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Karin Broberg - One of the best experts on this subject based on the ideXlab platform.
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Predicted AS3MT Proteins Methylate Arsenic and Support Two Major Phylogenetic AS3MT Groups.
Chemical research in toxicology, 2020Co-Authors: Jesper Torbøl Pedersen, Jessica De Loma, Michael Levi, Michael G. Palmgren, Karin BrobergAbstract:Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, methylate inorganic arsenic to mono-, di-, and trimethylated arsenic metabolites, which the organism can excrete. In humans and other eukaryotic organisms, the arsenite methyltransferase (AS3MT) protein methylates arsenite. AS3MT sequences from eukaryotic organisms group phylogenetically with predicted eubacterial AS3MT sequences, which has led to the suggestion that AS3MT was acquired from eubacteria by multiple events of horizontal gene transfer. In this study, we evaluated whether 55 (out of which 47 were predicted based on protein sequence similarity) sequences encoding putative AS3MT orthologues in 47 species from different kingdoms can indeed methylate arsenic. Fifty-three of the proteins showed arsenic methylating capacity. For example, the predicted AS3MT of the human gut bacterium Faecalibacterium prausnitzii methylated arsenic efficiently. We performed a kinetic analysis of 14 AS3MT proteins representing two phylogenetically distinct clades (Group 1 and 2) that each contain both eubacterial and eukaryotic sequences. We found that animal and bacterial AS3MTs in Group 1 rarely produce trimethylated arsenic, whereas Hydra vulgaris and the bacterium Rhodopseudomonas palustris in Group 2 produce trimethylated arsenic metabolites. These findings suggest that animals during evolution have acquired different arsenic methylating phenotypes from different bacteria. Further, it shows that humans carry two bacterial systems for arsenic methylation: one bacterium-derived AS3MT from Group 1 incorporated in the human genome and one from Group 2 in F. prausnitzii present in the gut microbiome.
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Arsenite methyltransferase (AS3MT) polymorphisms and arsenic methylation in children in rural Bangladesh.
Toxicology and applied pharmacology, 2018Co-Authors: Jessica De Loma, Rubhana Raqib, Marie Vahter, Helena Skröder, Karin BrobergAbstract:Abstract Background Arsenic methylation efficiency, a susceptibility factor for arsenic toxicity, is in adults partly explained by variation in arsenite methyltransferase (AS3MT) gene. Little is known about the role of AS3MT for children's arsenic methylation. Objectives Evaluating associations between AS3MT polymorphisms and children's arsenic methylation efficiency. Methods Bangladeshi children's arsenic exposure (9-years; n = 424) was assessed as sum urinary concentration of inorganic arsenic (iAs) and its metabolites (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) using HPLC-HG-ICPMS. Arsenic methylation efficiency was assessed by the individual metabolite fractions (%). AS3MT polymorphisms (rs7085104, rs3740400, rs3740393 and rs1046778) were genotyped using TaqMan SNP genotyping assays. Results We found higher %iAs and %MMA, and lower %DMA in urine, among rs1046778 TT carriers (median 8.8%, 9.6% and 81.1% for iAs, MMA and DMA, respectively), compared to CC carriers (median 7.0%, 8.3% and 84.9%). These associations were significant in multivariable-adjusted linear regression models: B-coefficients for TT vs CC were 1.26, 1.33 and −2.59 for iAs, MMA and DMA, respectively. Effect estimates were slightly stronger when restricting the analyses to children with urinary arsenic ≥58 μg/L (reducing the impact of ingested DMA). Estimates in girls were slightly stronger than in boys, although there were no significant differences between boys and girls. No clear associations were found for the other AS3MT polymorphisms. Conclusions One out of four AS3MT polymorphisms, previously associated with arsenic methylation in adults, was associated with arsenic methylation in children. Thus, AS3MT variation seems to influence arsenic methylation efficiency in children to a lesser extent than in adults.
