Dataset Information

Interactive Influence of N6AMT1 and As3MT Genetic Variations on Arsenic Metabolism in the Population of Inner Mongolia, China.

ABSTRACT: Chronic arsenic exposure via drinking water has become a worldwide public health concern. In humans, inorganic arsenic (iAs) is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) mainly mediated by arsenic (+3 oxidation state) methyltransferase (As3MT). We reported recently that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) was involved in arsenic metabolism, and examined its interactive effect with As3MT on arsenic metabolism in vitro To further evaluate the interactive effect of N6AMT1 and As3MT on arsenic biomethylation in humans, we conducted a human population-based study including 289 subjects living in rural villages in Inner Mongolia, China, and assessed their urinary arsenic metabolites profiles in relation to genetic polymorphisms and haplotypes of N6AMT1 and As3MT Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1003671, rs7282257, rs2065266, rs2738966, rs2248501) and the N6AMT1 haplotype 2_GGCCAT were significantly associated with the percentage of iAs (% iAs) in urine (e.g., for rs7282257, mean was 9.62% for TT, 6.73% for AA). Rs1003671 was also in a significant relationship with urinary MMA and DMA (the mean of %MMA was 24.95% for GA, 31.69% for GG; the mean of % DMA was 69.21% for GA, 59.82% for GG). The combined effect of N6AMT1 haplotype 2_GGCCAT and As3MT haplotype 2_GCAC showed consistence with the additive significance of each haplotype on % iAs: the mean was 5.47% and 9.36% for carriers with both and null haplotypes, respectively. Overall, we showed that N6AMT1 genetic polymorphisms were associated with arsenic biomethylation in the Chinese population, and its interaction with As3MT was observed in specific haplotype combinations.

SUBMITTER: Chen X

PROVIDER: S-EPMC5216648 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Interactive Influence of N6AMT1 and As3MT Genetic Variations on Arsenic Metabolism in the Population of Inner Mongolia, China.

Chen Xushen X Guo Xiaojuan X He Ping P Nie Jing J Yan Xiaoyan X Zhu Jinqiu J Zhang Luoping L Mao Guangyun G Wu Hongmei H Liu Zhiyue Z Aga Diana D Xu Peilin P Smith Martyn M Ren Xuefeng X

Toxicological sciences : an official journal of the Society of Toxicology 20160916 1

Chronic arsenic exposure via drinking water has become a worldwide public health concern. In humans, inorganic arsenic (iAs) is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) mainly mediated by arsenic (+3 oxidation state) methyltransferase (As3MT). We reported recently that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) was involved in arsenic metabolism, and examined its interactive effect with As3MT on arsenic metabolism in vitro To further evaluate the inte ...[more]

PMID: 27637898

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Project description:BackgroundArsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.ObjectivesWe evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood.MethodsSubjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays.ResultsSix AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression.ConclusionsPolymorphisms 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.

Project description:To reveal the characteristics of climate change and the controlling factors for vegetation dynamics in the Ordos, Inner Mongolia, China, 34 years (1982-2015) of regional climate variables and vegetation dynamics were investigated. The results show that: Annual mean air temperature (TMP) significantly increased with a linear slope of 0.473°C/10yr. Annual precipitation (PRE) had a non-significant positive trend nearly 5 times lower than the trend of potential evapotranspiration (PET). The average Normalized Difference Vegetation Index (NDVI) computed for the region was found to show a significant positive trend (6.131×10-4/yr). However, all climate variables displayed non-significant correlations with NDVI at annual scale. The reduction of desert and the increase of grassland over the past decades were accountable for the increased NDVI. Principal components analysis revealed that the regional climate change can be characterized as changes in temperature, humidity and the availability of radiant energy. Based on principal components regression coefficients, NDVI was mostly sensitive to humidity component, followed by growing season warmth (WMI). Spatially, 93.1% of the pixels displayed positive trend and 61.8% of the pixels displayed significant change over the past decades. Both principal regression analysis and partial correlation analysis revealed that NDVI in eastern part of Ordos was sensitive to TMP, whereas, NDVI in southern and western areas of Ordos displayed the high sensitivity to combined effects of PRE and cloud coverage (CLD). Partial correlation analyses also revealed that TMX was a surrogate for aridity, TMN was a representative of humidity, and temperature variations below the threshold of 5°C (CDI) were less important than WMI. We conclude that regional climate change can be characterized by warming and increased aridity. The significant positive trend of regional NDVI and the non-significant correlations between NDVI and climate variables at annual scale suggests the hidden role of the human activities.

Project description:Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N?=?103) and from cord blood from new-borns in Bangladesh (N?=?127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p?=?10(-6)) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10(-16)), NT5C2 (p<10(-16)), C10orf26 (p?=?10(-8)), USMG5 (p?=?10(-5)), TRIM8 (p?=?10(-4)), and CALHM2 (p?=?0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (r(s)?=?-0.22 to -0.54), and with increased expression of NT5C2 and USMG5 (r(s)?=?0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.

Dataset Information

Interactive Influence of N6AMT1 and As3MT Genetic Variations on Arsenic Metabolism in the Population of Inner Mongolia, China.

Publications

Interactive Influence of N6AMT1 and As3MT Genetic Variations on Arsenic Metabolism in the Population of Inner Mongolia, China.

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