Arsenic Methylation Capacity Research Articles

Betaine and choline status modify the effects of folic acid and creatine supplementation on arsenic methylation in a randomized controlled trial of Bangladeshi adults.

Methylation of ingested inorganic arsenic (InAs) to monomethyl- (MMAs) and dimethyl-arsenical species (DMAs) facilitates urinary arsenic elimination. Folate and creatine supplementation influenced arsenic methylation in a randomized controlled trial. Here, we examine if baseline status of one-carbon metabolism nutrients (folate, choline, betaine, and vitamin B12) modified the effects of FA and creatine supplementation on changes in homocysteine, guanidinoacetate (GAA), total blood arsenic, and urinary arsenic metabolite proportions and indices. Study participants (N = 622) received 400 or 800μg FA, 3g creatine, 400μg FA + 3g creatine, or placebo daily for 12weeks. Relative to placebo, FA supplementation was associated with greater mean increases in %DMAs among participants with betaine concentrations below the median than those with levels above the median (FDR < 0.05). 400μg FA/day was associated with a greater decrease in homocysteine among participants with plasma folate concentrations below, compared with those above, the median (FDR < 0.03). Creatine treatment was associated with a significant decrease in %MMAs among participants with choline concentrations below the median (P = 0.04), but not among participants above the median (P = 0.94); this effect did not significantly differ between strata (P = 0.10). Effects of FA and creatine supplementation on arsenic methylation capacity were greater among individuals with low betaine and choline status, respectively. The efficacy of FA and creatine interventions to facilitate arsenic methylation may be modified by choline and betaine nutritional status. Clinical Trial Registry Identifier: NCT01050556, U.S. National Library of Medicine, https://clinicaltrials.gov ; registered January 15, 2010.

Executive functions in school children from Montevideo, Uruguay and their associations with concurrent low-level arsenic exposure

ObjectiveArsenic is a known childhood neurotoxicant, but its neurotoxicity at low exposure levels is still not well established. The aim of our cross-sectional study was to test the association between low-level arsenic exposure and executive functions (EF) among children in Montevideo. We also assessed effect modification by arsenic methylation capacity, a susceptibility factor for the health effects of arsenic, and by B-vitamin intake, which impacts arsenic methylation. MethodsArsenic exposure was assessed as the specific gravity-adjusted sum of urinary arsenic metabolites (U-As) among 255 ~ 7 year-old children, and methylation capacity as the proportion of urinary monomethylarsonic acid (%MMA). Arsenic concentrations from kitchen water samples at participants’ homes were assessed. B-vitamin intake was calculated from the average of two 24-hour dietary recalls. EF was measured using three tests from the Cambridge Neuropsychological Test Automated Battery– Stockings of Cambridge (SOC), Intra-dimensional/extra-dimensional shift task (IED), and Spatial Span (SSP). Generalized linear models assessed the association between U-As and EF measures; models were adjusted for age, sex, maternal education, possessions score, Home Observation for Measurement of the Environment Inventory score, season, and school clusters. Additional analyses were conducted to address issues of residual confounding and sample size. A “B-vitamin index” was calculated using principal component analysis. Effect modification by the index and urinary %MMA was assessed in strata split at the respective medians of these variables. ResultsThe median (range) U-As and water arsenic levels were 9.9 µg/L (2.2, 47.7) and 0.45 µg/L (0.1, 18.9) respectively, indicating that exposure originated mainly from other sources. U-As was inversely associated with the number of stages completed (β = −0.02; 95% CI: −0.03, −0.002) and pre-executive shift errors (β = −0.08; 95% CI: −0.14, −0.02) of the IED task, and span length of the SSP task (β = −0.01; 95% CI: −0.02, −0.004). There was no clear pattern of effect modification by B-vitamin intake or urinary %MMA. ConclusionLow-level arsenic exposure may adversely affect executive function among children but additional, including longitudinal, studies are necessary to confirm these findings.

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.

Inorganic arsenic methylation capacity and breast cancer by immunohistochemical subtypes in northern Mexican women

BackgroundPreviously we reported that inorganic arsenic (iAs) methylation capacity was associated with breast cancer (BC). BC risk factors may vary according to immunohistochemical subtype. Here we explored the relationships between the capacity to methylate iAs and the risk of BC by subtype. MethodsA population-based case-control study was performed in northern Mexico. Patients with available information about BC subtypes (n = 499) were age-matched with healthy controls. Sociodemographic, reproductive, and lifestyle characteristics were obtained. Tumor marker information was obtained from medical records. Cases were classified as HR+ [estrogen receptor (ER+) and/or progesterone (PR+), and human epidermal growth factor receptor 2 (HER2-)], HER2+, or triple negative (TN). Urinary arsenic species were determined by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and methylation capacity parameters calculated. Conditional logistic regression models were used to estimate BC risk by subtypes. ResultsUrinary total arsenic varied from 0.60 to 303.29 μg/L. A significant positive association was found between % monomethylarsonic acid (%MMA) and HR + BC: one percent increase resulted in OR%MMA continuous = 2.73, 95% CI: 1.48, 5.05), and this association remained even when %iAs or % dimethylarsinic acid (%DMA) were added to the models with %MMA. MMA/iAs was positively associated with HR + BC (ORMMA/iAs continuous = 2.03, 95% CI: 1.33–3.10). A significant negative association was observed between DMA/MMA and HR + BC (ORDMA/MMA continuous = 0.43, 95% CI: 0.26, 0.71). MMA/iAs was positively associated with TN BC (OR MMA/iAs continuous = 4.05; 95% CI: 1.63, 10.04). ConclusionAltered iAs methylation capacity resulting in higher %MMA was associated with HR+ and TN BC but not with HER2+. MMA is the iAs metabolite more likely to be related to BC. Further research is needed to confirm these results and elucidate the underlying biological mechanisms.

Changes in urinary arsenic species and methylation capacity in original arsenic exposure cohort after water quality improvement.

Water quality improvement is the most efficient way to prevent arsenic exposure. After the cessation of arsenic ingestion, arsenic methylation capacity of the exposed population can change significantly. The factors associated with these changes remain poorly understood. Therefore, arsenic methylation capacity in a study cohort was estimated before and after water quality improvement in the present study. Results indicated that urinary content of the arsenic species in the study cohort significantly decreased after water quality improvement. In addition, the proportions of inorganic arsenic (%iAs) and monomethyl arsenic acid (%MMA) were significantly decreased, while proportions of dimethyl arsenic (%DMA) increased. The primary methylation index (PMI) and secondary methylation index (SMI) increased from 0.85 to 0.92 and 0.82 to 0.84, respectively. Arsenic species urinary content and arsenic methylation index varied slightly between the study cohort after water quality improvement and the control cohort. The rate of increase in PMI was higher than that in SMI. The study group aged 31-50years had the highest increase in PMI. Logistic regression revealed that %DMA before water quality improvement was negatively associated with the increase in PMI, while %iAs were positively related, and %MMA were positively associated with the increase in SMI. It is concluded that urinary arsenic species content and arsenic methylation capacity increased to the levels of the control cohort after water quality improvement. An increase in primary arsenic methylation capacity may be a burden on the secondary arsenic methylation capacity. The main role of arsenic methylation capacity recovery may be the cessation of arsenic exposure.

Low level arsenic exposure, B-vitamins, and achievement among Uruguayan school children.

Millions of children globally, including the U.S., are exposed to low levels of arsenic from water and food. Arsenic is a known neurotoxicant at high levels but its effects at lower exposure levels are understudied. Arsenic methylation capacity, influenced by B-vitamin intake and status, potentially influences arsenic toxicity. In a cross-secitonal study of 5-8 year-old children from Montevideo, we assessed the relationship between urinary arsenic (U-As) and academic achievement, and tested for effect modification by B-vitamin intake, status, and arsenic methylation capacity. Broad math and reading scores were calculated based on six subtests (calculation, math facts fluency, applied problems, sentence reading fluency, letter word identification, passage comprehension) from the Woodcock-Muñoz Achievement Battery. B-vitamin intake was assessed from two non-consecutive 24-h dietary recalls, serum folate and vitamin B-12 levels were measured in a subset of participants. Arsenic methylation capacity was measured as the proportion of urinary monomethylarsonic acid (%MMA). Multiple imputation using chained equations was conducted to account for missing covariate and exposure data. Ordinal regressions assessed associations between U-As and achievement score tertiles in the complete case and imputed samples. A "B-vitamin index" was calculated using principal component analysis. Interactions by urinary %MMA and the B-vitamin index were assessed. Median specific gravity adjusted U-As was 11.7 μg/L (range: 2.6, 50.1). We found no association between U-As and broad math and reading scores, nor effect modification by %MMA or B-vitamins. At low-levels of exposure, U-As does not appear to affect children's academic achievement.

Folic acid effects blood arsenic metabolites

TPS 621: Exposure to metals, Johan Friso Foyer, Floor 1, August 26, 2019, 3:00 PM - 4:30 PM Background/Aim: Arsenic exposure through drinking water affects at least 40 million people in Bangladesh and 140 million people worldwide. Inorganic arsenic (InAs) is methylated to mono- (MMAs) and di-methyl (DMAs) arsenicals; methylation to DMAs decreases toxicity and facilitates urinary arsenic excretion. Nutrients involved in one-carbon metabolism, the pathway that generates the methyl donor S-adenosyl-methionine, may influence arsenic methylation capacity. This study investigated folic acid (FA) and/or creatine treatment effect on the concentrations of arsenic metabolites and arsenic methylation indices in blood. Methods: In a 24-week randomized, placebo-controlled trial, 622 participants were randomized to receive FA (400 or 800 μg/day), 3 g creatine/day, 400 μg FA + 3 g creatine/day, or placebo. Participants received arsenic-removal water filters. Primary (PMI) and secondary methylation indices (SMI) were calculated as MMAs/InAs and DMAs/MMAs concentrations, respectively. Treatment effects on the concentrations of arsenic metabolites and methylation indices in blood were assessed using linear models with repeated measures. Results: In the 800 μg/day FA group, the mean decrease in ln(InAs concentration) exceeded that of the placebo group at week 12 (P = 0.001). We previously reported that 400 ug/day FA did not significantly lower total blood arsenic; however, in all groups receiving FA, the mean decreases in ln(MMAs concentration) exceeded that of the placebo group (e.g., MMAs concentration decreased by 20% and 27% in the 400 and 800 µg FA groups, respectively, and by 8.7% in the placebo group) (P < 0.05). Compared to placebo, the mean decreases in PMI were greater among FA groups (P < 0.05), and the mean increase in SMI was greater among all treatment groups, including creatine (P < 0.05). Conclusion: FA supplementation decreased the concentrations of InAs and MMAs and increased arsenic methylation capacity measured in blood. Creatine supplementation also increased arsenic methylation, but to a lesser extent than FA.

Factors affecting arsenic methylation capacity

Factors affecting arsenic methylation capacity

Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan.

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case-control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV%, low InAs%, and high DMAV%). High MMAV% significantly increased and high DMAV% and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83-30.06), 0.21 (0.04-1.23), and 0.20 (0.03-1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

Measurement of urinary arsenic profiles and DNA hypomethylation in a case-control study of urothelial carcinoma.

Environmental exposure to arsenic may be involved in the disturbance of DNA hypomethylation. The aim of this study is the first to explore the effect of interactions of urinary total arsenic levels, arsenic methylation capacity, 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasma folate, and global 5-methyl-2'-deoxycytidine (5-MedC) levels on the risk of urothelial carcinoma (UC). A hospital-based case-control study was constructed. The research involved the histological recruitment and pathological verification of 178 UC patients and 356 age-/sex-matched controls without prior history of cancer. Arsenic species were determined by high-performance liquid chromatography (HPLC)-hydride generation and atomic absorption. 5-MedC levels were detected by HPLC and triple-quadrupole mass spectrometry (MS). 8-OHdG was processed by an online solid-phase extraction LC-MS/MS. Plasma folate levels were measured using the chemiluminescent technology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by multiple logistic regression analysis. Results indicate that the high levels of total urinary arsenic, inorganic arsenic percentage, and 8-OHdG and the low levels of DMA % and plasma folate were independent factors of UC. In addition, global 5-MedC levels in the first quartile versus fifth quartile significantly increased the twofold OR of UC after potential factors were adjusted (95% CI:1.10-4.03). The interaction of 5-MedC level and high total arsenic level, insufficient arsenic capacity, high 8-OHdG, and low folate levels was insignificant. Results of stepwise logistic regression analysis indicate that high total urinary arsenic levels (Q3 versus Q1), low plasma folate level, and low global 5-MedC (Q4 versus Q5) significantly increased the ORs of UC. The above results suggest that high total arsenic, low plasma folate, and 5-MedC levels affect the ORs of UC independently.

Influence of AS3MT polymorphisms on arsenic metabolism and liver injury in APL patients treated with arsenic trioxide

Arsenic-induced side effects limit its application in the treatment of acute promyelocytic leukemia (APL). We recently demonstrated that AS3MT 14215 (rs3740390) genotypes were associated with urinary arsenic metabolites and hematological and biochemical values. To further decipher the role of AS3MT genotypes on arsenic metabolism and toxicity, AS3MT 27215 (rs11191446), 35587 (rs11191453), 35991 (rs10748835), and their interactive effects were examined in fifty APL patients treated with arsenic trioxide (As2O3) for the first time. Urinary arsenic metabolites and methylation capacity indexes were evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), primary methylation index (PMI, MMA/iAs), secondary methylation index (SMI, DMA/MMA), and total methylation index (TMI, [MMA+DMA]/iAs). Results showed 27215 (rs11191446) genotypes had no statistical significance in arsenic metabolism, as only 5 (10%) patients were the non-wild-type genotypes. 35587 (rs11191453) genotypes were significantly associated with MMA%, DMA%, and SMI. 35991 (rs10748835) genotypes were significantly associated with iAs%, DMA%, PMI, TMI, and the level of ALT and AST. Patients with both 35587 (rs11191453) TT and 35991 (rs10748835) AG+GG genotypes were significantly associated with DMA% and SMI. In addition, patients with both 35991 (rs10748835) AA and 35587 (rs11191453) TC+CC genotypes had the highest DMA%, SMI, and TMI, but the lowest iAs%, ALT and AST level, indicating that additive effects exist on arsenic metabolism and liver function. Our data promotes the realization that AS3MT 35587 (rs11191453), 35991 (rs10748835), especially their joint genotypes 35991 (rs10748835) AA / 35587 (rs11191453) TC+CC, is a novel predictive biomarker for the therapeutic efficacy of As2O3 in the treatment of APL.

Plasma selenium influences arsenic methylation capacity and developmental delays in preschool children in Taiwan

Inefficient arsenic methylation capacity has been associated with developmental delay in preschool children. Selenium has antioxidant and anti-inflammatory properties that protect experimental animals from chemically induced neurotoxicity. The present study was designed to explore whether plasma selenium levels affects arsenic methylation capacity related to developmental delay in preschool children. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 178 children with a developmental delay and 88 children without a delay were recruited. High-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry were used to determine urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV). Plasma selenium levels were measured by inductively coupled plasma mass spectrometry. As results, plasma selenium concentration was significantly inversely associated with the odds ratio (OR) of developmental delay. Plasma selenium concentration was positively associated with arsenic methylation capacity [percentage of inorganic arsenic and percentage of MMAV (MMAV%) decreased, and percentage of DMAV (DMAV%) increased]. High plasma selenium concentration and high DMA% significantly and additively interacted to decrease the OR of developmental delay; the OR and 95% confidence interval were 0.40 (0.18–0.90). This is the first study to show a combined dose-response effect of plasma selenium concentration and that efficient arsenic methylation capacity decreased the OR of developmental delay in preschool children.

Elevated arsenic exposure and efficient arsenic metabolism in indigenous women around Lake Poopó, Bolivia

Elevated concentrations of inorganic arsenic, one of the most potent environmental toxicants and carcinogens, have been detected in well water around Lake Poopó, Bolivia. This study aimed to assess human exposure to arsenic in villages around Lake Poopó, and also to elucidate whether the metabolism and detoxification of arsenic in this population is as efficient as previously indicated in other Andean areas. We recruited 201 women from 10 villages around Lake Poopó. Arsenic exposure was determined as the sum concentration of arsenic metabolites (inorganic arsenic; monomethylarsonic acid, MMA; and dimethylarsinic acid, DMA) in urine (U-As), measured by HPLC-HG-ICP-MS. Efficiency of arsenic metabolism was assessed by the relative fractions of the urinary metabolites. The women had a wide variation in U-As (range 12–407 μg/L, median 65 μg/L) and a markedly efficient metabolism of arsenic with low %MMA (median 7.7%, range: 2.2–18%) and high %DMA (80%, range: 54–91%) in urine. In multivariable-adjusted linear regression models, ethnicity (Aymara-Quechua vs. Uru), body weight, fish consumption and tobacco smoking were associated with urinary arsenic metabolite fractions. On average, the Uru women had 2.5 lower % (percentage unit) iAs, 2.2 lower %MMA and 4.7 higher %DMA compared with the Aymara-Quechua women. Our study identified several factors that may predict these women's arsenic methylation capacity, particularly ethnicity. Further studies should focus on mechanisms underlying these differences in arsenic metabolism efficiency, and its importance for the risk of arsenic-related health effects.

Preliminary study of urinary arsenic concentration and arsenic methylation capacity effects on neurodevelopment in very low birth weight preterm children under 24 months of corrected age.

The neurological prognoses of very low birth weight preterm (VLBWP) children during the first 2 years of life will influence their neurodevelopment during subsequent childhood years and adolescence. The objective of this study was to systemic investigate relationships of urinary arsenic (As) concentrations, the As methylation capability, and toenail As concentrations on cognitive, language, and motor development in VLBWP children under 24 months of corrected age.Participants (n = 60) in our study were recruited from October 2010 to April 2013. Urine and toenail samples were collected for evaluation to assess As exposure. The Bayley scales of infant development III were used to evaluate neurodevelopment at 2 years of corrected age. Concentrations of As species in urine and the As concentration in toenails were, respectively, analyzed using HPLC-HG-AAS and ICP-MS.The mean concentration of total As was 28.6 μg/g creatinine, and inorganic As was 1.01 μg/L in urine. The urine contained an average of 3% inorganic As, 2% monomethylarsonic acid, and 95% dimethylarsinic acid (DMA). The mean concentration of As in toenails was 225 ng/g. Children with a longer gestational age (≥28 weeks) and higher DMA % levels appeared to have the highest unadjusted cognitive and fine motor scores.Our study results suggest that gestational age is associated with neurodevelopment in VLBWP children. We recommend that further study simultaneously analyze multiple environmental contaminants that may have adverse effects on neurodevelopment, use biomarkers for the mother–child pair, and determine whether prenatal or postnatal As exposure has a greater influence on the neurological development of VLBWP children.

Corrigendum to "Polymorphisms of Arsenic (+3 Oxidation State) Methyltransferase and Arsenic Methylation Capacity Affect the Risk of Bladder Cancer".

Corrigendum to "Polymorphisms of Arsenic (+3 Oxidation State) Methyltransferase and Arsenic Methylation Capacity Affect the Risk of Bladder Cancer".

A follow-up study of the development of skin lesions associated with arsenic exposure duration.

Little information about the development of skin lesions in relation to arsenic exposure duration is available. Therefore, skin lesions in a cohort from the Bameng region of China were diagnosed in 2012 and 2017. The results indicated that the prevalence of hyperkeratosis, pigmentation and depigmentation in 2017 was 64.67, 6.67 and 12.67%. There were 42 and 34% of male subjects and female subjects suffered from skin lesions in 2012. Their morbidity rates were 10.43 and 8.98 per 1000 person-years. In 2017, the values were significantly increased. The prevalence and morbidity rate of skin lesions were positively correlated with age and arsenic levels in drinking water. Males had higher prevalence of skin lesions compared with female. However, the ≤ 40years female group had higher prevalence of skin lesions. In addition, the increased rate of skin lesions prevalence was negatively correlated with arsenic levels in drinking water. The odds ratios (ORs) showed that the risks of skin lesions were positively associated with the proportion of inorganic arsenic (%iAs) and monomethylarsonic acid (%MMA) in urine, and negatively correlated with arsenic methylation capacity in both 2012 and 2017. It can be concluded that females immigrated from other areas were more susceptible to developing skin lesions. A certain cumulative arsenic exposure dose, which may be existing, significantly increased the prevalence of skin lesions. Longer arsenic exposure duration might elevate the toxicity of iAs to skin lesions and reduce the positive effects of arsenic methylation capacity on skin lesions.

PO-081 Hypermethylation responses to inorganic arsenic exposure may increase the risk of liver cancer occurrence

Introduction Exposure to inorganic arsenic (InAs) has been known as a risk factor for liver cancer. However, documents have indicated that specific forms of arsenic may inhibit the activity of hepatitis viruses. This study investigated the association between InAs exposure and liver cancer occurrence while examining the effects of arsenic methylation capacity in an exposed cohort. Material and methods This study followed 4056 residents, an average of 19.2 years of follow-up, from an arseniasis area in Taiwan, and identified 90 liver cancer cases. The inorganic arsenic metabolites were determined by ICP-MS and methylation capacity was calculated from the combination of InAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). The primary methylation index (MMA/InAs) and the secondary methylation index (DMA/MMA) and their median high/low combinations were used. Cox proportional hazards model was performed to calculate the hazard ratio (HR) of liver cancer occurrence. Results and discussions The analyses revealed a significant association between liver cancer occurrence and arsenic methylation capacity, which demonstrated a lower risk of the participants with low secondary methylation index. The results showed that participants with lower primary and lower secondary methylation index than their respective median values were at a lower risk of liver cancer (HRs from 0.230 to 0.231) than those with high methylation capacity. The incidence density of liver cancer ranging from 48.2/100,000 (year-1) to 100.4/100,000 (year-1) for residents with low secondary methylation index and from 99.1/100,000 (year-1) to 186.8/100,000 (year-1) for residents with high secondary methylation index when the arsenic exposure dose was classified into quartiles. Conclusion Hypomethylation responses to InAs exposure may associate with lower liver cancer occurrence. Two mechanisms were conjectured. First, a specific forms of arsenic may inhibit the hepatitis viral activity. Second, hypermethylation activities among residents chronically exposed to inorganic arsenic may induce arsenic carcinogenesis, which warrants for further investigations.

Comparison of arsenic methylation capacity and polymorphisms of arsenic methylation genes between bladder cancer and upper tract urothelial carcinoma

Arsenic exposure is an environmental risk factor for urothelial carcinoma (UC). The natural history of upper tract urothelial carcinoma (UTUC) differs from that of bladder cancer (BC). However, the risk factors of BC and UTUC are not exactly the same and should be discussed separately. The aims of this study were to evaluate 1) the association between arsenic methylation capacity and UTUC and/or BC, separately, and 2) the association between polymorphisms of the arsenic metabolism-related genes AS3MT, GSTOs, and PNP against BC and/or UTUC, separately. We conducted a hospital-based study and collected 216 BC and 212 UTUC cases, and 813 healthy controls, from September 2007 to October 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. We found that inefficient arsenic methylation capacity was associated with BC in a significant dose-response relationship, but only found that high urinary total arsenic concentration was related to the risk of UTUC, also in a significant dose-response manner. Those with a total urinary arsenic level of > 30.28 μg/L compared to ≤ 9.78 μg/L, had a odds ratio (OR), and 95% confidence interval (CI) of UTUC, of 4.80 (2.22–10.39). The polymorphisms of AS3MT rs11191438, AS3MT rs10748835, and AS3MT rs1046778 were related to the risk of BC and UTUC, while the polymorphisms of AS3MT rs3740393, AS3MT rs11191453, and AS3MT rs11191454 were associated with arsenic methylation capacity. The AS3MT gene polymorphisms and arsenic methylation capacity appear to independently affect the risk of BC and UTUC.

Polymorphisms of Arsenic (+3 Oxidation State) Methyltransferase and Arsenic Methylation Capacity Affect the Risk of Bladder Cancer.

The mechanisms underlying how arsenic methylation capacity affects bladder cancer (BC) are still unclear. The objective of this study was to explore the effects of polymorphisms of arsenic (+3 oxidation state) methyltransferase (AS3MT) on BC risk. We conducted a hospital-based study and enrolled 216 BC and 648 healthy controls from 2007 to 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generation-atomic absorption spectrometry. The gene polymorphisms of AS3MT were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Inefficient arsenic methylation capacity (high monomethylarsonic acid percentage [MMA%] and low dimethylarsinic acid percentage [DMA%]) was associated with increased risk of BC in a dose-response relationship. AS3MT rs11191438 (C > G) G/G genotype, AS3MT rs10748835 (A > G) G/G genotype, and AS3MT rs1046778 (C > T) T/T genotype were found to be related to BC risk, where the odds ratio (OR) (95% CI) was 0.50 (0.31-0.82), 0.49 (0.30-0.79), and 0.54 (0.36-0.80), respectively. The combination of AS3MT haplotype 2 (AS3MT rs11191453, rs11191454, rs10748835, and rs1046778)'s high-risk haplotype (C-G-A-C, T-A-A-C, and T-G-G-T) was significantly associated with increased risk of BC. Among controls, only 3 of the 9 candidate genotypes evaluated, rs1119438 C/C, rs10748835 A/A and rs1046778 C/C, were associated with significantly higher MMA% compared with the other genotypes. No other genotypes or haplotypes were related to arsenic methylation capacity. High MMA%, low DMA% and AS3MT rs1046778 C/C + C/T genotype predicted a significantly higher risk of BC according to stepwise multiple logistic regression analyses. AS3MT gene polymorphisms and arsenic methylation capacity appeared to affect BC risk independently.

Arsenic methylation capacity in relation to nutrient intake and genetic polymorphisms in one-carbon metabolism

BackgroundNutrients and genetic polymorphisms participating in one-carbon metabolism may explain interindividual differences in inorganic arsenic (iAs) methylation capacity, which in turn may account for variations in susceptibility to iAs-induced diseases. Objectives1) To evaluate the association between polymorphisms in five one-carbon metabolism genes (FOLH1 c.223 T > C, MTHFD1 c.1958 G > A, MTHFR c.665 C > T, MTR c.2756 A > G, and MTRR c.66 A > G) and iAs methylation capacity; 2) To assess if previously reported associations between nutrient intake and iAs methylation capacity are modified by those polymorphisms. MethodsWomen (n = 1027) exposed to iAs in Northern Mexico were interviewed. Blood and urine samples were collected. Nutrient dietary intake was estimated using a validated food frequency questionnaire. iAs methylation capacity was calculated from urinary iAs species (iAs, monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) measured by high performance liquid chromatography (HPLC-ICP-MS). One polymorphism in each of the five genes evaluated was genotyped by allelic discrimination. Multivariable linear regression models were used to evaluate if genetic polymorphisms modified the associations between iAs methylation capacity parameters and nutrient intake. ResultsThe median (min-max) concentration of total arsenic (TAs) was 20.2 (1.3–2776.0) µg/g creatinine in the study population. Significant interactions for iAs metabolism were only found with FOLH1 c.223 T > C polymorphism and vitamin B12 intake, so that CT and CC genotype carriers had significantly lower %iAs, and higher DMA/iAs with an increased vitamin B12 intake, as compared to carriers of wild-type TT. ConclusionDifferences in dietary nutrient intake and genetic variants in one-carbon metabolism may jointly influence iAs methylation capacity. Confirmation of these interactions in other populations is warranted.