Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved.

BACKGROUND: It has been proposed that interactions between selenium and arsenic in the body may affect their kinetics and toxicity. However, it is unknown how the elements influence each other in humans. OBJECTIVES: We aimed to investigate potential interactions in the methylation of selenium and arsenic. METHODS: Urinary selenium (U-Se) and arsenic (U-As) were measured using inductively coupled plasma mass spectrometry (ICPMS) in samples collected from pregnant women (n=226) in rural Bangladesh at gestational weeks (GW) 8, 14, 19, and 30. Urinary concentrations of trimethyl selenonium ion (TMSe) were measured by HPLC-vapor generation-ICPMS, as were inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA). Methylation efficiency was assessed based on relative amounts (%) of arsenic and selenium metabolites in urine. Genotyping for the main arsenite and selenium methyltransferases, AS3MT and INMT, was performed using TaqMan probes or Sequenom. RESULTS: Multivariable-adjusted linear regression analyses indicated that %TMSe (at GW8) was positively associated with %MMA (ß=1.3, 95% CI: 0.56, 2.0) and U-As, and inversely associated with %DMA and U-Se in producers of TMSe (INMT rs6970396 AG+AA, n=74), who had a wide range of urinary TMSe (12-42%). Also, %TMSe decreased in parallel to %MMA during pregnancy, especially in the first trimester (-0.58 %TMSe per gestational week). We found a gene-gene interaction for %MMA (p-interaction=0.076 for haplotype 1). In analysis stratified by INMT genotype, the association between %MMA and both AS3MT haplotypes 1 and 3 was stronger in women with the INMT GG (TMSe nonproducers, 5th-95th percentile: 0.2-2%TMSe) vs. AG+AA genotype. CONCLUSIONS: Our findings for Bangladeshi women suggest a positive association between urinary %MMA and %TMSe. Genes involved in the methylation of selenium and arsenic may interact on associations with urinary %MMA. https://doi.org/10.1289/EHP1912.

Major Limitations in Using Element Concentrations in Hair as Biomarkers of Exposure to Toxic and Essential Trace Elements in Children.

BACKGROUND: Hair is a commonly used exposure biomarker for metals and other trace elements, but concern has been raised regarding its appropriateness for assessing the internal dose. OBJECTIVES: The aim of the present study was to evaluate children's hair as biomarker of internal dose for toxic (As, Mn, Cd, Pb) and essential elements (Mg, Ca, Fe, Co, Cu, Zn, Se, Mo). METHODS: In 207 children (9-10 years of age), originating from a population-based cohort in rural Bangladesh, we measured concentrations of the selected elements in hair ( closest to the scalp) using ICP-MS. We compared these with previously measured concentrations in erythrocytes, urine, and water. For a subset of children (n=19), we analyzed four consecutive 2 cm pieces of hair. RESULTS: There were strong associations between hair As and the other biomarkers (erythrocytes: rs=0.73, p<0.001; urine: rS=0.66, p<0.001); and water (rs=0.60, p<0.001); and there were significant correlations between Se in hair and erythrocytes (overall rs=0.38, p<0.001), and urine (rs=0.29, p<0.001). Hair Co and Mo showed weak correlations with concentrations in erythrocytes. Hair Mn was not associated with Mn in erythrocytes, urine, or water, and the geometric mean concentration increased almost five times from the 2 cm closest to the head to the 7th­8th cm (p<0.001). Also Mg, Ca, Co, Cd, and Pb increased from the scalp outward (>50% higher in 7th­8th cm compared with 1st­2nd cm, p<0.001). CONCLUSIONS: Hair was found to be a useful exposure biomarker of absorbed As and Se only. Of all measured elements, hair Mn seemed the least reflective of internal dose. https://doi.org/10.1289/EHP1239.

Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood.

