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Our previous studies have linked gestational methylmercury exposure, originating from seafood, to changes in maternal thyroid hormones and infant birth size in a Swedish birth cohort. Herein we aimed to determine associations between maternal thyroid hormones and infant birth size and elucidate if maternal hormones could mediate the relationship between methylmercury and lower birth size. In 515 women, without known thyroid disease, we assessed metal exposure by erythrocyte mercury concentrations (mainly methylmercury, reflecting exposure over the past months) in early third trimester measured with inductively coupled plasma-mass spectrometry. Plasma concentrations of total and free thyroxine (tT4 and fT4) and triiodothyronine (tT3 and fT3), and thyroid-stimulating hormone (TSH) were measured at an accredited clinical laboratory. In multivariable-adjusted linear regression models, maternal tT3 (per 1 nmol/L increase) was positively associated with birth weight (B: 125 g; 95% CI 36, 214) and length (B: 0.59 cm; 95% CI 0.21, 0.97). Maternal fT4 was inversely associated with birth weight (B: − 33 g; 95% CI − 57, − 9.5), driven by obese women (n = 76). Causal mediation analyses suggested that a doubling of erythrocyte mercury (> 1 µg/kg; n = 374) was associated with a mean tT3-mediated decrease in birth weight of 11 g (95% CI − 25, − 1.6) and in birth length of 0.1 cm (95% CI − 0.12, − 0.01), both equivalent to about 12% of the total effect. To conclude, tT3 was positively associated with infant birth size. Reduced tT3 levels appeared to mediate a minor part of the inverse association between methylmercury exposure and birth size.

Background Severe iodine deficiency adversely affects neurodevelopment; however, evidence regarding the association of non-severe deficiency and child cognitive functioning is inconclusive. Methods This prospective mother-child cohort study was nested in a population-based nutritional supplementation trial in Bangladesh (Maternal and Infant Nutrition Interventions in Matlab [MINIMat]). Participants with data on cognitive abilities at 5 and 10 years of age (n = 1530) and at least one measurement of urinary iodine concentration (UIC) (gestational week 8, 5, and 10 years) were selected. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Wechsler Intelligence Scale for Children (WISC-IV). UICs were measured with inductively coupled plasma mass spectrometry and thereafter adjusted for specific gravity. Results Median UICs in our population: (282 μg/L [pregnancy]; 406 μg/L [5 years]; 294 μg/L [10 years]) indicated that iodine intake corresponded to above ‘adequate’ or even ‘excessive’, according to the WHO classification. Maternal ‘UIC Conclusions Current findings add to the growing evidence of a causal association of early-life iodine intake with cognitive development, indicating that low iodine intake during childhood is associated with reduced processing speed and non-optimal gestational iodine intake is weakly associated with slightly poorer verbal development outcomes.

