROM AUTHOR]

Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine-5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids. [ABSTRACT FROM AUTHOR]

A strong correlation between chronic arsenic exposure and neuropsychological disorders leads to a growing concern about a potential risk of arsenic related neurodegeneration. Evidently, brain insulin signaling contributes to physiological effects, including energy homeostasis, and learning and memory. Arsenic has been shown to impair insulin signaling in adipocytes and myocytes, however, this impairment has not yet been explored in neurons. Here we showed that NaAsO 2 caused significant reduction in basal levels of glucose, plasma membrane glucose transporter, GLUT 3 and Akt phosphorylation in differentiated human neuroblastoma SH-SY5Y cells. NaAsO 2 significantly decreased insulin-mediated glucose uptake, as well as GLUT1 and 3 membrane translocation. Furthermore, the ability of insulin to increase Akt phosphorylation, a well-recognized insulin signaling response, was significantly lessened by NaAsO 2 treatment. In addition, the classical tyrosine phosphorylation response of insulin was reduced by NaAsO 2 , as evidenced by reduction of insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1(IRS-1). Moreover, NaAsO 2 lowered the ratio of p110, a catalytic subunit to p85, a regulatory subunit of PI3K causing an imbalance between p110 and p85, the conditions reported to contribute to insulin sensitivity. Additionally, increment of IRS-1 interaction with GSK3β, and p85-PI3K were observed in NaAsO 2 treated cells. These molecular modulations may be mechanistically attributed to neuronal insulin signaling impairment by arsenic. [ABSTRACT FROM AUTHOR]

Maternal arsenic exposure leads to adverse birth outcomes, but the critical window of this susceptibility keeps unclear. To determine whether the associations between maternal arsenic exposure and birth outcomes were trimester-specific, we conducted a birth cohort study of 1390 women from 2014 to 2016 in Wuhan, China. We examined associations between total urinary arsenic concentrations in three trimesters and birth weight, birth length and the risk of small for gestational age (SGA), and the differences of these associations across trimesters using generalized estimating equations. Maternal urinary arsenic concentrations varied across trimesters and were weakly correlated. Arsenic concentrations in the 3rd trimester, but not in the 1st and 2nd trimesters, were associated with birth outcomes. For each doubling of arsenic levels in the 3rd trimester, birth weight was decreased 24.27 g (95% confidence interval (CI): −46.99, −1.55), birth length was decreased 0.13 cm (95% CI: −0.22, −0.04), and the risk for SGA birth was increased 25% (95% CI: 1.03, 1.49). Further, stratified analyses indicated that these associations were only observed in female infants. Our findings indicate maternal arsenic levels in the 3rd trimester seemed to have significant impacts on birth outcomes, and also emphasize the public health interventions relevance to arsenic exposure in late pregnancy. [ABSTRACT FROM AUTHOR]

Background Inorganic arsenic (As) is methylated via one carbon metabolism (OCM) to mono- and dimethylated arsenicals (MMA and DMA), facilitating urinary excretion. Hyperhomocysteinemia (HHcys), a marker of impaired OCM, is a risk factor for As-induced skin lesions, but the influences of single nucleotide polymorphisms (SNPs) in OCM genes on Hcys, As metabolism and skin lesion risk is unclear. Objectives To (i) explore genetic sources of Hcys and the causal role of HHcys in As-induced skin lesion development using OCM genetic proxies for HHcys and (ii) identify OCM SNPs associated with urinary As metabolite proportions and/or skin lesion incidence. Methods We conducted a case-control study nested in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh which 876 incident skin lesion cases were matched to controls on sex, age, and follow-up time. We measured serum Hcys, urinary As metabolites, and 26 SNPs in 13 OCM genes. Results Serum Hcys and urinary %DMA were independently associated with increased and decreased odds of skin lesions, respectively. The T allele of MTHFR 677 C ➔ T (rs1801133) was associated with HHcys, higher %MMA, and lower %DMA, but not with skin lesions. Interactions between SNPs and water As on skin lesion risk were suggestive for three variants: the G allele of MTRR rs1801394 and T allele of FOLR1 rs1540087 were associated with lower odds of skin lesions with lower As (≤50 μg/L), and the T allele of TYMS rs1001761 was associated with higher odds of skin lesions with higher As. Conclusions While HHcys and decreased %DMA were associated with increased risk for skin lesions, and MTHFR 677 C ➔ T was a strong predictor of HHcys, MTHFR 677 C ➔ T was not associated with skin lesion risk. Future studies should explore (i) non-OCM and non-genetic determinants of Hcys and (ii) if genetic findings are replicated in other As-exposed populations, mechanisms by which OCM SNPs may influence the dose-dependent effects of As on skin lesion risk. [ABSTRACT FROM AUTHOR]