Arsenic urinary speciation in Mthfr deficient mice injected with sodium arsenate

Wlodarczyk, Bogdan J.; Spiegelstein, Ofer; Hill, D. M.; Le, X. Chris; Finnell, Richard H.

doi:10.1016/j.toxlet.2012.10.014

Cited by 9 publications

(4 citation statements)

References 41 publications

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“…Similar effects have been reported for B12, but data are limited and inconsistent (Hall and Gamble 2012; Heck et al 2007). Animal studies generally support the positive association between folate intake and efficiency of iAs metabolism (Wlodarczyk et al 2012; Spiegelstein et al 2003, 2005; Tsang et al 2012), but few studies have investigated the role of B12. Combined folate and B12 supplementation has been found to alleviate iAs-induced apoptosis, oxidative stress, and hepatotoxicity (Acharyya et al 2015; Mukherjee et al 2006; Chattopadhyay et al 2012), suggesting possible protective effects of these vitamins in iAs-associated diseases.…”

Section: Introductionmentioning

confidence: 98%

Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner

et al. 2018

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Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied. The role of factors that modulate iAs metabolism and toxicity in adults and their potential to influence diabetogenic effects of prenatal iAs exposure are also unclear. The goal of this study was to determine if prenatal exposure to iAs impairs glucose metabolism in mice and if maternal supplementation with folate and methylcobalamin (B12) can modify this outcome. C57BL/6J dams were exposed to iAs in drinking water (0, 100, and 1000 µg As/L) and fed a folate/B12 adequate or supplemented diet from before mating to birth of offspring. After birth, dams and offspring drank deionized water and were fed the folate/B12 adequate diet. The metabolic phenotype of offspring was assessed over the course of 14 weeks. Male offspring from iAs-exposed dams fed the folate/B12-adequate diet developed fasting hyperglycemia and insulin resistance. Maternal folate/B12 supplementation rescued this phenotype but had only marginal effects on iAs metabolism in dams. The diabetogenic effects of prenatal iAs exposure in male offspring were not associated with changes in global DNA methylation in the liver. Only minimal effects of prenatal iAs exposure or maternal supplementation were observed in female offspring. These results suggest that prenatal iAs exposure impairs glucose metabolism in a sex-specific manner and that maternal folate/B12 supplementation may improve the metabolic phenotype in offspring. Further studies are needed to identify the mechanisms underlying these effects.

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Section: Introductionmentioning

confidence: 98%

Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner

et al. 2018

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“…For example, one-carbon metabolism (OCM) is a biochemical pathway that is able to provide methyl groups for arsenic methylation, and related nutritional status is reported associated with arsenic methylation efficiency in pregnant and non-pregnant cohorts ( Bozack et al, 2018 ; Kurzius-Spencer et al, 2017 ; Laine et al, 2018 ). Methylenetetrahydrofolate reductase (encoded by MTHFR ) is an important enzyme involved in OCM, and plays a role in the supplement of SAM in arsenic metabolism ( Chung et al, 2010 ; Wlodarczyk et al, 2012 ). An association between MTHFR SNPs and arsenic metabolism was identified in both an animal model and an epidemiologic study ( Steinmaus et al, 2007 ; Wlodarczyk et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…Methylenetetrahydrofolate reductase (encoded by MTHFR ) is an important enzyme involved in OCM, and plays a role in the supplement of SAM in arsenic metabolism ( Chung et al, 2010 ; Wlodarczyk et al, 2012 ). An association between MTHFR SNPs and arsenic metabolism was identified in both an animal model and an epidemiologic study ( Steinmaus et al, 2007 ; Wlodarczyk et al, 2012 ). However, the effects of variants of MTHFR and other selected genes are not described in pregnant women.…”

Section: Introductionmentioning

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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“…Because methylation is an important process of inorganic arsenic detoxification, and reduced methylation capacity is believed to increase arsenic related diseases (Tseng 2007), it led us to speculate that the polymorphic MTHFR gene may contribute to the sensitivity of arsenic-induced congenital malformations. Additionally we have recently shown that different MTHFR activity significantly modulates arsenic excretion in mice (Wlodarczyk et al 2012). We made use of a previously created Mthfr knockout mouse (Chen et al 2001) to examine the potential interaction between genetic susceptibility conveyed by Mthfr gene, and in utero exposure of inorganic arsenic.…”

Section: Introductionmentioning

confidence: 99%

Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

Wlodarczyk

Zhu

Finnell

2014

Toxicology and Applied Pharmacology

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Background In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity vary widely and depend on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. Methods Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. Results When the dams in Mthfr+/− x Mthfr+/− matings were treated with 7.2mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr+/+ x Mthfr+/−, Mthfr+/− x Mthfr+/− and Mthfr−/− x Mthfr+/−) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote x wild-type versus wild-type x nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. Conclusions Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure.

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Arsenic urinary speciation in Mthfr deficient mice injected with sodium arsenate

Cited by 9 publications

References 41 publications

Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner

Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner

Gene-environment interaction and maternal arsenic methylation efficiency during pregnancy

Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

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