BACKGROUND: Several metals act as endocrine disruptors, but there are few large longitudinal studies about associations with puberty onset.OBJECTIVES: We evaluated whether early life cadmium, lead, and arsenic exposure was associated with timing of menarche. METHODS: In a mother-child cohort in rural Bangladesh (n = 935), the exposure was assessed by concentrations in maternal erythrocytes in early pregnancy and in girls' urine at 5 and 10 years of age using inductively coupled plasma mass spectrometry. The girls were interviewed twice, at aver-age ages 13.3 [standard deviation eth SD THORN = 0.43] and 13.8 (SD = 0.43) y, and the date of menarche, if present, was recorded. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox regression.RESULTS: In total, 77% of the girls (n = 717) had reached menarche by the second follow-up. The median age of menarche among all girls was 13.0 y (25th-75th percentiles: 12.4-13.7 y). At 10 years of age, median urinary cadmium was 0.25 mu g/L (5th-95th percentiles: 0.087-0.72 mu g/L), lead 1.6 mu g/L (0.70-4.2 mu g/L), and arsenic 54 mu g/L (19-395 mu g/L). Given the same age, girls in the highest quartile of urinary cadmium at 5 and 10 years of age had a lower rate of menarche than girls in the lowest quartile, with an adjusted hazard ratio of (HR) 0.80 (95% CI: 0.62, 1.01) at 5 years of age, and 0.77 (95% CI: 0.60, 0.98) at 10 years of age. This implies that girls in the highest cadmium exposure quartile during childhood had a higher age at menarche. Comparing girls in the highest to the lowest quartile of urinary lead at 10 years of age, the former had a higher rate of menarche [adjusted HR = 1.23 (95% CI: 0.97, 1.56)], implying lower age at menarche, whereas there was no association with urinary lead at 5 years of age. Girls born to mothers in the highest quartile of erythrocyte arsenic during pregnancy were less likely to have attained menarche than girls born to mothers in the low-est quartile [adjusted HR = 0.79 (95% CI: 0.62, 0.99)]. No association was found with girls' urinary arsenic exposure.DISCUSSION: Long-term childhood cadmium exposure was associated with later menarche, whereas the associations with child lead exposure were inconclusive. Maternal exposure to arsenic, but not cadmium or lead, was associated with later menarche. https://doi.org/10.1289/EHP11121

BACKGROUND: Detoxification of inorganic arsenic (iAs) occurs when it methylates to form monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Lower proportions of urinary iAs and MMA, and higher proportions of DMA indicate efficient methylation. The role of B-vitamins in iAs methylation in children with low-level arsenic exposure is understudied. OBJECTIVES: Our study objective was to assess the association between B-vitamin intake and iAs methylation in children with low-level arsenic exposure (

Humans living in the Andes Mountains have been historically exposed to arsenic from natural sources, including drinking water. Enzymatic methylation of arsenic allows it to be excreted more efficiently by the human body. Adaptation to high-arsenic environments via enhanced methylation and excretion of arsenic was first reported in indigenous women in the Argentinean Andes, but whether adaptation to arsenic is a general phenomenon across native populations from the Andes Mountains remains unclear. Therefore, we evaluated whether adaptation to arsenic has occurred in the Bolivian Andes by studying indigenous groups who belong to the Aymara-Quechua and Uru ethnicities and have lived in the Bolivian Andes for generations. Our population genetics methods, including genome-wide selection scans based on linkage disequilibrium patterns and allele frequency differences, in combination with targeted and whole-genome sequencing and genotype-phenotype association analyses, detected signatures of positive selection near the gene encoding arsenite methyltransferase (AS3MT), the main arsenic methylating enzyme. This was among the strongest selection signals (top 0.5% signals via locus-specific branch length and extended haplotype homozygosity tests) at a genome-wide level in the Bolivian study groups. We found a large haplotype block of 676 kb in the AS3MT region and identified candidate functional variants for further analysis. Moreover, our analyses revealed associations between AS3MT variants and the fraction of mono-methylated arsenic in urine and showed that the Bolivian study groups had the highest frequency of alleles associated with more efficient arsenic metabolism reported so far. Our data support the idea that arsenic exposure has been a driver for human adaptation to tolerate arsenic through more efficient arsenic detoxification in different Andean populations.