BACKGROUND: Exposure to inorganic arsenic (iAs) through drinking water causes cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length in blood have been associated with cancer risk. We elucidated if arsenic exposure alters mtDNAcn and telomere length in individuals with different arsenic metabolizing capacity. METHODS: We studied two groups in the Salta province, Argentina, one in the Puna area of the Andes (N = 264, 89% females) and one in Chaco (N = 169, 75% females). We assessed arsenic exposure as the sum of arsenic metabolites [iAs, methylarsonic acid (MMA), dimethylarsinic acid (DMA)] in urine (U-As) using high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. Efficiency of arsenic metabolism was expressed as percentage of urinary metabolites. MtDNAcn and telomere length were determined in blood by real-time PCR. RESULTS: Median U-As was 196 (5-95 percentile: 21-537) µg/L in Andes and 80 (5-95 percentile: 15-1637) µg/L in Chaco. The latter study group had less-efficient metabolism, with higher %iAs and %MMA in urine compared with the Andean group. U-As was significantly associated with increased mtDNAcn (log2 transformed to improve linearity) in Chaco (ß = 0.027 per 100 µg/L, p = 0.0085; adjusted for age and sex), but not in Andes (ß = 0.025, p = 0.24). U-As was also associated with longer telomere length in Chaco (ß = 0.016, p = 0.0066) and Andes (ß = 0.0075, p = 0.029). In both populations, individuals with above median %iAs showed significantly higher mtDNAcn and telomere length compared with individuals with below median %iAs. CONCLUSIONS: Arsenic was associated with increased mtDNAcn and telomere length, particularly in individuals with less-efficient arsenic metabolism, a group who may have increased risk for arsenic-related cancer.

Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene.

BACKGROUND: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans. OBJECTIVE: This study aimed to elucidate the human metabolism of selenium to TMSe. DESIGN: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 µg/L in mothers, 14 µg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 µg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. RESULTS: TMSe "producers" were prevalent (approximately one-third) among the Bangladeshi women and their children, in whom TMSe constituted ∼10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-µg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine N-methyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P < 0.001, false-discovery rate corrected) in both cohorts. CONCLUSIONS: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394.

Environmental exposure to metals and children's growth to age 5 years: a prospective cohort study.

In this prospective cohort study, based on 1,505 mother-infant pairs in rural Bangladesh, we evaluated the associations between early-life exposure to arsenic, cadmium, and lead, assessed via concentrations in maternal and child urine, and children's weights and heights up to age 5 years, during the period 2001-2009. Concurrent and prenatal exposures were evaluated using linear regression analysis, while longitudinal exposure was assessed using mixed-effects linear regression. An inverse association was found between children's weight and height, age-adjusted z scores, and growth velocity at age 5 years and concurrent exposure to cadmium and arsenic. In the longitudinal analysis, multivariable-adjusted attributable differences in children's weight at age 5 years were -0.33 kg (95% confidence interval (CI): -0.60, -0.06) for high (≥95th percentile) arsenic exposure and -0.57 kg (95% CI: -0.88, -0.26) for high cadmium exposure, in comparison with children with the lowest exposure (≤5th percentile). Multivariable-adjusted attributable differences in height were -0.50 cm (95% CI: -1.20, 0.21) for high arsenic exposure and -1.6 cm (95% CI: -2.4, -0.77) for high cadmium exposure. The associations were apparent primarily among girls. The negative effects on children's growth at age 5 years attributable to arsenic and cadmium were of similar magnitude to the difference between girls and boys in terms of weight (-0.67 kg, 95% CI: -0.82, -0.53) and height (-1.3 cm, 95% CI: -1.7, -0.89).

Early-life exposure to lithium and boron from drinking water.