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Human Adaptation to Arsenic-Rich Environments
Molecular biology and evolution, 2015Co-Authors: Carina M. Schlebusch, Karin Engström, Marie Vahter, Lucie M. Gattepaille, Mattias Jakobsson, Karin BrobergAbstract:Adaptation drives genomic changes; however, evidence of specific adaptations in humans remains limited. We found that inhabitants of the northern Argentinean Andes, an arid region where elevated arsenic concentrations in available drinking water is common, have unique arsenic metabolism, with efficient methylation and excretion of the major metabolite dimethylated arsenic and a less excretion of the highly toxic monomethylated metabolite. We genotyped women from this population for 4,301,332 single nucleotide polymorphisms (SNPs) and found a strong association between the AS3MT (arsenic [+3 oxidation state] methyltransferase) gene and mono- and dimethylated arsenic in urine, suggesting that AS3MT functions as the major gene for arsenic metabolism in humans. We found strong genetic differentiation around AS3MT in the Argentinean Andes population, compared with a highly related Peruvian population (FST = 0.014) from a region with much less environmental arsenic. Also, 13 of the 100 SNPs with the highest genome-wide Locus-Specific Branch Length occurred near AS3MT. In addition, our examination of extended haplotype homozygosity indicated a selective sweep of the Argentinean Andes population, in contrast to Peruvian and Colombian populations. Our data show that adaptation to tolerate the environmental stressor arsenic has likely driven an increase in the frequencies of protective variants of AS3MT, providing the first evidence of human adaptation to a toxic chemical.
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genetic variation in arsenic 3 oxidation state methyltransferase AS3MT arsenic metabolism and risk of basal cell carcinoma in a european population
Environmental and Molecular Mutagenesis, 2015Co-Authors: Karin Engström, Marie Vahter, Walter Goessler, Tony Fletcher, Giovanni Leonardi, Eugen Gurzau, Kvetoslava Koppova, Peter Rudnai, Rajiv Kumar, Karin BrobergAbstract:Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N = 529) and controls (N = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P = 0.032) and %MMA (P = 0.020) in urine, and higher %DMA (P = 0.033); individuals with the CGCT haplotype had higher %MMA (P < 0.001) and lower %DMA (P < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from <0.001 to 0.082), except for the CCTC haplotype (OR 1.0, CI 0.9-1.2, P value 0.85). The results suggest that carriage of AS3MT haplotypes associated with less-efficient arsenic methylation, or lack of AS3MT haplotypes associated with a more-efficient arsenic methylation, results in higher risk of arsenic-related BCC. The fact that AS3MT haplotype status modified arsenic metabolism, and in turn the arsenic-related BCC risk, supports a causal relationship between low-level arsenic exposure and BCC.
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Genetic variation in arsenic (+3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population
Environmental and molecular mutagenesis, 2014Co-Authors: Karin Engström, Marie Vahter, Walter Goessler, Tony Fletcher, Giovanni Leonardi, Eugen Gurzau, Kvetoslava Koppova, Peter Rudnai, Rajiv Kumar, Karin BrobergAbstract:Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N = 529) and controls (N = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P = 0.032) and %MMA (P = 0.020) in urine, and higher %DMA (P = 0.033); individuals with the CGCT haplotype had higher %MMA (P < 0.001) and lower %DMA (P < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from
Miroslav Styblo - One of the best experts on this subject based on the ideXlab platform.
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Diverse genetic backgrounds play a prominent role in the metabolic phenotype of CC021/Unc and CC027/GeniUNC mice exposed to inorganic arsenic.
