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Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes.
Bozack, AK, Boileau, P, Wei, L, Hubbard, AE, Sillé, FCM, Ferreccio, C, Acevedo, J, Hou, L, Ilievski, V, Steinmaus, CM, et al
Environmental health : a global access science source. 2021;(1):79
Abstract
BACKGROUND Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS. METHODS DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs. RESULTS In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate. CONCLUSIONS Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.
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Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects.
Stýblo, M, Venkatratnam, A, Fry, RC, Thomas, DJ
Archives of toxicology. 2021;(5):1547-1572
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Abstract
The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAsIII and DMAsIII in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAsIII and DMAsIII in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAsIII and DMAsIII formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.
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A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.
Castriota, F, Rieswijk, L, Dahlberg, S, La Merrill, MA, Steinmaus, C, Smith, MT, Wang, JC
Environmental health perspectives. 2020;(1):16001
Abstract
BACKGROUND The prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear. OBJECTIVES We conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development. METHODS We explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings. RESULTS While several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic β-cell dysfunction. DISCUSSION This review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517.
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Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair.
Tam, LM, Price, NE, Wang, Y
Chemical research in toxicology. 2020;(3):709-726
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Abstract
Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.
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Response of cytokinins and nitrogen metabolism in the fronds of Pteris sp. under arsenic stress.
Pavlíková, D, Zemanová, V, Pavlík, M, Dobrev, PI, Hnilička, F, Motyka, V
PloS one. 2020;(5):e0233055
Abstract
Given the close relationship between cytokinins (CKs), photosynthesis and nitrogen metabolism, this study assessed the effect of arsenic (As) contamination on these metabolic components in the As-hyperaccumulators Pteris cretica L. var. Albo-lineata (Pc-A) and var. Parkerii (Pc-P) as well as the As-non-hyperaccumulator Pteris straminea Mett. ex Baker (Ps). The ferns were cultivated in a pot experiment for 23 weeks in soil spiked with As at the levels 20 and 100 mg·kg-1. For the purpose of this study, the CKs were placed into five functionally different groups according to their structure and physiological roles: bioactive forms (bCKs; CK free bases); inactive or weakly active forms (dCKs; CK N-glucosides); transport forms (tCKs; CK ribosides); storage forms (sCKs; O-glucosides); and primary products of CK biosynthesis (ppbCKs; CK nucleotides). An important finding was higher CKs total content, accumulation of sCKs and reduction of dCKs in As-hyperaccumulators in contrast to non-hyperaccumulator ferns. A significant depletion of C resources was confirmed in ferns, especially Ps, which was determined by measuring the photosynthetic rate and chlorophyll fluorescence. A fluorescence decrease signified a reduction in the C/N ratio, inducing an increase of bioactive CKs forms in Pc-P and Ps. The impact of As on N utilization was significant in As-hyperaccumulators. The glutamic acid/glutamine ratio, an indicator of primary N assimilation, diminished in all ferns with increased As level in the soil. In conclusion, the results indicate a large phenotypic diversity of Pteris species to As and suggest that the CKs composition and the glutamic acid/glutamine ratio can be used as a tool to diagnose As stress in plants.
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Micronucleus assay for monitoring the genotoxic effects of arsenic in human populations: A systematic review of the literature and meta-analysis.
Dong, J, Wang, JQ, Qian, Q, Li, GC, Yang, DQ, Jiang, C
Mutation research. Reviews in mutation research. 2019;:1-10
Abstract
The micronucleus (MN) assay has been used to determine the potential genotoxic effects in human populations exposed to arsenic. Some of these studies found an increase in MN frequency among exposed individuals, but others found no increase or inconclusive results. Thus, the main purpose of this current study was to investigate whether MN can be used as a biomarker for the arsenic exposure, as well as whether or not the different cell types that have been used to monitor MN frequency differ in their sensitivity to upon arsenic exposure. A systematic literature review was conducted followed by a meta-analysis. The review identified 25 useful studies with data from 3232 exposed individuals (15 studies assaying lymphocytes, 16 assaying buccal cells, and 9 assaying urothelial cells), with 18 studies measuring drinking water exposure, 5 measuring occupational exposure, one measuring coal burning, and one measuring dietary exposure. The meta-analysis indicated that the overall estimates of Mean Ratio (MR, defined as the mean value of the response in the exposed group divided by the mean value of the response in the reference group) were 2.95 (95% confidence interval (CI): 2.00 to 4.35), 2.36 (95% CI: 1.77 to 3.15), and 2.82 (95% CI: 1.86 to 4.28) for MN assays conducted with lymphocytes, buccal cells, and urothelial cells in the MN assay, respectively. Subgroup analysis showed that when the exposure method was drinking water, the MN frequencies increased significantly in lymphocytes (MR = 3.59, 95% CI: 2.30 to 5.60), in buccal cells (MR = 2.35, 95% CI: 1.76 to 3.15), and in urothelial cells (MR = 3.16, 95% CI: 2.02 to 4.97). However, when the exposure method was the occupational setting or others, the MN detection using the three types of cells did not find significant differences between groups. Subgroup analysis also showed that lymphocyte MN frequencies increased significantly in both routine-culture MN assays (MR = 2.88, 95% CI: 1.15 to 7.24) and cytokinesis-block MN assays (MR = 2.89, 95% CI: 1.84 to 4.55). The performance of the MN assay with different types of cells was also compared, but no significant differences were found. Therefore, our analysis indicates that MN can be used as an effective biomarker for monitoring arsenic-exposed populations, and that MN assays conducted with lymphocytes, buccal cells, and urothelial cells do not differ in their ability to detect the genetic damage from arsenic.