Background: Observational studies have indicated that elevated maternal fluoride exposure during pregnancy may impair child neurodevelopment but a potential impact on birth outcomes is understudied. Objectives: To evaluate the impact of gestational fluoride exposure on birth outcomes (birth size and gestational age at birth) and to assess the potential mediating role of maternal thyroid hormones. Methods: We studied 583 mother-child dyads in the NICE cohort in northern Sweden. Maternal fluoride exposure was assessed by measuring urinary concentrations at late pregnancy (median: 29th gestational week) using an ion selective electrode. Plasma levels of free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH) were measured with electrochemiluminescence immunoassays. The infant's weight, length, head circumference, and gestational age at birth were extracted from hospital records. Results: Median urinary fluoride concentration was 0.71 mg/L (5th-95th percentile 0.31–1.9 mg/L; specific gravity adjusted). In multivariable-adjusted regression models, every 1 mg/L increase of maternal urinary fluoride was associated with a mean increase in birth weight by 84 g (95%CI: 30, 138), length by 0.41 cm (95%CI: 0.18, 0.65), head circumference by 0.3 cm (95%CI: 0.1, 0.4), and with increased odds of being born large for gestational age (OR = 1.39, 95%CI: 1.03, 1.89). Every 1 mg/L increase of maternal urinary fluoride was also associated with a mean increase of the plasma fT3:fT4 ratio (B = 0.007, 95%CI: 0.000, 0.014), but not with the hormones or TSH. In mediation analyses, the maternal fT3:fT4 ratio did not explain the urinary fluoride-birth size relationships. Discussion: Gestational urinary fluoride concentrations were associated with increased size at birth and even with increased odds of being born large for gestational age. The fluoride-related associations with increased size at birth were not explained by changes in maternal thyroid hormone levels.

Iodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy.We aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy.We included 531 pregnant women (aged 22-40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27-33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations).Median (IQR) micronutrient concentrations were 112 μg/L (80-156 μg/L) for UIC, 67 μg/L (58-76 μg/L) for plasma selenium, and 973 μg/L (842-1127 μg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 μg/L and 70 μg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98%4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and1200 μg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and85 μg/L with tT3.Pregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Background: Several endocrine-disrupting metals may affect thyroid function, but the few available studies of exposure during pregnancy and thyroid hormones are inconclusive. Objective: To explore if environmental exposure to cadmium (Cd), lead (Pb), and methylmercury (MeHg) impacts thyroid function in pregnancy, and interacts with iodine and selenium status. Methods: Women in a Swedish birth cohort provided blood and urine samples in early third trimester. Concentrations of erythrocyte Cd, Pb, and Hg (n = 544), urinary Cd and iodine (n = 542) and plasma selenium (n = 548) were measured using inductively coupled plasma-mass spectrometry. Free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH), were measured in plasma (n = 548) with electrochemiluminescence immunoassays. Metal-hormone associations were assessed in regression models, and metal mixture effects and metal-nutrient interactions were explored in Bayesian kernel machine regression (BKMR). Results: In multivariable-adjusted regression models, a doubling of urinary Cd was associated with a mean increase in tT4 of 2.7 nmol/L (95% CI: 0.78, 4.6), and in fT3 and tT3 of 0.06 pmol/L (0.02, 0.10) and 0.09 nmol/L (0.05, 0.13), respectively. A doubling of urinary Cd was associated with a −0.002 (−0.003, −0.001) and −0.03 (−0.05, −0.02) decrease in the fT4:tT4 and fT3:tT3 ratio, respectively. A doubling of erythrocyte Hg (>1 µg/kg) was associated with a decrease in fT3 and tT3 by −0.11 pmol/L (−0.16, −0.05) and −0.11 nmol/L (−0.16, −0.06), respectively, and a −0.013 (−0.02, −0.01) decrease in the fT3:fT4 ratio. BKMR did not indicate any mixture effect of toxic metals or interactions between metals and iodine or selenium in relation to the hormones. Conclusion: Our findings suggest that exposure to Cd and Hg, at levels globally prevalent through the diet, may affect thyroid function during pregnancy, independently of iodine and selenium levels. Further studies on potential implications for maternal and child health are warranted.