Toxicology, 2021Co-Authors: Christelle Douillet, Rebecca C. Fry, Immaneni Lakshmi Meenakshi, Fernando Pardo-manuel De Villena, Miroslav StybloAbstract:Abstract Arsenic methyltransferase (AS3MT) is the key enzyme in the pathway for the methylation of inorganic arsenic (iAs), a potent human carcinogen and diabetogen. AS3MT converts iAs to mono- and dimethylated arsenic species (MAs, DMAs) that are excreted mainly in urine. Polymorphisms in AS3MT is a key genetic factor affecting iAs metabolism and toxicity. The present study examined the role of AS3MT polymorphisms in the susceptibility to the diabetogenic effects of iAs exposure using two Collaborative Cross mouse strains, CC021/Unc and CC027/GeniUnc, carrying different AS3MT haplotypes. Male mice from the two strains were exposed to iAs in drinking water (0, 0.1 or 50 ppm) for 11 weeks. Blood glucose and plasma insulin levels were measured after 6 -h fasting and 15 min after i.p. injection of glucose. Body composition was determined using magnetic resonance imaging. To asses iAs metabolism, the concentrations of iAs, MAs and DMAs were measured in urine. The results show that CC021 mice, both iAs-exposed and controls, had higher body fat percentage, lower fasting blood glucose, higher fasting plasma insulin, and were more insulin resistant than their CC027 counterparts. iAs exposure had a minor effect on diabetes indicators and only in CC027 mice. Blood glucose levels 15 min after glucose injection were significantly higher in CC027 mice exposed to 0.1 ppm iAs than in control mice. No significant differences were found in the concentrations or proportions of arsenic species in urine of CC021 and CC027 mice at the same exposure level. These results suggest that the differences in AS3MT haplotypes did not affect the profiles of iAs or its metabolites in mouse urine. The major differences in diabetes indicators were associated with the genetic backgrounds of CC021 and CC027 mice. The effects of iAs exposure, while minor, were genotype- and dose-dependent.
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arsenic metabolism in mice carrying a borcs7 AS3MT locus humanized by syntenic replacement
Environmental Health Perspectives, 2020Co-Authors: Beverly H. Koller, David J. Thomas, Christelle Douillet, John N. Snouwaert, Leigh A. Jania, Hisham Elmasri, Miroslav StybloAbstract:Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risk...
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Arsenic Metabolism in Mice Carrying a BORCS7/AS3MT Locus Humanized by Syntenic Replacement.
Environmental health perspectives, 2020Co-Authors: Beverly H. Koller, David J. Thomas, Christelle Douillet, John N. Snouwaert, Leigh A. Jania, Hisham El-masri, Miroslav StybloAbstract:Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risk...
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Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure
Archives of Toxicology, 2017Co-Authors: Christelle Douillet, R. Jesse Saunders, Madelyn C. Huang, Ellen N. Dover, Chongben Zhang, Miroslav StybloAbstract:Susceptibility to toxic effects of inorganic arsenic (iAs) depends, in part, on efficiency of iAs methylation by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT -knockout (KO) mice that cannot efficiently methylate iAs represent an ideal model to study the association between iAs metabolism and adverse effects of iAs exposure, including effects on metabolic phenotype. The present study compared measures of glucose metabolism, insulin resistance and obesity in male and female wild-type (WT) and AS3MT -KO mice during a 24-week exposure to iAs in drinking water (0.1 or 1 mg As/L) and in control WT and AS3MT -KO mice drinking deionized water. Results show that effects of iAs exposure on fasting blood glucose (FBG) and glucose tolerance in either WT or KO mice were relatively minor and varied during the exposure. The major effects were associated with AS3MT KO. Both male and female control KO mice had higher body mass with higher percentage of fat than their respective WT controls. However, only male KO mice were insulin resistant as indicated by high FBG, and high plasma insulin at fasting state and 15 min after glucose challenge. Exposure to iAs increased fat mass and insulin resistance in both male and female KO mice, but had no significant effects on body composition or insulin resistance in WT mice. These data suggest that AS3MT KO is associated with an adverse metabolic phenotype that is characterized by obesity and insulin resistance, and that the extent of the impairment depends on sex and exposure to iAs, including exposure to iAs from mouse diet.
