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Timothy A. Garrow - One of the best experts on this subject based on the ideXlab platform.

  • Hepatic Activity and Transcription of Betaine-Homocysteine Methyltransferase, Methionine Synthase, and Cystathionine Synthase in Periparturient Dairy Cows Are Altered to Different Extents by Supply of Methionine and Choline.
    The Journal of nutrition, 2016
    Co-Authors: Z. Zhou, Timothy A. Garrow, Xianwen Dong, D. Luchini, Juan J. Loor
    Abstract:

    BACKGROUND Compared with choline, Met enhances milk yield and feed intake, and elicits a better immuno-metabolic status in periparturient cows. It is unknown whether hepatic activity and transcription of Betaine-Homocysteine Methyltransferase (BHMT), 5-methyltetrahydrofolate-Homocysteine Methyltransferase (MTR), and cystathionine β-synthase (CBS) are responsive to Met and choline supply. OBJECTIVE This study sought to characterize hepatic BHMT, MTR, and CBS transcription and activity in response to Met and choline supplementation. METHODS Forty multiparous cows were used in a 2 × 2 factorial design from -21 d through 30 d around parturition to assess effects of dietary rumen-protected Met (0% or 0.08% dry matter basis) or rumen-protected choline (0 or 60 g · cow-1 · d-1). Liver tissue obtained on days -10, 7, 20, and 30 was used for analyses. RESULTS Met-supplemented cows had greater methionine adenosyltransferase 1A (MAT1A) (0.38 compared with 0.27; SEM = 0.05; P = 0.02) and phosphatidylethanolamine Methyltransferase (PEMT) (0.74 compared with 0.58; SEM = 0.08; P = 0.05) expression. Greater S-adenosylHomocysteine hydrolase (SAHH) (0.93 compared with 0.74; SEM = 0.05; P = 0.01) and CBS (1.16 compared with 1.02; SEM = 0.07; P = 0.04), as well as lower MTR activity (23.4 compared with 29.7 nmol product · h-1 · mg protein-1; SEM = 2.9; P = 0.04), also were detected in Met- but not choline-supplemented cows. Although BHMT and MTR expression and BHMT enzyme activity did not change (P > 0.05), MTR enzyme activity was lower in choline-supplemented cows (23.5 compared with 29.6 nmol product · h-1 · mg protein-1; SEM = 2.9; P = 0.05). CONCLUSIONS These findings indicate that greater synthesis of phosphatidylcholine and antioxidants contribute to the better performance and immuno-metabolic status in Met-supplemented cows. Failure to generate a comparable amount of endogenous Met from choline could be one reason that choline-fed cows fail to achieve comparable performance and health benefits during the periparturient period.

  • Betaine Homocysteine Methyltransferase Is Active in the Mouse Blastocyst and Promotes Inner Cell Mass Development
    The Journal of biological chemistry, 2012
    Co-Authors: Martin B. Lee, Timothy A. Garrow, Michael Lever, Baohua Zhang, Jacquetta M. Trasler, Megan Kooistra, Amanda L. Fortier, Jay M. Baltz
    Abstract:

    Methyltransferases are an important group of enzymes with diverse roles that include epigenetic gene regulation. The universal donor of methyl groups for Methyltransferases is S-adenosylmethionine (AdoMet), which in most cells is synthesized using methyl groups carried by a derivative of folic acid. Another mechanism for AdoMet synthesis uses Betaine as the methyl donor via the enzyme Betaine-Homocysteine Methyltransferase (BHMT, EC 2.1.1.5), but it has been considered to be significant only in liver. Here, we show that mouse preimplantation embryos contain endogenous Betaine; Bhmt mRNA is first expressed at the morula stage; BHMT is abundant at the blastocyst stage but not other preimplantation stages, and BHMT activity is similarly detectable in blastocyst homogenates but not those of two-cell or morula stage embryos. Knockdown of BHMT protein levels and reduction of enzyme activity using Bhmt-specific antisense morpholinos or a selective BHMT inhibitor resulted in decreased development of embryos to the blastocyst stage in vitro and a reduction in inner cell mass cell number in blastocysts. The detrimental effects of BHMT knockdown were fully rescued by the immediate methyl-carrying product of BHMT, methionine. A physiological role for Betaine and BHMT in blastocyst viability was further indicated by increased fetal resorption following embryo transfer of BHMT knockdown blastocysts versus control. Thus, mouse blastocysts are unusual in being able to generate AdoMet not only by the ubiquitous folate-dependent mechanism but also from Betaine metabolized by BHMT, likely a significant pool of methyl groups in blastocysts.