The transfer of lithium and boron from exposed mothers to fetuses and breast-fed infants was investigated in areas in northern Argentina and Chile with up to 700 µg lithium/L and 5-10 mg boron/L in drinking water. Maternal and cord blood concentrations were strongly correlated and similar in size for both lithium (47 and 70 µg/L, respectively) and boron (220 and 145 µg/L, respectively). The first infant urine produced after birth contained the highest concentrations (up to 1700 µg lithium/L and 14,000 µg boron/L). Breast-milk contained 40 and 60% of maternal blood concentrations of lithium and boron, respectively (i.e. about 30 and 250 µg/L, respectively, in high exposure areas), and infant urine concentrations decreased immediately after birth (120 µg lithium/L and 920 µg boron/L). We conclude that lithium and boron easily passed the placenta to the fetus, and that exclusively breast-fed infants seemed to have lower exposure than formula-fed infants.

Environmental exposure to arsenic and cadmium during pregnancy and fetal size: a longitudinal study in rural Bangladesh.

Prenatal exposures to arsenic (As) and cadmium (Cd) have been associated with decreased size at birth. We here studied associations of prenatal As and Cd exposures with multiple fetal size parameters measured by ultrasound in gestational week (GW) 14 and 30 in a population-based mother-child cohort in rural Bangladesh. We measured As (n=1929) and Cd (n=1616) in urine during pregnancy. In the longitudinal evaluation of combined exposure, urinary Cd (UCd) showed an inverted U-shaped association (turning-point 1.5 µg Cd/L) with all fetal size parameters, while UAs showed no significant association. Cross-sectional analyses indicated that associations with UCd were somewhat stronger in early gestation. Stratification indicated stronger associations between UCd and fetal size in girls than in boys, and in poorer than in richer families, while UAs was weakly associated with fetal size in boys. In conclusion, particularly Cd, but also As, appeared to influence fetal development in a sex-dependent manner.

Persistent exposure to arsenic via drinking water in rural Bangladesh despite major mitigation efforts.

OBJECTIVES: Elevated arsenic levels in tube-well water in Bangladesh have prompted extensive mitigation projects. We evaluated the effectiveness of long-term mitigation efforts by longitudinally measuring arsenic exposure in pregnant women and their children, the most susceptible population groups. METHODS: The study was nested in a population-based nutrition intervention in Matlab, Bangladesh. Mother-child pairs (n = 1951) were followed from 2001 to 2003, beginning in early gestation and continuing to 5 years postpartum. We measured arsenic concentrations in urine (U-As) of the 5-year-old children by using high-performance liquid chromatography online with hydride generation and inductively coupled plasma mass spectrometry and compared them with earlier childhood U-As and maternal U-As during pregnancy. RESULTS: Children had elevated U-As at 5 years old (median = 51 µg/L, 5th-95th percentiles = 16-355 µg/L), and U-As distribution was similar to that observed in the mothers during gestation. Children's U-As at 5 years old significantly correlated with their U-As at 1.5 years old and to maternal U-As during early and late gestation. CONCLUSIONS: Despite major mitigation efforts, arsenic exposure remains highly elevated in rural Bangladesh. Further mitigation strategies are required and must be rigorously evaluated for long-term efficacy.

Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status.

Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.

Arsenic exposure and risk of spontaneous abortion, stillbirth, and infant mortality.

BACKGROUND: Millions of people worldwide are drinking water with elevated arsenic concentrations. Epidemiologic studies, mainly cross-sectional in design, have suggested that arsenic in drinking water may affect pregnancy outcome and infant health. We assessed the association of arsenic exposure with adverse pregnancy outcomes and infant mortality in a prospective cohort study of pregnant women. METHODS: A population-based, prospective cohort study of 2924 pregnant women was carried out during 2002-2004 in Matlab, Bangladesh. Spontaneous abortion was evaluated in relation to urinary arsenic concentrations at gestational week 8. Stillbirth and infant mortality were evaluated in relation to the average of urinary arsenic concentrations measured at gestational weeks 8 and 30. RESULTS: : The odds ratio of spontaneous abortion was 1.4 (95% confidence interval [CI] = 0.96-2.2) among women with urine arsenic concentrations in the fifth quintile (249-1253 µg/L; median = 382 µg/L), compared with women in the first quintile (<33 µg/L). There was no clear evidence of increased rates of stillbirth. The rate of infant mortality increased with increasing arsenic exposure: the hazard ratio was 5.0 (95% CI = 1.4-18) in the fifth quintile of maternal urinary arsenic concentrations (268-2019 µg/L; median = 390 µg/L), compared with the first quintile (<38 µg/L). CONCLUSIONS: We found evidence of increased risk of infant mortality with increasing arsenic exposure during pregnancy, with less evidence of associations with spontaneous abortion or stillbirth risk.