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Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice
Archives of toxicology, 2016Co-Authors: Madelyn C. Huang, Christelle C. Douillet, Miroslav StybloAbstract:Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that AS3MT knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine. The present study used targeted analysis to investigate the KO-associated changes in PC profiles in the liver, the site of PC synthesis. Results show that AS3MT KO has a systemic effect on PC metabolism and that this effect is sex dependent.
David J. Thomas - One of the best experts on this subject based on the ideXlab platform.
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arsenic metabolism in mice carrying a borcs7 AS3MT locus humanized by syntenic replacement
Environmental Health Perspectives, 2020Co-Authors: Beverly H. Koller, David J. Thomas, Christelle Douillet, John N. Snouwaert, Leigh A. Jania, Hisham Elmasri, Miroslav StybloAbstract:Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risk...
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Arsenic Metabolism in Mice Carrying a BORCS7/AS3MT Locus Humanized by Syntenic Replacement.
Environmental health perspectives, 2020Co-Authors: Beverly H. Koller, David J. Thomas, Christelle Douillet, John N. Snouwaert, Leigh A. Jania, Hisham El-masri, Miroslav StybloAbstract:Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risk...
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AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility.
Environmental research, 2014Co-Authors: Ray Antonelli, David J. Thomas, Kan Shao, Reeder Sams, John CowdenAbstract:Abstract Background Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations. Objective To examine the impact of genotypic polymorphisms on iAs metabolism. Methods We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration. Results In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism. Discussion Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs. Conclusions Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility.
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Methylation of arsenic by recombinant human wild-type arsenic (+3 oxidation state) methyltransferase and its methionine 287 threonine (M287T) polymorph: Role of glutathione.
Toxicology and applied pharmacology, 2012Co-Authors: Lan Ding, David J. Thomas, Zuzana Drobna, R. Jesse Saunders, Felecia S. Walton, Pencheng Xun, Miroslav StybloAbstract:Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the pathway for methylation of arsenicals. A common polymorphism in the AS3MT gene that replaces a threonyl residue in position 287 with a methionyl residue (AS3MT/M287T) occurs at a frequency of about 10% among populations worldwide. Here, we compared catalytic properties of recombinant human wild-type (wt) AS3MT and AS3MT/M287T in reaction mixtures containing S-adenosylmethionine, arsenite (iAs(III)) or methylarsonous acid (MAs(III)) as substrates and endogenous or synthetic reductants, including glutathione (GSH), a thioredoxin reductase (TR)/thioredoxin (Trx)/NADPH reducing system, or tris (2-carboxyethyl) phosphine hydrochloride (TCEP). With either TR/Trx/NADPH or TCEP, wtAS3MT or AS3MT/M287T catalyzed conversion of iAs(III) to MAs(III), methylarsonic acid (MAs(V)), dimethylarsinous acid (DMAs(III)), and dimethylarsinic acid (DMAs(V)); MAs(III) was converted to DMAs(III) and DMAs(V). Although neither enzyme required GSH to support methylation of iAs(III) or MAs(III), addition of 1mM GSH decreased K(m) and increased V(max) estimates for either substrate in reaction mixtures containing TR/Trx/NADPH. Without GSH, V(max) and K(m) values were significantly lower for AS3MT/M287T than for wtAS3MT. In the presence of 1mM GSH, significantly more DMAs(III) was produced from iAs(III) in reactions catalyzed by the M287T variant than in wtAS3MT-catalyzed reactions. Thus, 1mM GSH modulates AS3MT activity, increasing both methylation rates and yield of DMAs(III). AS3MT genotype exemplified by differences in regulation of wtAS3MT and AS3MT/M287T-catalyzed reactions by GSH may contribute to differences in the phenotype for arsenic methylation and, ultimately, to differences in the disease susceptibility in individuals chronically exposed to inorganic arsenic.
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Formation of methylated oxyarsenicals and thioarsenicals in wild-type and arsenic (+3 oxidation state) methyltransferase knockout mice exposed to arsenate
Analytical and bioanalytical chemistry, 2012Co-Authors: Hua Naranmandura, Kanwal Rehman, David J. ThomasAbstract:Arsenic (+3 oxidation state) methyltransferase (AS3MT) plays a central role in the enzymatically catalyzed conversion of inorganic arsenic into methylated metabolites. Most studies of the metabolism and disposition of arsenicals following exposure to inorganic arsenic focus on the formation and fate of methylated oxyarsenicals. However, recent research has shown methylated thioarsenicals to be another important class of metabolites of inorganic arsenic. Here, we report on the presence of methylated oxy- and thioarsenicals in urine and liver from wild-type mice that efficiently methylate inorganic arsenic and from AS3MT knockout mice that lack arsenic methyltransferase activity. Following a single oral dose of 0.5 mg of arsenic as arsenate/kg body weight, urine from wild-type mice contained methylated oxyarsenicals and unknown arsenicals. Further analysis identified one unknown arsenical in urine of wild-type mice as dimethylmonothioarsinic acid. In addition, another unknown arsenical in urine of wild-type mice that occurred in the urine of about 20 % of arsenate-treated mice. The presence of low levels of methylated arsenicals in liver digests of AS3MT knockout mice may reflect the activity of other methyltransferases or the absorption of methylated arsenicals formed by the microbiota of the gastrointestinal tract. The lack of methylated thioarsenicals in urine of AS3MT knockout mice suggests a close link between the processes that form methylated oxy- and thioarsenicals.
Zuzana Drobna - One of the best experts on this subject based on the ideXlab platform.
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Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure
Archives of Toxicology, 2017Co-Authors: Madelyn C. Huang, Zuzana Drobna, R. Jesse Saunders, Christelle Douillet, Kejun Zhou, Wenlian Chen, Joseph A. Galanko, Elizabeth Martin, Rebecca C. Fry, Wei JiaAbstract:Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered AS3MT expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. AS3MT -knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and AS3MT -KO (KO) C57BL/6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate ( l -sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that AS3MT KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that AS3MT may be involved in other cellular processes beyond iAs methylation.
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association between variants in arsenic 3 oxidation state methyltranserase AS3MT and urinary metabolites of inorganic arsenic role of exposure level
Toxicological Sciences, 2016Co-Authors: Zuzana Drobna, Saroja V Voruganti, Keri Barron, Carmen Gonzalezhorta, Blanca Sanchezramirez, Lourdes Ballinascasarrubias, Roberto Hernandez Ceron, Damian Viniegra Morales, Francisco Baeza A Terrazas, Maria C IshidaAbstract:Abstract Variants in AS3MT, the gene encoding arsenic (+3 oxidation state) methyltranserase, have been shown to influence patterns of inorganic arsenic (iAs) metabolism. Several studies have suggested that capacity to metabolize iAs may vary depending on levels of iAs exposure. However, it is not known whether the influence of variants in AS3MT on iAs metabolism also vary by level of exposure. We investigated, in a population of Mexican adults exposed to drinking water As, whether associations between 7 candidate variants in AS3MT and urinary iAs metabolites were consistent with prior studies, and whether these associations varied depending on the level of exposure. Overall, associations between urinary iAs metabolites and AS3MT variants were consistent with the literature. Referent genotypes, defined as the genotype previously associated with a higher percentage of urinary dimethylated As (DMAs%), were associated with significant increases in the DMAs% and ratio of DMAs to monomethylated As (MAs), and significant reductions in MAs% and iAs%. For 3 variants, associations between genotypes and iAs metabolism were significantly stronger among subjects exposed to water As >50 versus ≤50 ppb (water As X genotype interaction P < .05). In contrast, for 1 variant (rs17881215), associations were significantly stronger at exposures ≤50 ppb. Results suggest that iAs exposure may influence the extent to which several AS3MT variants affect iAs metabolism. The variants most strongly associated with iAs metabolism-and perhaps with susceptibility to iAs-associated disease-may vary in settings with exposure level.
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Oxidation state specific analysis of arsenic species in tissues of wild-type and arsenic (+3 oxidation state) methyltransferase-knockout mice.
Journal of environmental sciences (China), 2016Co-Authors: Jenna M. Currier, Zuzana Drobna, Christelle Douillet, Miroslav StybloAbstract:Arsenic methyltransferase (AS3MT) catalyzes the conversion of inorganic arsenic (iAs) to its methylated metabolites, including toxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII). Knockout (KO) of AS3MT was shown to reduce the capacity to methylate iAs in mice. However, no data are available on the oxidation states of As species in tissues of these mice. Here, we compare the oxidation states of As species in tissues of male C57BL/6 AS3MT-KO and wild-type (WT) mice exposed to arsenite (iAsIII) in drinking water. WT mice were exposed to 50mg/L As and AS3MT-KO mice that cannot tolerate 50mg/L As were exposed to 0, 15, 20, 25 or 30mg/L As. iAsIII accounted for 53% to 74% of total As in liver, pancreas, adipose, lung, heart, and kidney of AS3MT-KO mice; tri- and pentavalent methylated arsenicals did not exceed 10% of total As. Tissues of WT mice retained iAs and methylated arsenicals: iAsIII, MAsIII and DMAsIII represented 55%-68% of the total As in the liver, pancreas, and brain. High levels of methylated species, particularly MAsIII, were found in the intestine of WT, but not AS3MT-KO mice, suggesting that intestinal bacteria are not a major source of methylated As. Blood of WT mice contained significantly higher levels of As than blood of AS3MT-KO mice. This study is the first to determine oxidation states of As species in tissues of AS3MT-KO mice. Results will help to design studies using WT and AS3MT-KO mice to examine the role of iAs methylation in adverse effects of iAs exposure.
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Association Between Variants in Arsenic (+3 Oxidation State) Methyltranserase (AS3MT) and Urinary Metabolites of Inorganic Arsenic: Role of Exposure Level.
Toxicological sciences : an official journal of the Society of Toxicology, 2016Co-Authors: Zuzana Drobna, Keri Barron, Roberto Hernandez Ceron, Damian Viniegra Morales, V. Saroja Voruganti, Carmen González-horta, Blanca Sánchez-ramírez, Lourdes Ballinas-casarrubias, Francisco A. Baeza TerrazasAbstract:Abstract Variants in AS3MT, the gene encoding arsenic (+3 oxidation state) methyltranserase, have been shown to influence patterns of inorganic arsenic (iAs) metabolism. Several studies have suggested that capacity to metabolize iAs may vary depending on levels of iAs exposure. However, it is not known whether the influence of variants in AS3MT on iAs metabolism also vary by level of exposure. We investigated, in a population of Mexican adults exposed to drinking water As, whether associations between 7 candidate variants in AS3MT and urinary iAs metabolites were consistent with prior studies, and whether these associations varied depending on the level of exposure. Overall, associations between urinary iAs metabolites and AS3MT variants were consistent with the literature. Referent genotypes, defined as the genotype previously associated with a higher percentage of urinary dimethylated As (DMAs%), were associated with significant increases in the DMAs% and ratio of DMAs to monomethylated As (MAs), and significant reductions in MAs% and iAs%. For 3 variants, associations between genotypes and iAs metabolism were significantly stronger among subjects exposed to water As >50 versus ≤50 ppb (water As X genotype interaction P
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Analysis of maternal polymorphisms in arsenic (+3 oxidation state)-methyltransferase AS3MT and fetal sex in relation to arsenic metabolism and infant birth outcomes: Implications for risk analysis
Reproductive toxicology (Elmsford N.Y.), 2016Co-Authors: Zuzana Drobna, Miroslav Styblo, Elizabeth M. Martin, Kyungsu Kim, Lisa Smeester, Paige A. Bommarito, Marisela Rubio-andrade, Gonzalo G. García-vargas, Fei Zou, Rebecca C. FryAbstract:Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the metabolism of inorganic arsenic (iAs). Polymorphisms of AS3MT influence adverse health effects in adults, but little is known about their role in iAs metabolism in pregnant women and infants. The relationships between seven single nucleotide polymorphisms (SNPs) in AS3MT and urinary concentrations of iAs and its methylated metabolites were assessed in mother-infant pairs of the Biomarkers of Exposure to ARsenic (BEAR) cohort. Maternal alleles for five of the seven SNPs (rs7085104, rs3740400, rs3740393, rs3740390, and rs1046778) were associated with urinary concentrations of iAs metabolites, and alleles for one SNP (rs3740393) were associated with birth outcomes/measures. These associations were strongly dependent upon the male sex of the fetus but independent of fetal genotype for AS3MT. These data highlight a potential sex-dependence of the relationships among maternal genotype, iAs metabolism and infant health outcomes.
Marie Vahter - One of the best experts on this subject based on the ideXlab platform.
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Arsenite methyltransferase (AS3MT) polymorphisms and arsenic methylation in children in rural Bangladesh.
Toxicology and applied pharmacology, 2018Co-Authors: Jessica De Loma, Rubhana Raqib, Marie Vahter, Helena Skröder, Karin BrobergAbstract:Abstract Background Arsenic methylation efficiency, a susceptibility factor for arsenic toxicity, is in adults partly explained by variation in arsenite methyltransferase (AS3MT) gene. Little is known about the role of AS3MT for children's arsenic methylation. Objectives Evaluating associations between AS3MT polymorphisms and children's arsenic methylation efficiency. Methods Bangladeshi children's arsenic exposure (9-years; n = 424) was assessed as sum urinary concentration of inorganic arsenic (iAs) and its metabolites (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) using HPLC-HG-ICPMS. Arsenic methylation efficiency was assessed by the individual metabolite fractions (%). AS3MT polymorphisms (rs7085104, rs3740400, rs3740393 and rs1046778) were genotyped using TaqMan SNP genotyping assays. Results We found higher %iAs and %MMA, and lower %DMA in urine, among rs1046778 TT carriers (median 8.8%, 9.6% and 81.1% for iAs, MMA and DMA, respectively), compared to CC carriers (median 7.0%, 8.3% and 84.9%). These associations were significant in multivariable-adjusted linear regression models: B-coefficients for TT vs CC were 1.26, 1.33 and −2.59 for iAs, MMA and DMA, respectively. Effect estimates were slightly stronger when restricting the analyses to children with urinary arsenic ≥58 μg/L (reducing the impact of ingested DMA). Estimates in girls were slightly stronger than in boys, although there were no significant differences between boys and girls. No clear associations were found for the other AS3MT polymorphisms. Conclusions One out of four AS3MT polymorphisms, previously associated with arsenic methylation in adults, was associated with arsenic methylation in children. Thus, AS3MT variation seems to influence arsenic methylation efficiency in children to a lesser extent than in adults.
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Human Adaptation to Arsenic-Rich Environments
Molecular biology and evolution, 2015Co-Authors: Carina M. Schlebusch, Karin Engström, Marie Vahter, Lucie M. Gattepaille, Mattias Jakobsson, Karin BrobergAbstract:Adaptation drives genomic changes; however, evidence of specific adaptations in humans remains limited. We found that inhabitants of the northern Argentinean Andes, an arid region where elevated arsenic concentrations in available drinking water is common, have unique arsenic metabolism, with efficient methylation and excretion of the major metabolite dimethylated arsenic and a less excretion of the highly toxic monomethylated metabolite. We genotyped women from this population for 4,301,332 single nucleotide polymorphisms (SNPs) and found a strong association between the AS3MT (arsenic [+3 oxidation state] methyltransferase) gene and mono- and dimethylated arsenic in urine, suggesting that AS3MT functions as the major gene for arsenic metabolism in humans. We found strong genetic differentiation around AS3MT in the Argentinean Andes population, compared with a highly related Peruvian population (FST = 0.014) from a region with much less environmental arsenic. Also, 13 of the 100 SNPs with the highest genome-wide Locus-Specific Branch Length occurred near AS3MT. In addition, our examination of extended haplotype homozygosity indicated a selective sweep of the Argentinean Andes population, in contrast to Peruvian and Colombian populations. Our data show that adaptation to tolerate the environmental stressor arsenic has likely driven an increase in the frequencies of protective variants of AS3MT, providing the first evidence of human adaptation to a toxic chemical.
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genetic variation in arsenic 3 oxidation state methyltransferase AS3MT arsenic metabolism and risk of basal cell carcinoma in a european population
Environmental and Molecular Mutagenesis, 2015Co-Authors: Karin Engström, Marie Vahter, Walter Goessler, Tony Fletcher, Giovanni Leonardi, Eugen Gurzau, Kvetoslava Koppova, Peter Rudnai, Rajiv Kumar, Karin BrobergAbstract:Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N = 529) and controls (N = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P = 0.032) and %MMA (P = 0.020) in urine, and higher %DMA (P = 0.033); individuals with the CGCT haplotype had higher %MMA (P < 0.001) and lower %DMA (P < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from <0.001 to 0.082), except for the CCTC haplotype (OR 1.0, CI 0.9-1.2, P value 0.85). The results suggest that carriage of AS3MT haplotypes associated with less-efficient arsenic methylation, or lack of AS3MT haplotypes associated with a more-efficient arsenic methylation, results in higher risk of arsenic-related BCC. The fact that AS3MT haplotype status modified arsenic metabolism, and in turn the arsenic-related BCC risk, supports a causal relationship between low-level arsenic exposure and BCC.
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Genetic variation in arsenic (+3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population
Environmental and molecular mutagenesis, 2014Co-Authors: Karin Engström, Marie Vahter, Walter Goessler, Tony Fletcher, Giovanni Leonardi, Eugen Gurzau, Kvetoslava Koppova, Peter Rudnai, Rajiv Kumar, Karin BrobergAbstract:Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N = 529) and controls (N = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P = 0.032) and %MMA (P = 0.020) in urine, and higher %DMA (P = 0.033); individuals with the CGCT haplotype had higher %MMA (P < 0.001) and lower %DMA (P < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from
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n 6 adenine specific dna methyltransferase 1 n6amt1 polymorphisms and arsenic methylation in andean women
Environmental Health Perspectives, 2013Co-Authors: Florencia Harari, Gabriela Concha, Karin Engström, Marie Vahter, Graciela Colque, Karin BrobergAbstract:Background: In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro. Objective: We evaluated the role of N6AMT1 polymorphisms in arsenic methylation efficiency in humans. Methods: We assessed arsenic methylation efficiency in 188 women exposed to arsenic via drinking water (~ 200 µg/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. We performed genotyping for N6AMT1 and AS3MT polymorphisms by Taqman assays, and gene expression (in blood; n = 63) with Illumina HumanHT-12 v4.0. Results: Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1997605, rs2205449, rs2705671, rs16983411, and rs1048546) and two N6AMT1 haplotypes were significantly associated with the percentage of MMA (%MMA) in urine, even after adjusting for AS3MT haplotype. %MMA increased monotonically according to the number of alleles for each SNP (e.g., for rs1048546, mean %MMA was 7.5% for GG, 8.8% for GT, and 9.7% for TT carriers). Three SNPs were in linkage disequilibrium (R2 > 0.8). Estimated associations for joint effects of N6AMT1 (haplotype 1) and AS3MT (haplotype 2) were generally consistent with expectations for additive effects of each haplotype on %MMA. Carriers of N6AMT1 genotypes associated with lower %MMA showed the lowest N6AMT1 expression, but associations were monotonic according to copy number for only one genotype and one haplotype. Conclusions: N6AMT1 polymorphisms were associated with arsenic methylation in Andean women, independent of AS3MT. N6AMT1 polymorphisms may be susceptibility markers for arsenic-related toxic effects.