  • Molecular characterization and analysis of the porcine Betaine Homocysteine Methyltransferase and Betaine Homocysteine Methyltransferase-2 genes.
    Gene, 2010
    Co-Authors: Radhika S. Ganu, Timothy A. Garrow, Monika Sodhi, Laurie A. Rund, Lawrence B. Schook
    Abstract:

    Abstract Betaine Homocysteine Methyltransferase (BHMT) and BHMT-2 enzymes methylate Homocysteine to form methionine using Betaine and S-methylmethionine, respectively. These activities are observed only in the liver of adult rodents, but in adult humans and pigs these activities are detected in both the liver and kidney, indicating the pig is a more appropriate model for studying the biochemical and physiological roles of these enzymes in human biology. Porcine BHMT and BHMT-2 cDNAs were cloned and sequenced, and their 5′ and 3′ UTR were amplified using RLM-RACE. The BHMT transcript had significantly longer 5′ and 3′ UTRs than BHMT-2. The pig BHMT and BHMT-2 genes span approximately 26 and 16 kb, respectively, and both genes have 8 exons. The deduced amino acid sequences of BHMT and BHMT-2 contain 407 and 363 amino acids, respectively, and shared 78% amino acid identity. No promoter element (TATA or CAAT box) was observed for either BHMT or BHMT-2, although a CpG island surrounding the promoter and transcriptional start site was observed in both genes implying that methylation could regulate their expression. Using qPCR, it was determined that BHMT and BHMT-2 transcripts are very abundant in liver and kidney cortex, whereas the expression is significantly less in other tissues. These findings confirm that the expression pattern of BHMT and BHMT-2 genes in pigs is similar to humans, supporting the use of the pig as an animal model to study the genetics and regulation of BHMT and BHMT-2 expression.

  • Betaine-Homocysteine S-Methyltransferase-2 is an S-methylmethionine-Homocysteine Methyltransferase.
    Journal of Biological Chemistry, 2008
    Co-Authors: Sandra S. Szegedi, Carmen Castro, Markos Koutmos, Timothy A. Garrow
    Abstract:

    We demonstrate that purified recombinant human BetaineHomocysteine Methyltransferase-2 (BHMT-2) is a zinc metalloenzyme that uses S-methylmethionine (SMM) as a methyl donor for the methylation of Homocysteine. Unlike the highly homologous Betaine-Homocysteine Methyltransferase (BHMT), BHMT-2 cannot use Betaine. The Km of BHMT-2 for SMM was determined to be 0.94 mm, and it has a turnover number similar to BHMT. Several compounds were tested as inhibitors of recombinant human BHMT and BHMT-2. The SMM-specific Methyltransferase activity of BHMT-2 is not inhibited by dimethylglycine and Betaine, whereas the former is a potent inhibitor of BHMT. Methionine is a stronger inhibitor of BHMT-2 than BHMT, and S-adenosylmethionine does not inhibit BHMT but is a weak inhibitor of BHMT-2. BHMT can use SMM as a methyl donor with a kcat/Km that is 5-fold lower than the kcat/Km for Betaine. However, SMM does not inhibit BHMT activity when it is presented to the enzyme at concentrations that are 10-fold greater than the subsaturating amounts of Betaine used in the assay. Based on these data, it is our current hypothesis that in vivo most if not all of the SMM-dependent methylation of Homocysteine occurs via BHMT-2.

  • Liver Choline Dehydrogenase and Kidney Betaine-Homocysteine Methyltransferase Expression Are Not Affected by Methionine or Choline Intake in Growing Rats
    The Journal of nutrition, 2006
    Co-Authors: Sandy Slow, Timothy A. Garrow
    Abstract:

    Choline dehydrogenase (CHDH) and Betaine-Homocysteine Methyltransferase (BHMT) are 2 enzymes involved in choline oxidation. BHMT is expressed at high levels in rat liver and its expression is regulated by dietary Met and choline. BHMT is also found in rat kidney, albeit in substantially lower amounts, but it is not known whether kidney BHMT expression is regulated by dietary Met or choline. Similarly, CHDH activity is highest in the liver and kidney, but the regulation of its expression by diet has not been thoroughly investigated. Sprague Dawley rats (∼50 g) were fed, for 9 d in 2 x 3 factorial design (n = 8), an L-amino acid-defined diet varying in L-Met (0.125, 0.3, or 0.8%) and choline (0 or 25 mmol/kg diet). Liver and kidney BHMT and CHDH were assessed using enzymatic, Western blot, and real-time PCR analyses. Liver samples were also fixed for histological analysis. Liver BHMT activity was 1.3-fold higher in rats fed the Met deficient diet containing choline, which was reflected in corresponding increases in mRNA content and immunodetectable protein. Independent of dietary choline, supplemental Met increased hepatic BHMT activity ∼30%. Kidney BHMT and liver CHDH expression were refractory to these diets. Some degree of fatty liver developed in all rats fed a choline-devoid diet, indicating that supplemental Met cannot completely compensate for the lack of dietary choline in growing rats. J. Nutr. 136: 2279-2283, 2006.

Karin Broberg - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

Karin Engström - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

Gabriela Concha - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

Rubhana Raqib - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)

  • polymorphisms in arsenic iii oxidation state Methyltransferase as3mt predict gene expression of as3mt as well as arsenic metabolism
    Environmental Health Perspectives, 2010
    Co-Authors: Karin Engström, Simona Jurkovic Mlakar, Gabriela Concha, Barbro Nermell, Rubhana Raqib, Alejandro Cardozo, Marie Vahter, Karin Broberg
    Abstract:

    Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five Methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The Methyltransferase genes were arsenic(+III)Methyltransferase (AS3MT), DNAMethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine NMethyltransferase (PEMT) and Betaine-Homocysteine Methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. (Less)