Dataset Information

Arsenic Metabolism in Mice Carrying a BORCS7/AS3MT Locus Humanized by Syntenic Replacement.

ABSTRACT: BACKGROUND:Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies. OBJECTIVES:The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice. METHODS:We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice. RESULTS:AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of As3mt. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific AS3MTd2d3 splicing variant that has been linked to schizophrenia. CONCLUSIONS:These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of AS3MTd2d3 in schizophrenia. https://doi.org/10.1289/EHP6943.

SUBMITTER: Koller BH

PROVIDER: S-EPMC7418654 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Arsenic Metabolism in Mice Carrying a <i>BORCS7/AS3MT</i> Locus Humanized by Syntenic Replacement.

Koller Beverly H BH Snouwaert John N JN Douillet Christelle C Jania Leigh A LA El-Masri Hisham H Thomas David J DJ Stýblo Miroslav M

Environmental health perspectives 20200811 8

<h4>Background</h4>Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies.<h4>Objec ...[more]

PMID: 32779937

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Project description:Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leverage this model to study sex differences in the context of iAs exposure. Objectives: The aim of this study iwas to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. Methods: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and epididymales gonadal adipose depot were harvested for iAs quantification as well as sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and HOMA-IR. Results: We detected sex divergence in liver and adipose markers of diabetes (e.g., insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) male mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. Discussion: Our study underscoreds the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings also suggest suggested that humanized females are protected from metabolic dysfunction relative to humanized males in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence, including the potential role of miR-34a and/or Klf11.

Project description:Arsenic (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.We 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.Subjects 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.Six 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.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.

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.

Project description:BackgroundCommon genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated.ObjectivesWe estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.MethodsWe generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency <1%), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).ResultsWe identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [β=-9.4 (95% CI: -13.9, -4.8)], SHS [β=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [β=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [β=-8.7 (95% CI: -11.9, -5.4)].DiscussionRare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.

Dataset Information

Arsenic Metabolism in Mice Carrying a BORCS7/AS3MT Locus Humanized by Syntenic Replacement.

Publications

Arsenic Metabolism in Mice Carrying a <i>BORCS7/AS3MT</i> Locus Humanized by Syntenic Replacement.

Similar Datasets

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