Burden of cadmium in early childhood: longitudinal assessment of urinary cadmium in rural Bangladesh.

Chronic cadmium exposure is associated with many adverse health effects in adults, but little is known about the scenario early in life. This study assessed cadmium exposure and body burden in young children, born to women with known cadmium exposure via rice. As part of our ongoing population-based, longitudinal study of health effects of early-life toxicants exposure in rural Bangladesh, we measured cadmium in urine of about 350 children at 1.5 and 5 years of age, and in 92 children at 3 months of age. Median cadmium concentrations in urine were 0.30, 0.16 and 0.30 microg/L at 3 months, 1.5 and 5 years of age, respectively (0.6 microg/L in mothers). Cadmium concentrations in infant's urine correlated with concentrations in maternal breast milk, saliva, and urine. As expected, concentrations in urine increased from 1.5 to 5 years of age. Rice (median 47 microgCd/kg) is most likely the main source of exposure. In conclusion, we found unexpectedly high cadmium exposure among children in rural Bangladesh. Urinary cadmium concentrations were particularly elevated at 3 months of age, indicating limited reabsorption and accumulation of cadmium in the kidneys, known to be the main site of cadmium burden in older children and adults.

Chronic exposure to cadmium and arsenic strongly influences concentrations of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine.

Exposure to arsenic (As), cadmium (Cd), and lead (Pb) may generate oxidative stress, which can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine, a sensitive marker of oxidatively damaged DNA. We have evaluated oxidative stress induced by chronic mixed exposure to As, Cd, and Pb, as well as the influence of As metabolism and nutritional status, i.e., levels of ferritin (Ft), selenium (Se), zinc (Zn), and manganese (Mn) and body weight. 8-OxodG was measured in urine from 212 women in early pregnancy from Matlab, in rural Bangladesh, using LC-MS/MS. Cd and Pb were analyzed in urine and erythrocytes, and Se, Mn, and Zn were analyzed in erythrocytes, all by ICPMS. As and As metabolites were analyzed in urine by HPLC-ICPMS. Ferritin was analyzed in plasma by radioimmunoassay. The median concentration of 8-oxodG was 8.3 nmol/L (adjusted for specific gravity), range 1.2-43, corresponding to a median of 4.7 microg/g creatinine, range 1.8-32. 8-OxodG was positively associated with urinary Cd (beta=0.32, p< 0.001), urinary As (beta=0.0007, p=0.001), the fraction of the monomethylated arsenic metabolite in urine (beta=0.0026, p=0.004), and plasma Ft (beta=0.20, p< 0.001). A joint effect was seen for urinary Cd and As, but whether this effect was additive or multiplicative was difficult to discern.

Pre- and postnatal arsenic exposure and child development at 18 months of age: a cohort study in rural Bangladesh.

