Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

N-6-Adenine-Specific DNA Methyltransferase 1 (N6AMT1) Polymorphisms and Arsenic Methylation in Andean Women

Harari, Florencia ; Engström, Karin LU ; Concha, Gabriela ; Colque, Graciela ; Vahter, Marie and Broberg Palmgren, Karin LU orcid (2013) In Environmental Health Perspectives 121(7). p.797-803
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 (similar to 200 mu g/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by... (More)
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 (similar to 200 mu g/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 (R-2 > 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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DMA, gene x environment interactions, inorganic arsenic, methylation, MMA, polymorphisms
in
Environmental Health Perspectives
volume
121
issue
7
pages
797 - 803
publisher
National Institute of Environmental Health Sciences
external identifiers
  • wos:000323711000018
  • scopus:84879598553
  • pmid:23665909
ISSN
1552-9924
DOI
10.1289/ehp.1206003
language
English
LU publication?
yes
id
15ab0c74-ee43-4a6c-95c4-62ed1085c71d (old id 4062545)
date added to LUP
2016-04-01 14:27:34
date last changed
2022-01-28 00:46:18
@article{15ab0c74-ee43-4a6c-95c4-62ed1085c71d,
  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 (similar to 200 mu g/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 (R-2 > 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.}},
  author       = {{Harari, Florencia and Engström, Karin and Concha, Gabriela and Colque, Graciela and Vahter, Marie and Broberg Palmgren, Karin}},
  issn         = {{1552-9924}},
  keywords     = {{DMA; gene x environment interactions; inorganic arsenic; methylation; MMA; polymorphisms}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{797--803}},
  publisher    = {{National Institute of Environmental Health Sciences}},
  series       = {{Environmental Health Perspectives}},
  title        = {{N-6-Adenine-Specific DNA Methyltransferase 1 (N6AMT1) Polymorphisms and Arsenic Methylation in Andean Women}},
  url          = {{https://lup.lub.lu.se/search/files/3989209/4864864.pdf}},
  doi          = {{10.1289/ehp.1206003}},
  volume       = {{121}},
  year         = {{2013}},
}