Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism.

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Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism. / Engström, Karin; Vahter, Marie; Jurkovic Mlakar, Simona; Concha, Gabriela; Nermell, Barbro; Raqib, Rubhana; Cardozo, Alejandro; Broberg Palmgren, Karin.

I: Environmental Health Perspectives, Vol. 119, 2011, s. 182-188.

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Engström, Karin ; Vahter, Marie ; Jurkovic Mlakar, Simona ; Concha, Gabriela ; Nermell, Barbro ; Raqib, Rubhana ; Cardozo, Alejandro ; Broberg Palmgren, Karin. / Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism. I: Environmental Health Perspectives. 2011 ; Vol. 119. s. 182-188.

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TY - JOUR

T1 - Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism.

AU - Engström, Karin

AU - Vahter, Marie

AU - Jurkovic Mlakar, Simona

AU - Concha, Gabriela

AU - Nermell, Barbro

AU - Raqib, Rubhana

AU - Cardozo, Alejandro

AU - Broberg Palmgren, Karin

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - AS3MT

KW - arsenic

KW - BHMT

KW - DNMT1a

KW - DNMT3b

KW - gene expression

KW - methylation

KW - one-carbon metabolism

KW - PEMT

KW - polymorphism

U2 - 10.1289/ehp.1002471

DO - 10.1289/ehp.1002471

M3 - Article

VL - 119

SP - 182

EP - 188

JO - EHP Toxicogenomics

T2 - EHP Toxicogenomics

JF - EHP Toxicogenomics

SN - 1552-9924

ER -