BACKGROUND: Exposure to arsenic through drinking water has been associated with impaired cognitive function in school-aged children in cross-sectional studies; however, there are few longitudinal studies and little information on effects of exposure in early life when the brain is generally most vulnerable. METHODS: A longitudinal cohort study beginning in early pregnancy was conducted in rural Bangladesh, where arsenic concentrations in well water vary considerably. We assessed the effects of pre- and postnatal arsenic exposure on development of 2112 children at 18 months of age with Bayley Scales of Infant Development-II (mental and psychomotor development indices), Wolke's Behavior Rating Scale and maternal report of language. We related the measures of child development to arsenic concentrations in maternal urine in gestational weeks 9 and 30 and child's urinary arsenic at 18 months of age. Details of socio-economic background, home stimulation and anthropometric measurements of mothers and children were also available. RESULTS: Median maternal urinary arsenic concentration averaged over early and late gestation was 96 µg/l, whereas children's urine contained 35 µg/l of arsenic. There was no significant effect of any of the arsenic exposure measures on any of the child development measures after controlling for social and economic confounders, child's age and sex. CONCLUSION: Contrary to expectations, we found no indications of adverse effects of pre- or postnatal arsenic exposure on child development at 18 months. It remains possible that duration of exposure is critical and that effects will become apparent later in childhood.

Low 8-oxo-7,8-dihydro-2'-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic.

BACKGROUND: Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors. OBJECTIVES: To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG. MATERIALS AND METHODS: Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied. RESULTS: Median concentration of 8-oxodG was 4.7 nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7 microg/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290 microg/L (range 94-720; 380 microg/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX). CONCLUSION: Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations.

Maternal and early life exposure to manganese in rural Bangladesh.

Manganese exposure and biomarker concentrations during early pregnancy and lactation were investigated in 408 women living in an area with elevated concentrations of both arsenic and manganese in drinking water derived from wells. About 40% of the water samples had manganese concentrations above the World Health Organization's guideline value and showed a strong inverse correlation with arsenic concentrations. Water manganese was found to correlate to urine concentrations, but not to blood or breast milk concentrations. No correlations were found among manganese concentrations in urine, blood, or breast milk. Compared to other populations, manganese concentrations in both urine and blood, but not breast milk, were elevated in the Bangladeshi women and more similar to those of occupationally exposed groups. The lack of associations with water manganese is likely due to variable exposure via water and food, and differences in bioavailability, as well as a complex and/or strict regulation of intestinal manganese absorption, in turn being influenced by nutritional as well as physiological and genetic factors. The results indicate that elevated maternal manganese exposure does not necessarily lead to exposure of breast-fed infants, stressing the importance of breast feeding in high manganese areas. However, the implications of fetal exposurefrom elevated maternal exposure need further investigation.

Effect of arsenic exposure during pregnancy on infant development at 7 months in rural Matlab, Bangladesh.

BACKGROUND: Exposure to arsenic-contaminated drinking water during pregnancy is associated with low birth weight and fetal loss, and there is concern that the infants' development may be affected. OBJECTIVE: We assessed the effects of in utero arsenic exposure during pregnancy on infants' problem-solving ability and motor development. METHODS: We conducted a large population-based study of nutritional supplementation with 4,436 pregnant women in Matlab, Bangladesh, an area of high-arsenic-contaminated tube wells. We measured arsenic concentration in spot urine specimens at 8 and 30 weeks of pregnancy. We assessed a subsample of 1,799 infants, born to these mothers, at 7 months of age on two problem-solving tests (PSTs), the motor scale of the Bayley Scales of Infant Development-II, and behavior ratings. RESULT: Arsenic concentrations in maternal urine were high, with a median (interquartile range) of 81 microg/L (37-207 microg/L) at 8 weeks of gestation and of 84 microg/L (42-230 microg/L) at 30 weeks. Arsenic exposure was related to many poor socioeconomic conditions that also correlated with child development measures. Multiple regressions of children's motor and PST scores and behavior ratings, controlling for socioeconomic background variables, age, and sex, showed no significant effect of urinary arsenic concentration on any developmental outcome. CONCLUSION: We detected no significant effect of arsenic exposure during pregnancy on infant development. However, it is possible that other effects are as yet unmeasured or that effects will become apparent at a later age.

Impaired arsenic metabolism in children during weaning.

