Arsenic metabolism differs between child and adult patients during acute arsenic poisoning.

Epidemiological studies on chronic arsenic poisoning have clarified the relationship between various adverse effects and methylation efficiency or methylation capacity. However, no study has similarly investigated such effects on patients with acute arsenic poisoning. In the present work, we studied 61 patients with acute oral arsenic poisoning occurring after consumption of an arsenic trioxide-laced meal (curry soup). The cohort included children (defined as under 15 year old [y/o], n = 22) and adults (over 16 y/o, n = 39) whose urinary arsenic profiles were analyzed. None of these patients had received treatment with chelating agents. The estimated median (IQR) arsenic intake was 64.5 mg (48.3-80.5 mg) in children and 76.0 mg (56.0-91.0 mg) in adults, and these values were not significantly different. Symptoms of poisoning in children improved approximately 1 week after hospitalization. However, the symptoms in most adults deteriorated with severe signs of arsenic poisoning. Urinary arsenic profiles of all the patients were analyzed to obtain the following information: % monomethylarsonic acid (MMA), % dimethylarsinic acid (DMA), second methylation ratio (DMA/MMA), and secondary methylation index (SMI, DMA/MMA + DMA). The levels of these parameters may help identify patients at risk for worsening symptoms. %MMA, an indicator of incomplete methylation, increased more in adults, who experienced more severe symptom progression, compared with children. In contrast, %DMA, which indicates more complete and efficient methylation, increased particularly in children with mild symptoms. Overall the present results indicate that children possess an excellent capacity for methylation (second methylation ratio) of arsenic to DMA and therefore, experience relatively less severe progression of symptomology during acute arsenic poisoning.

The association of tryptophan and phenylalanine are associated with arsenic-induced skin lesions in a Chinese population chronically exposed to arsenic via drinking water: a case-control study.

OBJECTIVES: We investigated the association of specific serum amino acids (AAs) with the odds of arsenic-induced skin lesions (AISL) and their ability to distinguish patients with AISL from people chronically exposed to arsenic. DESIGN: Case-control study. SETTING: Three arsenic-exposed villages in Wuyuan County, Hetao Plain, Inner Mongolia, China were evaluated. PARTICIPANTS: Among the 450 residents aged 18-79 years, who were chronically exposed to arsenic via drinking water, 56 were diagnosed as having AISL (defined as cases). Another 56 participants without AISL, matched by gender and age (±1 year) from the same population, were examined as controls. MAIN OUTCOME MEASURES AND METHODS: AA levels were determined by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics analysis. Potential confounding variables were identified via a standardised questionnaire and clinical examination. Multivariable conditional logistic regression model and receiver operating characteristic curve analyses were performed to investigate the relationship between specific AAs and AISL. RESULTS: Tryptophan and phenylalanine levels were negatively associated with AISL (p<0.05). Compared with that in the first quartile, the adjusted OR of AISL in the second, third and fourth quartiles were decreased by 44%, 88% and 79% for tryptophan and 30%, 80% and 80% for phenylalanine, respectively. The combination of these two higher-level AAs showed the lowest OR for AISL (OR=0.08; 95% CI 0.02 to 0.25; p<0.001). Furthermore, both AAs showed a moderate ability to distinguish patients with AISL from the control, with the area under the curve (AUC; 95% CI) as 0.67 (0.57 to 0.77) for tryptophan and 0.70 (0.60 to 0.80) for phenylalanine (p<0.05). The combined pattern with AUC (95% CI) was 0.72 (0.62 to 0.81), showing a sensitivity of 76.79% and specificity of 58.93% (p<0.001). CONCLUSIONS: Specific AAs may be linked to AISL and play important roles in early AISL identification. TRIAL REGISTRATION NUMBER: NCT02235948.

Inorganic arsenic exposure increased expression of Fas and Bax gene in vivo and vitro.

Accumulating evidences have shown that apoptosis plays an important role in mediating the therapeutic effects and toxicity of arsenic. Fas and Bax genes are critical regulatory genes for apoptosis. In this study, we investigated the association between levels of Fas and Bax expression and the three arsenic species (inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in vivo and vitro. Three arsenic species in urine were measured and levels of Fas and Bax expression were examined by the quantitative real-time PCR (qPCR) for all subjects. We found that Fas and Bax mRNA expression in the exposed group were significantly higher than that in the control group. The levels of gene expression were positively correlated with the concentrations of urinary iAs, MMA and DMA in all subjects. Sodium arsenite induced Fas and Bax mRNA expression, then MMA and DMA did not induce mRNA expression in MDA-MB-231 and XWLC-05 cells. The findings of the present study indicated that iAs, MMA, and DMA had different effects on expression of Bax and Fas gene.

Chronic arsenic intoxication diagnostic score (CAsIDS).

Arsenic and its compounds are well-established, potent, environmentally widespread and persistent toxicants with metabolic, genotoxic, mutagenic, teratogenic, epigenetic and carcinogenic effects. Arsenic occurs naturally in the Earth's crust, but anthropogenic arsenic emissions have surmounted the emissions from important natural sources such as volcanism. Inorganic arsenicals exhibit acute and chronic toxicities in virtually all cell types and tissues, and hence arsenic intoxication affects multiple systems. Whereas acute arsenic intoxication is rare and relatively easy to diagnose, chronic arsenic intoxication (CAsI) is common but goes often misdiagnosed. Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication. CAsIDS can help physicians establish the diagnosis of CAsI and associated conditions.

Effects of Nrf2 deficiency on arsenic metabolism in mice.

Inorganic arsenic (iAs) is a known toxicant and carcinogen. Worldwide arsenic exposure has become a threat to human health. The severity of arsenic toxicity is strongly correlated with the speed of arsenic metabolism (methylation) and clearance. Furthermore, oxidative stress is recognized as a major mechanism for arsenic-induced toxicity. Nuclear factor-E2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, is clearly involved in alleviation of arsenic-induced oxidative damage. Multiple studies demonstrate that Nrf2 deficiency mice are more vulnerable to arsenic-induced intoxication. However, what effect Nrf2 deficiency might have on arsenic metabolism in mice is still unknown. In the present study, we measured the key enzymes involved in arsenic metabolism in Nrf2-WT and Nrf2-KO mice. Our results showed that basal transcript levels of glutathione S-transferase omega 2 (Gsto2) were significantly higher and GST mu 1 (Gstm1) lower in Nrf2-KO mice compared to Nrf2-WT control. Arsenic speciation and methylation rate in liver and urine was then studied in mice treated with 5mg/kg sodium arsenite for 12h. Although there were some alterations in arsenic metabolism enzymes between Nrf2-WT and Nrf2-KO mice, the Nrf2 deficiency had no significant effect on arsenic methylation. These results suggest that the Nrf2-KO mice are more sensitive to arsenic than Nrf2-WT mainly because of differences in adaptive antioxidant detoxification capacity rather than arsenic methylation capacity.

An Unusual Case of Acute Psychosis With Obsessive-Compulsive Features Following Arsenic Poisoning.

Arsenic exposure, particularly the chronic type, can lead to poisoning with manifestations presenting in multiple organ systems. However, acute psychosis is not a commonly described manifestation of arsenic exposure. In this report, we present the case of a patient who developed acute psychosis with hallucinations, disorganized thinking, and obsessive-compulsive symptoms following chronic occupational arsenic exposure. The patient was treated with the combination of an antipsychotic and an antidepressant and he responded well with significant improvement in both the acute psychosis and obsessive-compulsive symptoms. The authors concluded that patients can develop atypical symptoms, including acute psychosis, following arsenic poisoning. In the case described in this report, the patient also presented with a new onset of obsessive-compulsive symptoms. Given this rare manifestation of arsenic poisoning for which there is no clearly defined treatment regimen, this case suggests that the use of a combination of an antipsychotic and an antidepressant may be considered in the rare event of psychosis with obsessive-compulsive features following arsenic poisoning.

DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic.

Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

Strain differences in arsenic-induced oxidative lesion via arsenic biomethylation between C57BL/6J and 129X1/SvJ mice.

Arsenic is a common environmental and occupational toxicant with dramatic species differences in its susceptibility and metabolism. Mouse strain variability may provide a better understanding of the arsenic pathological profile but is largely unknown. Here we investigated oxidative lesion induced by acute arsenic exposure in the two frequently used mouse strains C57BL/6J and 129X1/SvJ in classical gene targeting technique. A dose of 5 mg/kg body weight arsenic led to a significant alteration of blood glutathione towards oxidized redox potential and increased hepatic malondialdehyde content in C57BL/6J mice, but not in 129X1/SvJ mice. Hepatic antioxidant enzymes were induced by arsenic in transcription in both strains and many were higher in C57BL/6J than 129X1/SvJ mice. Arsenic profiles in the liver, blood and urine and transcription of genes encoding enzymes involved in arsenic biomethylation all indicate a higher arsenic methylation capacity, which contributes to a faster hepatic arsenic excretion, in 129X1/SvJ mice than C57BL/6J mice. Taken together, C57BL/6J mice are more susceptible to oxidative hepatic injury compared with 129X1/SvJ mice after acute arsenic exposure, which is closely associated with arsenic methylation pattern of the two strains.

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure.

Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL/6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation.

Ameliorative effect of two Ayurvedic herbs on experimentally induced arsenic toxicity in calves.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic arsenic poisoning due to contaminated subsoil water is a threat to society in West Bengal, India and in Bangladesh. The human being may also be affected by the exposed cattle from the affected area by consuming milk, egg, meat and others. In Ayurveda, several herbs like Haridra (turmeric), Shunthi (dried ginger root) and others are used for the management of arsenic poisoning. AIM OF THE STUDY: The study was conducted to find out the ameliorative effect of turmeric and ginger powder against experimentally induced arsenic toxicity in calves. MATERIALS AND METHODS: Twenty four calves were divided into four groups (group I, II, III and IV) having six animals in each group. Animals of group I, II and III were orally administered with sodium arsenite at 1mg/kg body weight for 90 days and in addition group II and group III animals were treated orally with turmeric and ginger powder respectively at 10mg/kg body weight from 46th day onwards. Group IV animals were given food and water without drug and served as control. Arsenic content was estimated in faeces, hair, urine and plasma in every 15 days. Bio-chemical, haematological and anti-oxidant parameters were also assessed. RESULTS: Turmeric and ginger powder significantly (P<0.05) reduced the plasma and hair arsenic levels through increased excretion via faeces and urine. Haemoglobin level, TEC and TLC were decreased in groups I, II and III, however these were improved significantly (P<0.05) from 75th day onwards in turmeric and ginger treated groups. Increased activity of AST and ALT were significantly decreased (P<0.05) from 75th day onwards in group II and III. Blood urea nitrogen and plasma creatinine were also significantly decreased (P<0.05) in group II and III than group I from 60th day onwards. The SOD and catalase activity were significantly (P<0.05) reduced in groups I, II and III, but these were restored at the end of the experiment in turmeric and ginger treated groups. CONCLUSION: The test drugs are found significantly effective not only to eliminate arsenic from the body but also give protection from possible damage caused by arsenic exposure, it may be concluded from the present study that turmeric and ginger can be helpful in the therapy of chronic arsenic toxicity in calves.

Metabolism and toxicity of arsenicals in mammals.

Arsenic (As) is a metalloid usually found in organic and inorganic forms with different oxidation states, while inorganic form (arsenite As-III and arsenate As-v) is considered to be more hazardous as compared to organic form (methylarsonate and dimethylarsinate), with mild or no toxicity in mammals. Due to an increasing trend to using arsenicals as growth promoters or for treatment purposes, the understanding of metabolism and toxicity of As gets vital importance. Its toxicity is mainly depends on oxi-reduction states (As-III or As-v) and the level of methylation during the metabolism process. Currently, the exact metabolic pathways of As have yet to be confirmed in humans and food producing animals. Oxidative methylation and glutathione conjugation is believed to be major pathways of As metabolism. Oxidative methylation is based on conversion of Arsenite in to mono-methylarsonic acid and di-methylarsenic acid in mammals. It has been confirmed that As is only methylated in the presence of glutathione or thiol compounds, suggesting that As is being methylated in trivalent states. Subsequently, non-conjugated trivalent arsenicals are highly reactive with thiol which converts the trivalent arsenicals in to less toxic pentavalent forms. The glutathione conjugate stability of As is the most important factor for determining the toxicity. It can lead to DNA damage by alerting enzyme profile and production of reactive oxygen and nitrogen species which causes the oxidative stress. Moreover, As causes immune-dysfunction by hindering cellular and humeral immune response. The present review discussed different metabolic pathways and toxic outcomes of arsenicals in mammals which will be helpful in health risk assessment and its impact on biological world.

Specific histone modification responds to arsenic-induced oxidative stress.

To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P<0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: ß=0.16; P=0.042, H3K18ac: ß=-0.24; P=0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage.

Arsenic Metabolism in Children Differs From That in Adults.

Arsenic toxicity in adults is associated with methylation efficiency, influenced by factors such as gender, genetics, and nutrition. The aim of this study was to evaluate influencing factors for arsenic metabolism in children. For 488 children (9 years), whose mothers participated in a study on arsenic exposure during pregnancy (nested into the MINIMat trial) in rural Bangladesh, we measured urinary concentrations of inorganic arsenic (iAs) and its metabolites methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by HPLC-HG-ICPMS. Methylation efficiency was assessed by relative amounts (%) of the metabolites. We evaluated the impact of factors such as maternal urinary metabolite pattern, arsenic exposure, gender, socioeconomic status, season of sampling, and nutritional factors, including erythrocyte selenium (Ery-Se), and plasma folate and vitamin B12.Children had higher %DMA and lower %iAs in urine compared to their mothers, unrelated to their lower exposure [median urinary arsenic (U-As) 53 vs 78 µg/l]. Surprisingly, selenium status (Ery-Se) was strongly associated with children's arsenic methylation; an increase in Ery-Se from the 5-95th percentile was associated with: +1.8 percentage points (pp) for %iAs (P = .001), +1.4 pp for %MMA (P = .003), and -3.2 pp for %DMA (P < .001). Despite this, Ery-Se was positively associated with U-As (5-95th percentile: +41 µg/l, P = .026). As expected, plasma folate was inversely associated with %iAs (5-95th percentile: -1.9 pp, P = .001) and positively associated with %DMA (5-95th percentile: +2.2 pp, P = .008). Children methylated arsenic more efficiently than their mothers. Also influencing factors, mainly selenium and folate, differed. This warrants further research.

Arsenic groundwater contamination and its health effects in Patna district (capital of Bihar) in the middle Ganga plain, India.

We investigated the extent and severity of groundwater arsenic (As) contamination in five blocks in Patna district, Bihar, India along with As in biological samples and its health effects such as dermatological, neurological and obstetric outcome in some villages. We collected 1365 hand tube-well water samples and analyzed for As by the flow injection hydride generation atomic absorption spectrometer (FI-HG-AAS). We found 61% and 44% of the tube-wells had As above 10 and 50 µg/l, respectively, with maximum concentration of 1466 µg/l. Our medical team examined 712 villagers and registered 69 (9.7%) with arsenical skin lesions. Arsenical skin lesions were also observed in 9 children of 312 screened. We analyzed 176 biological samples (hair, nail and urine). Out of these, 69 people had arsenical skin lesions and rest without skin lesions. We found 100% of the biological samples had As above the normal levels (concentrations of As in hair, nail and urine of unexposed individuals usually ranges from 20 to 200 µg/kg, 20-500 µg/kg and <100 µg/l, respectively), indicating many people are sub-clinically affected. Arsenical neuropathy was observed in 40.5% of 37 arsenicosis patients with 73.3% prevalence for predominant sensory neuropathy and 26.7% for sensor-motor. Among patients, different clinical and electrophysiological neurological features and abnormal quantitative sensory perception thresholds were also noted. The study also found that As exposed women with severe skin lesions had adversely affected their pregnancies. People including children in the affected areas are in danger. To combat As situation in affected areas, villagers urgently need (a) provision of As-safe water for drinking and cooking, (b) awareness about the danger of As toxicity, and (c) nutritious food.

[Tracing for arsenic exposure--a differentiation of arsenic compounds is essential for the health assessment]. / Der Arsenbelastung auf der Spur.

Arsenic is ubiquitous and harmful to health in occupation and environment. Arsenic exposure is measured through analysis of arsenic compounds in urine. The identification of several arsenic species is necessary to understand the hazardous potential of the arsenic compounds which differ highly in their toxicity. To estimate the extent of an occupational exposure to arsenic, arsenic species were evaluated for the first time by the working group "Setting of Threshold Limit Values in Biological Material" of the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area and Biologische Arbeitsstoffreferenzwerte (BAR) of 0.5 µg / L urine for arsenic (III), 0.5 µg / L urine for arsenic (V), 2 µg / L urine for monomethylarsonic acid (MMA) and 10 µg / L urine for dimethylarsinic acid (DMA) were set. If the reference value for total arsenic is exceeded, a further differentiation of arsenic species now enables to estimate the individual health risks taking into account special influences such as seafood consumption.

Role of linoleic acid in arsenical palmar keratosis.

BACKGROUND: Chronic arsenic exposure can lead to palmoplantar keratosis. In the stratum corneum of skin, linoleic acid is of the utmost importance to the inflammation, keratinization, and regeneration processes. OBJECTIVES: The aims of this study were: (i) to present quantitative information on the linoleic acid fraction of intercorneocyte lipids, and (ii) to elucidate the role of linoleic acid in the pathophysiology of arsenical keratosis. METHODS: Lipid extracts were collected from keratotic lesions in seven patients, seven arsenic-exposed subjects, and seven non-exposed control subjects. Linoleic acid levels of the specimens were estimated by reverse-phase high-performance liquid chromatography (RP-HPLC). RESULTS: There was a significant (P < 0.001) increase in mean ± standard error (SE) linoleic acid levels in arsenical keratosis patients (palm: 25.66 ± 4.95 µg/cm(2); dorsum: 28.25 ± 6.20 µg/cm(2)) compared with arsenic-exposed (palm: 2.75 ± 0.85 µg/cm(2); dorsum: 1.96 ± 0.64 µg/cm(2)) and non-exposed (palm: 1.52 ± 0.61 µg/cm(2); dorsum: 1.28 ± 0.39 µg/cm(2)) control subjects. There was no significant difference (P = 0.556) in linoleic acid concentration in the non-affected skin of the dorsum of the hand (28.25 ± 6.20 µg/cm(2)) compared with that in the palmar sites (25.66 ± 4.95 µg/cm(2)) in the patient group. The change in linoleic acid levels in the arsenic-exposed control group did not differ from that in non-exposed controls (P = 1.000). CONCLUSIONS: Linoleic acid concentration is elevated in arsenical keratosis; this finding warrants further investigation to ascertain whether linoleic acid plays a direct role in the pathophysiology of arsenical keratosis.

Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study.

Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ~400 genome-wide microsatellite markers spaced ~10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly.

Pregnant women in Timis County, Romania are exposed primarily to low-level (<10µg/l) arsenic through residential drinking water consumption.

Excessive arsenic content in drinking water poses health risks to millions of people worldwide. Inorganic arsenic (iAs) in groundwater exceeding the 10µg/l maximum contaminant level (MCL) set by the World Health Organization (WHO) is characteristic for intermediate-depth aquifers over large areas of the Pannonian Basin in Central Europe. In western Romania, near the border with Hungary, Arad, Bihor, and Timis counties use drinking water coming partially or entirely from iAs contaminated aquifers. In nearby Arad and Bihor counties, more than 45,000 people are exposed to iAs over 10µg/l via public drinking water sources. However, comparable data are unavailable for Timis County. To begin to address this data gap, we determined iAs in 124 public and private Timis County drinking water sources, including wells and taps, used by pregnant women participating in a case-control study of spontaneous loss. Levels in water sources were low overall (median=3.0; range=<0.5-175µg/l), although higher in wells (median=3.1, range=<0.5-1.75) than in community taps (median=2.7, range=<0.5-36.4). In a subsample of 20 control women we measured urine biomarkers of iAs exposure, including iAs (arsenite and arsenate), dimethylarsinic acid (DMA), and methylarsonic acid (MMA). Median values were higher among 10 women using iAs contaminated drinking water sources compared to 10 women using uncontaminated sources for urine total iAs (6.6 vs. 5.0µg/l, P=0.24) and DMA (5.5 vs. 4.2µg/l, P=0.31). The results suggested that the origin of urine total iAs (r=0.35, P=0.13) and DMA (r=0.31, P=0.18) must have been not only iAs in drinking-water but also some other source. Exposure of pregnant women to arsenic via drinking water in Timis County appears to be lower than for surrounding counties; however, it deserves a more definitive investigation as to its origin and the regional distribution of its risk potential.

Arsenic methylation capacity and obesity are associated with insulin resistance in obese children and adolescents.

The goal of the present study was to compare the arsenic methylation capacities in elementary school and junior high school students in an area of Taiwan with low arsenic exposure, and explore the influence of both arsenic methylation capacity and obesity on insulin resistance in these children and adolescents using the HOMA-IR index. We recruited 303 elementary school students and 319 junior high school students in Taipei City from September 2007 to November 2011. Concentrations of inorganic arsenic (arsenite + arsenate), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) were determined by a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Insulin resistance was determined by HOMA-IR. Elementary school students had significantly lower inorganic arsenic percentage and a higher DMA(V) percentage than junior high school students. It seems that the former had better arsenic methylation capability than the latter. The HOMA-IR value was significantly and positively related to the sum of the urinary inorganic and methylated arsenic (TotalAs) concentrations and also the BMI Z score, with the regression coefficients (ß) being 0.058 (p < 0.001) and 0.001 (p = 0.027), respectively. The higher BMI values and higher TotalAs concentration were associated with higher HOMA-IR values in children and adolescents in Taiwan.