Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure

Douillet, Christelle; Huang, Madelyn C.; Saunders, R. Jesse; Dover, Ellen N.; Zhang, Chongben; Stýblo, Miroslav

doi:10.1007/s00204-016-1890-9

Cited by 37 publications

(34 citation statements)

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“…These evidences support that the methylation and GSH mediated reduction, detoxify the toxic arsenic. Arsenic detoxification further depletes brain GSH [137]. Arsenic and its metabolite are accumulated in the kidney, lungs, heart, spleen, and brain of humans; and viral infection may further enhance the accumulation in the brain [138,139].…”

Section: Arsenic (As)mentioning

confidence: 99%

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Patwa

Flora

2020

IJMS

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Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

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Section: Arsenic (As)mentioning

confidence: 99%

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Patwa

Flora

2020

IJMS

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“…After completion of the experiments examining metabolism of the single oral dose of iAs, the F2 Hs/Hs and WT/WT mice were caged together (one litter per cage) and maintained on the purified diet and DIW for 5 wk to allow for clearance of iAs from the body. After this time, the concentrations of total As in urine of Hs/Hs and WT/WT mice ranged from 4 to

, that is, the levels that are typical for urine of unexposed mice ( Douillet et al. 2017 ; Drobná et al.…”

Section: Resultsmentioning

confidence: 99%

“…AIN-93G) during the second and the third days. Our published data showed that iAs content in this type of diet ranges from 10 to

( Douillet et al. 2017 ; Huang et al.…”

Section: Methodsmentioning

confidence: 95%

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

Koller

Snouwaert

Douillet³

et al. 2020

Environ Health Perspect

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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 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 in schizophrenia. https://doi.org/10.1289/EHP6943

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“…The SNP-arsenic interactions for As3MT polymorphisms have been investigated in both animal models and human cohort studies ( Hernández et al, 2014 ; Huang et al, 2017a ; Huang et al, 2017b ; Pierce et al, 2013 ; Wu et al, 2014 ). Among them, the Health Effects of Arsenic Longitudinal Study (HEALS) and BEAR pregnancy cohort both provide some evidence about the association between genetic variants and specific health outcomes, as well as the SNP-arsenic interaction.…”

Section: Discussionmentioning

confidence: 99%

Gene-environment interaction and maternal arsenic methylation efficiency during pregnancy

Gao

Mostofa

Quamruzzaman

et al. 2019

Environment International

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Background: Single nucleotide polymorphisms (SNPs) may influence arsenic methylation efficiency, affecting arsenic metabolism. Whether gene-environment interactions affect arsenic metabolism during pregnancy remains unclear, which may have implications for pregnancy outcomes. Objective: We aimed to investigate main effects as well as potential SNP-arsenic interactions on arsenic methylation efficiency in pregnant women. Method: We recruited 1613 pregnant women in Bangladesh, and collected two urine samples from each participant, one at 4–16 weeks, and the second at 21–37 weeks of pregnancy. We determined the proportions of each arsenic metabolite [inorganic As (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA)%] from the total urinary arsenic level of each sample. A panel of 63 candidate SNPs was selected for genotyping based on their reported associations with arsenic metabolism (including in As3MT, N6AMT1, and GST02 genes). We used linear regression models to assess the association between each SNP and DMA% with an additive allelic assumption, as well as SNP-arsenic interaction on DMA%. These analyses were performed separately for two urine collection time-points to capture differences in susceptibility to arsenic toxicity. Result: Intron variants for As3MT were associated with DMA%. rs9527 (β = − 2.98%, P FDR = 0.008) and rs1046778 (β = 1.64%, P FDR = 0.008) were associated with this measure in the early gestational period; rs3740393 (β = 2.54%, P FDR = 0.002) and rs1046778 (β = 1.97%, P FDR = 0.003) in the mid-to-late gestational period. Further, As3MT, GSTO2, and N6AMT1 polymorphisms showed different effect sizes on DMA% conditional on arsenic exposure levels. However, SNP-arsenic interactions were not statistically significant after adjusting for false discovery rate (FDR), rs1048546 in N6AMT1 had the highest significance level in the SNP-arsenic interaction test during mid-to-late gestation (β = −1.8% vs. 1.4%, P GXE_FDR = 0.075). Finally, As3MT and As3MT/CNNM2 haplotypes were associated with DMA% at both time points. Conclusion: We found that not all genetic associations reported in arsenic methylation efficiency replicate in pregnant women. Arsenic exposure level has a limited effect in modifying the association between genetic variation and arsenic methylation efficiency.

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Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure

Cited by 37 publications

References 50 publications

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

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

Gene-environment interaction and maternal arsenic methylation efficiency during pregnancy

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