BACKGROUND: Methylation of inorganic arsenic (iAs) via one-carbon metabolism is a susceptibility factor for a range of arsenic-related health effects, but there is no data on the importance of arsenic metabolism for effects on child development. AIM: To elucidate the development of arsenic metabolism in early childhood. METHODS: We measured iAs, methylarsonic acid (MA) and dimethylarsinic acid (DMA), the metabolites of iAs, in spot urine samples of 2400 children at 18 months of age. The children were born to women participating in a population-based longitudinal study of arsenic effects on pregnancy outcomes and child development, carried out in Matlab, a rural area in Bangladesh with a wide range of arsenic concentrations in drinking water. Arsenic metabolism was evaluated in relation to age, sex, anthropometry, socio-economic status and arsenic exposure. RESULTS: Arsenic concentrations in child urine (median 34 microg/L, range 2.4-940 microg/L), adjusted to average specific gravity of 1.009 g/mL, were considerably higher than that measured at 3 months of age, but lower than that in maternal urine. Child urine contained on average 12% iAs, 9.4% MA and 78% DMA, which implies a marked change in metabolite pattern since infancy. In particular, there was a marked increase in urinary %MA, which has been associated with increased risk of health effects. CONCLUSION: The arsenic metabolite pattern in urine of children at 18 months of age in rural Bangladesh indicates a marked decrease in arsenic methylation efficiency during weaning.

Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh.

Chronic exposure to arsenic, a potent carcinogen and toxicant, via drinking water is a worldwide public health problem. Because little is known about early-life effects of arsenic on immunity, we evaluated the impact of in utero exposure on infant immune parameters and morbidity in a pilot study. Pregnant women were enrolled at 6-10 weeks of gestation in Matlab, a rural area of Bangladesh, extensively affected by arsenic contamination of tubewell water. Women (n=140) delivering at local clinics were included in the study. Anthropometry and morbidity data of the pregnant women and their children, as well as infant thymic size by sonography were collected. Maternal urine and breast milk were collected for immune marker and arsenic assessment. Maternal urinary arsenic during pregnancy showed significant negative correlation with interleukin-7 (IL-7) and lactoferrin (Ltf) in breast milk and child thymic index (TI). Urinary arsenic was also positively associated with fever and diarrhea during pregnancy and acute respiratory infections (ARI) in the infants. The effect of arsenic exposure on ARI was only evident in male children. The findings suggest that in utero arsenic exposure impaired child thymic development and enhanced morbidity, probably via immunosuppression. The effect seemed to be partially gender dependent. Arsenic exposure also affected breast milk content of trophic factors and maternal morbidity.

Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.

OBJECTIVES: The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism. METHODS: We evaluated the association between urinary metabolite pattern and polymorphisms in three gene-groups related to arsenic metabolism: (1) methyltransferases, (2) other genes involved in one-carbon metabolism and (3) genes involved in reduction reactions. Forty-nine polymorphisms were successfully genotyped in indigenous women (N=104) from northern Argentina, exposed to approximately 200 microg/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA). RESULTS: Genetic factors affecting arsenic metabolite pattern included two polymorphisms in arsenic (+III) methyltransferase (AS3MT) (rs3740400, rs7085104), where carriers had lower %MMA and higher %DMA. These single nucleotide polymorphisms (SNPs) were in strong linkage disequilibrium (LD) with three intronic AS3MT SNPs, previously reported to be associated with arsenic metabolism, indicating the existence of a strongly methylating, population-specific haplotype. The CYP17A1 rs743572, 27kilobasepairs (kbs) upstream of AS3MT, was in strong LD with the AS3MT SNPs and thus had similar effects on the metabolite profile. Smaller effects were also seen for one-carbon metabolism genes choline dehydrogenase (CHDH) (rs9001, rs7626693) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) (rs1801394) and genes involved in reduction reactions, glutaredoxin (GLRX) (rs3822751) and peroxiredoxin 2 (PRDX2) (rs10427027, rs12151144). Genotypes associated with more beneficial arsenic metabolite profile (low %MMA and/or high %DMA in urine) were more common in this population, which has been exposed to arsenic in drinking water for thousands of years. CONCLUSIONS: Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism.