N-6-Adenine-Specific DNA Methyltransferase 1 (N6AMT1) Polymorphisms and Arsenic Methylation in Andean Women |
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| Authors: | Florencia Harari Karin Engstr?m Gabriela Concha Graciela Colque Marie Vahter Karin Broberg |
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| Affiliation: | 1.Institute of Environmental Medicine, Unit of Metals and Health, Karolinska Institutet, Stockholm, Sweden;2.Department of Laboratory Medicine, Section of Occupational and Environmental Medicine, Lund University, Lund, Sweden;3.Swedish National Food Agency, Department of Risk-Benefit Assessment, Uppsala, Sweden;4.Hospital Dr. Nicolás Cayetano Pagano, San Antonio de los Cobres, Argentina |
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| Abstract: | 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. |
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| Keywords: | DMA, gene × environment interactions, inorganic arsenic, methylation, MMA, polymorphisms |
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