Cadmium (Cd) exposure during gestation has been associated with altered DNA methylation at birth, but it is not known if the changes in methylation persist into childhood.To evaluate whether gestational Cd-related changes of DNA methylation persist from birth to 9 years of age.We studied mother-child dyads in a longitudinal cohort in rural Bangladesh. Cadmium concentrations in maternal blood (erythrocyte fraction; Ery-Cd) at gestational week 14 and in child urine (U-Cd, long-term exposure marker) at 9 years were measured using inductively coupled plasma mass spectrometry. The epigenome-wide DNA methylation was measured in mononuclear cells (PBMCs) prepared from cord blood and peripheral blood at 9 years in 71 children (hereafter referred to as the explorative group) by Infinium HumanMethylation450K BeadChip. Replication of one differentially methylated region (DMR; 9 CpG sites) was performed in PBMCs of 160 9-year-old children (validation group) by EpiTyper MALDI-TOF mass spectrometry.The median maternal Ery-Cd concentration was 1.24 µg/kg (range 0.35, 4.55) in the explorative group and 0.83 µg/kg (0.08, 2.97) in the validation group. The median U-Cd concentration in the 9-year-old children was 0.26 µg/L (0.09, 1.06) in the explorative group and 0.32 µg/L (0.07, 1.33) in the validation group. In the explorative group, we identified ten DMRs, both in cord blood and in PBMCs at 9 years, that were associated with maternal Ery-Cd. Eight out of the ten DMRs were hypomethylated and three of the hypomethylated DMRs were located in the HLA region on chromosome 6. One of the DMRs (hypomethylated) in the HLA region (upstream of the zinc finger protein 57 homolog, ZFP57 gene) was replicated in the validation group, and we found that it was hypomethylated in relation to maternal Ery-Cd, but not child U-Cd.Gestational exposure to Cd appears to be associated with regional changes, especially hypomethylated, in DNA methylation that linger from birth up to prepubertal age.

Background Cadmium (Cd) exposure has adverse health effects in children. Diet contributes to Cd exposure, but dietary components could affect body Cd levels. Objective To examine associations between diet and urinary Cd (U-Cd) in children. Methods In this cross-sectional study conducted in Montevideo, Uruguay, Cd exposure of 5–8 year old children (n = 279 with complete data) was assessed in first morning urine (U-Cd), a marker of long-term exposure, measured by ICP-MS and adjusted for specific gravity. Distribution of U-Cd was (median [5%, 95%]: 0.06 [0.02, 0.17] μg/L); data were natural-log-transformed (ln) for statistical analyses. Serum ferritin (SF), an indicator of iron stores, was measured in fasting samples. Trained nutritionists completed two non-consecutive 24-h dietary recalls with both child and caregiver present. Measures of iron, zinc, calcium and fiber intake, and the consumption of grains, root vegetables, milk, and foods rich in heme iron (white and read meats) and non-heme iron (legumes, spinach, broccoli, tomatoes, dried fruit) were derived. Multivariable ordinary least squares (OLS) and ordinal regressions were used to examine associations among tertiles of water Cd, SF, diet, and U-Cd. OLS models were further stratified by sex. Results In covariate-adjusted models, SF was not related to ln-U-Cd. Children in highest tertile of iron and zinc intake had lower ln-U-Cd: (−0.23 [−0.42, −0.03]) and (−0.25 [−0.44, −0.05]), respectively, compared to the reference group. Children consuming higher amounts of foods rich in heme iron had slightly lower ln-U-Cd (−0.17 [−0.36, 0.03]). High grain consumption was related to higher ln-U-Cd (0.25 [0.06, 0.45]). Conclusions Diets rich in grains were related to higher urinary Cd levels among children living in the context of low Cd pollution. Higher intake of iron and zinc was related to lower Cd levels. Given that urinary Cd is mainly a marker of long-term exposure, these findings should be further corroborated.