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Heavy metals in food crops: Health risks, fate, mechanisms, and management.
Rai, PK, Lee, SS, Zhang, M, Tsang, YF, Kim, KH
Environment international. 2019;:365-385
Abstract
Food security is a high-priority issue for sustainable global development both quantitatively and qualitatively. In recent decades, adverse effects of unexpected contaminants on crop quality have threatened both food security and human health. Heavy metals and metalloids (e.g., Hg, As, Pb, Cd, and Cr) can disturb human metabolomics, contributing to morbidity and even mortality. Therefore, this review focuses on and describes heavy metal contamination in soil-food crop subsystems with respect to human health risks. It also explores the possible geographical pathways of heavy metals in such subsystems. In-depth discussion is further offered on physiological/molecular translocation mechanisms involved in the uptake of metallic contaminants inside food crops. Finally, management strategies are proposed to regain sustainability in soil-food subsystems.
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Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.
Bozack, AK, Hall, MN, Liu, X, Ilievski, V, Lomax-Luu, AM, Parvez, F, Siddique, AB, Shahriar, H, Uddin, MN, Islam, T, et al
The American journal of clinical nutrition. 2019;(2):380-391
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Abstract
BACKGROUND Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. OBJECTIVE This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. DESIGN In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. RESULTS Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. CONCLUSIONS The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.
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On the Use of Hair Analysis for Assessing Arsenic Intoxication.
Katz, SA
International journal of environmental research and public health. 2019;(6)
Abstract
Correlations between the concentrations of arsenic in scalp hair and in drinking water as well as in blood and/or urine have been reported. These correlations clearly show exposure⁻absorption⁻excretion relationships. In addition, arsenic metabolites such as monomethylarsonic acid and dimethylarsinic acid have been identified and quantified in these tissues and fluids, leaving little doubt that elevated levels of arsenic in the hair can reflect systemic arsenic intoxication. Consequently, hair analysis has potential merit as a screening procedure for poisoning by arsenic. However, questions regarding the exogenous versus the endogenous deposition of arsenic in the hair, and uncertainties about the normal level of arsenic in the hair remain unresolved. Pending their resolution, the determination of arsenic in hair should remain a screening tool, and clinical signs and symptoms should be employed to complete the diagnosis of arsenic poisoning.
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Isolation, Characterization, and Metal Response of Novel, Acid-Tolerant Penicillium spp. from Extremely Metal-Rich Waters at a Mining Site in Transbaikal (Siberia, Russia).
Glukhova, LB, Frank, YA, Danilova, EV, Avakyan, MR, Banks, D, Tuovinen, OH, Karnachuk, OV
Microbial ecology. 2018;(4):911-924
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Abstract
The role of fungi in metal cycling in acidic environments has been little explored to date. In this study, two acid-tolerant and metal-resistant Penicillium isolates, strains ShG4B and ShG4C, were isolated from a mine site in the Transbaikal area of Siberia (Russia). Waters at the mine site were characterized by extremely high metal concentrations: up to 18 g l-1 Fe and > 2 g l-1 each of Cu, Zn, Al, and As. Both isolates were identified as Penicillium spp. by phylogenetic analyses and they grew well in Czapek medium acidified to pH 2.5. Resistance to Cu, Cd, Ni, Co, and arsenate was in the range of 1-10 g l-1. Further experiments with Penicillium strain ShG4C demonstrated that growth in Cu-containing media was accompanied by the precipitation of Cu-oxalate (moolooite) and the formation of extracellular vesicles enriched in Cu on the mycelia. Vesicles were greatly reduced in size in Cd-containing media and were not formed in the presence of Ni or Co. Cd-oxalate was detected as a crystalline solid phase in Cd-exposed mycelia. Hydrated Ni-sulfate (retgersite) and Co-sulfate (bieberite) were detected in mycelia grown in the presence of Ni and Co, respectively. The results demonstrated that acid-tolerant and metal-resistant Penicillium constitute a component in extremophilic microbiomes, contributing to organic matter breakdown and formation of secondary solid phases at pH ranges found in acid rock drainage.