Food and water are common exposure sources of arsenic and lead among children. Whereas dietary sources of these toxicants are fairly well-studied, the contribution of drinking water to toxicant exposures is not well characterized in many populations, particularly in the Global South.To assess the extent to which consumption of household drinking water contributes to arsenic and lead exposure among Uruguayan schoolchildren with low-level exposure.Children, aged 5-8 years, were enrolled into the Salud Ambiental Montevideo study during 2009-2013 from schools in Montevideo, Uruguay. Participants reported water intake as part of two 24-h dietary recalls. Concentrations of arsenic were measured in first morning void urine samples, and adjusted for urinary specific gravity. Lead concentrations were measured in venous blood samples. Drinking water samples were collected from participants' homes and toxicant concentrations measured. Data analyses involved a triangulation approach. First, multivariable linear regressions estimated the associations between toxicant exposure through drinking water, calculated for each child as the product of water intake and water toxicant concentration, and the respective toxicant biomarker concentrations among children with complete data on all variables (Sample A; n = 40). Second, regressions were repeated for participants with complete data on all variables except water intakes (Sample B; n = 195), after water intakes were imputed. Finally, models were constructed for participants of Sample B (n = 195) based on drinking water intakes assumed to be fixed at 25th, 50th, 75th percentile intakes of participants in sample A.Toxicant exposure via drinking water intake was low. The triangulation approach revealed no associations between toxicant exposure through household water intake and the respective toxicant biomarker concentrations.Studies with larger samples and repeated measures are needed to confirm these findings. Nevertheless, it appears that at low water toxicant concentrations, typical water consumption is not a major contributor to children's exposure.

Background/Aim: Trace elements concentrations have been implicated in cardiometabolic risk in children. Previously, studies have largely focused on individual elements, however, more akin to the re...

There is growing interest in understanding the contribution of environmental toxicant exposure in early life to development of cardiometabolic diseases (CMD) in adulthood. We aimed to assess associations of early life exposure to arsenic and cadmium with biomarkers of CMD in children in rural Bangladesh. From a longitudinal mother-child cohort in Matlab, Bangladesh, we followed up 540 pairs. Exposure to arsenic (U–As) and cadmium (U–Cd) was assessed by concentrations in urine from mothers at gestational week 8 (GW8) and children at ages 4.5 and 9 years. Blood pressure and anthropometric indices were measured at 4.5 and 9 years. Metabolic markers (lipids, glucose, hemoglobin A1c, adipokines, estimated glomerular filtration rate (eGFR) were determined in plasma/blood of 9 years old children. In linear regression models, adjusted for child sex, age, height-for-age z score (HAZ), BMI-for-age z score (BAZ), socioeconomic status (SES) and maternal education, each doubling of maternal and early childhood U–Cd was associated with 0.73 and 0.82 mmHg increase in systolic blood pressure (SBP) respectively. Both early and concurrent childhood U–Cd was associated with diastolic (D)BP (β = 0.80 at 4.5 years; β = 0.75 at 9 years). Each doubling of U–Cd at 9 years was associated with decrements of 4.98 mg/dL of total cholesterol (TC), 1.75 mg/dL high-density lipoprotein (HDL), 3.85 mg/dL low-density lipoprotein (LDL), 0.43 mg/dL glucose and 4.29 units eGFR. Each doubling of maternal U–Cd was associated with a decrement of 1.23 mg/dL HDL. Both maternal and childhood U–As were associated with decrement in TC and HDL. Multiple comparisons were checked with family-wise error rate Bonferroni-type-approach. The negative associations of arsenic and cadmium with biomarkers of CMD in preadolescent children indicated influence of both metal(loid)s on fat and carbohydrate metabolism, while cadmium additionally influenced kidney function and BP. Thus, fewer outcomes were associated with U–As compared to U–Cd at preadolescence.

The uterine environment may be important for the chromosomal telomere length (TL) at birth, which, in turn, influences disease susceptibility throughout life. However, little is known about the importance of specific nutritional factors.We assessed the impact of multiple maternal nutritional factors on TL in placenta and cord blood.In a population-based mother-child cohort in northwestern Argentina, we measured maternal weight, BMI, body fat percentage (BFP), and several nutrients [selenium, magnesium, calcium, zinc, manganese, iodine, vitamin B-12, folate, 25-hydroxycholecalciferol (25(OH)D3)], hemoglobin, and homocysteine in maternal whole blood, serum, plasma, or urine during pregnancy (mean gestational week 27). We measured the relative TL (rTL) in placenta (n = 99) and cord blood (n = 98) at delivery by real-time PCR. Associations were evaluated by multivariable-adjusted linear regression.The women's prepregnancy BMI (kg/m2; mean ± SD: 23.7 ± 4.1), body weight (55.4 ± 9.9 kg), and BFP (29.9 ± 5.5%), but not height (153 ± 5.3 cm), were inversely associated with placental rTL (P 0.01 for all), with ∼0.5 SD shorter rTL for an IQR increase in prepregnancy body weight, BMI, or BFP. Also, impedance-based BFP, but not lean body mass, in the third trimester was associated with shorter placental rTL. In addition, serum vitamin B-12 (232 ± 96 pmol/L) in pregnancy (P = 0.038), but not folate or homocysteine, was associated with shorter placental rTL (0.2 SD for an IQR increase). In contrast, plasma 25(OH)D3 (46 ± 15 nmol/L) was positively associated with placental rTL (P 0.01), which increased by 0.4 SD for an IQR increase in 25(OH)D3. No clear associations of the studied maternal nutritional factors were found with cord blood rTL.Maternal BMI, BFP, and vitamin B-12 were inversely associated, whereas 25(OH)D3 was positively associated, with placental TL. No association was observed with cord blood TL. Future studies should elucidate the role of placental TL for child health.

BACKGROUND: Our studies of children in a rural Bangladeshi area, with varying concentrations of arsenic in well-water, indicated modest impact on child verbal cognitive function at 5 years of age. OBJECTIVES: Follow-up of arsenic exposure and children's cognitive abilities at school-age. METHODS: In a nested sub-cohort of the MINIMat supplementation trial, we assessed cognitive abilities at 10 years of age (n = 1523), using Wechsler Intelligence Scale for Children (WISC-IV). Arsenic in maternal urine and erythrocytes in early pregnancy, in child urine at 5 and 10 years, and in hair at 10 years, was measured using Inductively Coupled Plasma Mass Spectrometry. RESULTS: Median urinary arsenic at 10 years was 58 µg/L (range 7.3-940 µg/L). Multivariable-adjusted regression analysis showed that, compared to the first urinary arsenic quintile at 10 years (

Background Arsenic methylation efficiency, a susceptibility factor for arsenic toxicity, is in adults partly explained by variation in arsenite methyltransferase (AS3MT) gene. Little is known about the role of AS3MT for children's arsenic methylation. Objectives Evaluating associations between AS3MT polymorphisms and children's arsenic methylation efficiency. Methods Bangladeshi children's arsenic exposure (9-years; n = 424) was assessed as sum urinary concentration of inorganic arsenic (iAs) and its metabolites (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) using HPLC-HG-ICPMS. Arsenic methylation efficiency was assessed by the individual metabolite fractions (%). AS3MT polymorphisms (rs7085104, rs3740400, rs3740393 and rs1046778) were genotyped using TaqMan SNP genotyping assays. Results We found higher %iAs and %MMA, and lower %DMA in urine, among rs1046778 TT carriers (median 8.8%, 9.6% and 81.1% for iAs, MMA and DMA, respectively), compared to CC carriers (median 7.0%, 8.3% and 84.9%). These associations were significant in multivariable-adjusted linear regression models: B-coefficients for TT vs CC were 1.26, 1.33 and −2.59 for iAs, MMA and DMA, respectively. Effect estimates were slightly stronger when restricting the analyses to children with urinary arsenic ≥58 μg/L (reducing the impact of ingested DMA). Estimates in girls were slightly stronger than in boys, although there were no significant differences between boys and girls. No clear associations were found for the other AS3MT polymorphisms. Conclusions One out of four AS3MT polymorphisms, previously associated with arsenic methylation in adults, was associated with arsenic methylation in children. Thus, AS3MT variation seems to influence arsenic methylation efficiency in children to a lesser extent than in adults.

Oxidative stress (OS) is an important consequence of exposure to toxic metals but it is unclear to what extent low-level metal exposures contribute to OS in children. We examined the cross-sectional association between urinary concentrations of arsenic (As), cadmium (Cd), and lead (Pb) and urinary markers of OS: F2–8α isoprostane and 8-hydroxy-2-deoxy-guanosine (8-OHdG). We also tested effect modification by dietary intakes. Of the 211 children aged 6–8 years living in Montevideo who were eligible for the study because they had at least one OS marker measured via ELISA, 143 were included in a complete-case analysis. Urinary metals were measured with inductively coupled plasma mass spectrometry (ICP-MS: Pb, Cd) and high-performance liquid chromatography online with hydride generation ICP-MS (As-metabolites); concentrations were log2-transformed. All urinary markers were adjusted for specific gravity of urine. Two 24-h dietary recalls were conducted to estimate children's dietary intakes, including total fruit and vegetable consumption and vitamin C, zinc and fiber intake. Ordinary least square (OLS) and weighted quantile sum (WQS) regressions were used to estimate the association between metals and each OS marker as outcome. Metal exposure was generally low: median urinary As, Cd, Pb 9.6 μg/L, 0.06 μg/L and 1.9 μg/L, respectively. Median 8-isoprostane concentration was 1.1 and 8-OHdG 39.6 ng/mL. Log2-transformed urinary As concentrations were positively associated with 8-OHdG concentrations (10.90 [3.82, 17.97]) in covariate-adjusted OLS models which also took account of exposure to Cd and Pb. In WQS, a mixture index was also associated with higher 8-OHdG (8.71 [1.12, 16.3] for each 25% increase in index value), mostly driven by As exposure. There was little evidence of effect modification by dietary antioxidants. In sum, even at low-level, As exposure is associated with detectable oxidative damage to the DNA.

Background Few studies have evaluated the association between low-level arsenic (As) exposure and cognitive performance among children. Objectives In this cross-sectional study, we assessed the association between low-level As exposure and cognitive performance among 5–8 year-old children in Montevideo, and tested effect modification by As methylation capacity and children's dietary folate intake. Methods We measured total urinary As (UAs) concentrations and the proportion of monomethylarsonic acid (MMA) in the urine of 328 children. Seven subtests of the standardized Woodcock-Munoz cognitive battery were used to assess cognitive performance, from which, the general intellectual abilities (GIA) score was derived. Total folate intake was estimated from two 24-h dietary recalls. Linear regression analyses were performed. Effect modification was assessed by stratifying at the median %MMA value and tertiles of total folate intake calculated as micrograms (µg) of dietary folate equivalents (dfe). Results The median UAs was 11.9 µg/l (range = 1.4–93.9), mean folate intake was 337.4 (SD = 123.3) µg dfe, and median %MMA was 9.42 (range = 2.6–24.8). There was no association between UAs and cognitive abilities, and no consistent effect modification by %MMA. UAs was associated inversely with concept formation, and positively with cognitive efficiency and numbers reversed subtest in the lowest folate intake tertile; UAs was also positively associated with sound integration in the second tertile and concept formation in the highest tertile of folate intake. There was no consistent pattern of effect modification by %MMA or folate intake. Conclusion There was no association between low-level As exposure and general cognitive abilities.

Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother–child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children’s concurrent urinary As, was positively associated with IGFBP3 concentrations (β = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated. Electronic supplementary material The online version of this article (10.1007/s00204-018-2239-3) contains supplementary material, which is available to authorized users.

Background: We have previously reported inverse associations of prenatal and childhood cadmium exposure with cognition in 5-year-old Bangladeshi children. Objectives: To assess if cadmium exposure affected cognition and behavior in the Bangladeshi children at 10 years. Methods: Cadmium exposure was assessed by urinary concentrations at 10 (n = 1498) and 5 years of age (n = 1453), and of the mothers in early pregnancy (n = 1299), measured by ICP-MS. Cognitive abilities were assessed with Wechsler Intelligence Scale for Children (4th edition) and behavior with the parent-rated Strengths and Difficulties Questionnaire. Results: In multivariable-adjusted models, urinary cadmium at 10 years was inversely associated with Full scale IQ and most of the sub-scales. Associations were mainly observed in boys, in whom the difference in Full scale IQ was 7.0 scores (95% CI: –11, −2.7), corresponding to 0.21 SD, when comparing those in the highest (range: 0.30–2.6 μg/L) and lowest tertile of urinary cadmium (0.036–0.18 μg/L). Urinary cadmium at 5 years was inversely, but not significantly, associated with IQ. Children in the highest exposure tertile at 10 years also had poorer Prosocial behavior scores. The association appeared strongest in girls, in whom the corresponding OR for Prosocial scores in relation to cadmium exposure at 10 years and prenatally was 0.58 (95% CI: 0.34, 0.99) and 0.48 (95% CI: 0.25, 0.93), respectively. Conclusion: Childhood cadmium exposure was associated with lower intelligence in boys, and there were indications of altered behavior in girls for both prenatal and childhood exposures. Findings are of concern as similar exposure levels are common world-wide. Keywords: Cadmium, Neurotoxicity, Development, Child IQ, Food pollutant, Urine

Background Early-life exposure to arsenic (As), cadmium (Cd), and lead (Pb) has been linked to smaller birth and early childhood anthropometry, but little is known beyond the first years in life. Objectives To evaluate the impact of gestational and childhood exposures to As, Cd, and Pb on growth up to 10 years of age. Methods We studied 1530 mother–child dyads from a nested sub-cohort of the MINIMat trial in rural Matlab, Bangladesh. Metal concentrations in maternal erythrocytes during pregnancy and in children’s urine at 10y were measured by inductively coupled plasma mass spectroscopy. Child height and weight were measured at 19 occasions from birth until 10y and converted to height-for-age Z-scores (HAZ) and weight-for-age Z-scores (WAZ). Associations between log2-transformed metal concentrations and growth parameters were assessed with multivariable-adjusted regression models. Results Children’s concurrent urinary Cd (median 0.24 µg/L), reflecting long-term exposure, was inversely associated with WAZ (B: −0.072; 95% confidence interval (CI): −0.12, −0.020; p = 0.007), and possibly HAZ (B: −0.046; 95% CI: −0.096, 0.0014; p = 0.057), at 10y. The association with WAZ was stronger in boys than in girls. Maternal erythrocyte Cd (median 0.90 µg/kg) during pregnancy was inversely associated with WAZ during childhood only in boys (B: −0.071, 95% CI: −0.14, −0.0047, p = 0.036). Concurrent urinary Pb (median 1.6 µg/L) was inversely associated with WAZ (B: −0.084; 95% CI: −0.16, −0.0085; p = 0.029) and HAZ (B: −0.087; 95% CI: −0.15, −0.021; p = 0.010) in boys, but not in girls. Neither gestational nor childhood As exposure (median maternal erythrocyte As 4.3 µg/kg and children’s urinary As 57 µg/L) was associated with growth up to 10y. Conclusions While all effect estimates were small, environmental exposure to Cd and Pb is common and impaired growth is of public health concern, especially for children already at risk of reduced growth due to malnutrition. Gender differences in susceptibility need further investigation.

Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N = 80 women) and DNA methylation (N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap. (Less)

Objectives 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. Methods 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-Munoz 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. Results 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. Conclusion At low-levels of exposure, U–As does not appear to affect children's academic achievement.

Background The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. Method In a mother–child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3). Results Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2–0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. Conclusions Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations. Electronic supplementary material The online version of this article (10.1186/s12916-019-1309-6) contains supplementary material, which is available to authorized users.