Toxic metals and essential trace elements in placenta and their relation to placental function.

INTRODUCTION: Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. OBJECTIVE: To assess the impact of toxic and essential trace elements in placenta on placental function. METHODS: Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. RESULTS: Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 µg/kg, respectively. In the adjusted regression, selenium (>147 µg/kg) was inversely associated with placental weight (B: -158; 95 % CI: -246, -71, per doubling), as was lead at low selenium (B: -23.6; 95 % CI: -43.2, -4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: -0.01; 95 % CI: -0.019, -0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: -11; 95 % CI: -20, -0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. CONCLUSION: Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation.

Arsenic exposure and increased C-reactive protein are independently associated with lower erythrocyte glutathione peroxidase activity in Bangladeshi children.

Toxic metal contaminants present in food and water have widespread effects on health and disease. Chalcophiles, such as arsenic, cadmium, and mercury, show a high affinity to selenium and exposure to these metals could have a modulating effect on enzymes dependent on selenocysteine in their active sites. The aim of this study was to assess the influence of these metals on the activity of the selenoprotein glutathione peroxidase 1 (GPX1) in erythrocytes of 100 children residing in rural Bangladesh, where drinking water often contains arsenic. GPX1 expression, as measured using high-throughput immunoblotting, showed little correlation with GPX activity (rs = 0.02, p = 0.87) in blood samples. Toxic metals and selenium measured in erythrocytes using inductively coupled plasma mass spectrometry (ICP-MS) and C-reactive protein (CRP) measured in plasma, were all considered as effectors of this divergence in GPX enzymatic activity. Arsenic concentrations in erythrocytes were most influential for GPX1 activity (rs = -0.395, p < 0.0001), and CRP levels also negatively impacted GPX1 activity (rs = -0.443, p < 0.0001). These effects appear independent of each other as arsenic concentrations and CRP showed no correlation (rs = 0.124, p = 0.2204). Erythrocyte selenium, cadmium, and mercury did not show any correlation with GPX1 activity, nor with CRP or arsenic. Our findings suggest that childhood exposure to inorganic arsenic, as well as inflammation triggering the release of CRP, may negatively affect GPX1 activity in erythrocytes.

Associations of gestational and early-life exposure to toxic metals and fluoride with a diagnosis of food allergy or atopic eczema at 1 year of age.

Studies have indicated that early-life exposure to toxic metals and fluoride affects the immune system, but evidence regarding their role in allergic disease development is scarce. We aimed to evaluate the relations of exposure to such compounds in 482 pregnant women and their infants (4 months of age) with food allergy and atopic eczema diagnosed by a paediatric allergologist at 1 year of age within the Swedish birth-cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Urinary cadmium and erythrocyte cadmium, lead, and mercury concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS), urinary inorganic arsenic metabolites by ICP-MS after separation by ion exchange chromatography, and urinary fluoride by an ion-selective electrode. The prevalence of food allergy and atopic eczema was 8 and 7%, respectively. Gestational urinary cadmium, reflecting chronic exposure, was associated with increased odds of infant food allergy (OR [95% CI]: 1.34 [1.09, 1.66] per IQR [0.08 µg/L]). Both gestational and infant urinary fluoride were associated, albeit at a statistically non-significant level, with increased atopic eczema odds (1.48 [0.98, 2.25], 1.36 [0.95, 1.95], per doubling, respectively). By contrast, gestational and infant erythrocyte lead was associated with decreased odds of atopic eczema (0.48 [0.26, 0.87] per IQR [6.6 µg/kg] and 0.38 [0.16, 0.91] per IQR [5.94 µg/kg], respectively), and infant lead with decreased odds of food allergy (0.39 [0.16, 0.93] per IQR [5.94 µg/kg]). Multivariable adjustment had marginal impact on the estimates above. After additional adjustment for fish intake biomarkers, the methylmercury associated atopic-eczema odds were considerably increased (1.29 [0.80, 2.06] per IQR [1.36 µg/kg]). In conclusion, our results indicate that gestational cadmium exposure might be associated with food allergy at 1 year of age and, possibly, early-life exposure to fluoride with atopic eczema. Further prospective and mechanistic studies are needed to establish causality.

Urinary phosphate is associated with cardiovascular disease incidence.

INTRODUCTION: Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. OBJECTIVE: To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). METHODS: We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004-2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. RESULTS: After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5-95) in urine and plasma were 2.4 (1.40-3.79) mmol/mmol creatinine and 1.13 (0.92-1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148-1918) mg/day. No correlations were observed between urinary and plasma P (r = -0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)-independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). CONCLUSION: Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirements.

Biomarkers of seafood intake during pregnancy - Pollutants versus fatty acids and micronutrients.

Intake of fish and seafood during pregnancy may have certain beneficial effects on fetal development, but measurement of intake using questionnaires is unreliable. Here, we assessed several candidate biomarkers of seafood intake, including long-chain omega 3 fatty acids (n-3 LCPUFA), selenium, iodine, methylmercury, and different arsenic compounds, in 549 pregnant women (gestational week 29) in the prospective birth cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Proportions of the fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) in erythrocytes were measured using gas chromatography with flame ionization detector. Selenium was measured in blood plasma and erythrocytes, mercury and arsenic in erythrocytes, and iodine and several arsenic compounds in urine, using inductively coupled plasma mass spectrometry, arsenic compounds after first being separated by ion exchange high-performance liquid chromatography (HPLC). Each biomarker was related to intake of total seafood and to intake of fatty and lean fish, and shellfish in third trimester, estimated from a semi-quantitative food frequency questionnaire filled out in gestational week 34. The pregnant women reported a median total seafood intake of 184 g/week (5th-95th percentiles: 34-465 g/week). This intake correlated most strongly with erythrocyte mercury concentrations (rho = 0.49, p < 0.001), consisting essentially of methylmercury, followed by total arsenic in erythrocytes (rho = 0.34, p < 0.001), and arsenobetaine in urine (rho = 0.33, p < 0.001), the main form of urinary arsenic. These biomarkers correlated well with intake of both fatty fish, lean fish, and shellfish. Erythrocyte DHA and plasma selenium correlated, although weakly, mainly with fatty fish (rho = 0.25 and 0.22, respectively, both p < 0.001). In conclusion, elevated concentrations of erythrocyte mercury and urinary arsenobetaine can be useful indicators of seafood intake, more so than the n-3 LCPUFAs. However, the relative importance of the biomarkers may differ depending on the type and amount of seafood consumed.

Reducing the complexity of high-dimensional environmental data: An analytical framework using LASSO with considerations of confounding for statistical inference.

PURPOSE: Frameworks for selecting exposures in high-dimensional environmental datasets, while considering confounding, are lacking. We present a two-step approach for exposure selection with subsequent confounder adjustment for statistical inference. METHODS: We measured cognitive ability in 338 children using the Woodcock-Muñoz General Intellectual Ability (GIA) score, and potential associated features across several environmental domains. Initially, 111 variables theoretically associated with GIA score were introduced into a Least Absolute Shrinkage and Selection Operator (LASSO) in a 50% feature selection subsample. Effect estimates for selected features were subsequently modeled in linear regressions in a 50% inference (hold out) subsample, first adjusting for sex and age and later for covariates selected via directed acyclic graphs (DAGs). All models were adjusted for clustering by school. RESULTS: Of the 15 LASSO selected variables, eleven were not associated with GIA score following our inference modeling approach. Four variables were associated with GIA scores, including: serum ferritin adjusted for inflammation (inversely), mother's IQ (positively), father's education (positively), and hours per day the child works on homework (positively). Serum ferritin was not in the expected direction. CONCLUSIONS: Our two-step approach moves high-dimensional feature selection a step further by incorporating DAG-based confounder adjustment for statistical inference.

Early Life Environmental Exposure to Cadmium, Lead, and Arsenic and Age at Menarche: A Longitudinal Mother-Child Cohort Study in Bangladesh.

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 average ages 13.3 [standard deviation (SD)=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 0.25µg/L (5th-95th percentiles: 0.087-0.72µg/L), lead 1.6µg/L (0.70-4.2µg/L), and arsenic 54µg/L (19-395µg/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 lowest 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.

Gestational and childhood urinary iodine concentrations and children's cognitive function in a longitudinal mother-child cohort in rural Bangladesh.

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 <150 µg/L' was associated with lower full-scale and verbal scores at 5 and 10 years, although the associations were weakened in the fully adjusted models. A tendency of decreased verbal scores was also observed for maternal 'UIC ≥500 µg/L' but not for the corresponding child iodine category (≥300 µg/L). Child 'UIC <100 µg/L' was associated with lower processing speed (B=-3.1, 95% CI [-6.2, -0.1]; P-value = 0.041) compared with the reference group (100 µg/L≤ UIC <300 µg/L). 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.

Association of maternal urinary fluoride concentrations during pregnancy with size at birth and the potential mediation effect by maternal thyroid hormones: The Swedish NICE birth cohort.

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.

Human adaptation to arsenic in Bolivians living in the Andes.

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.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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, and <1200 µg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 µg/L with tT3. CONCLUSIONS: 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.

Maternal exposure to cadmium during pregnancy is associated with changes in DNA methylation that are persistent at 9 years of age.

BACKGROUND: 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. OBJECTIVES: To evaluate whether gestational Cd-related changes of DNA methylation persist from birth to 9 years of age. METHODS: 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. RESULTS: 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. CONCLUSION: Gestational exposure to Cd appears to be associated with regional changes, especially hypomethylated, in DNA methylation that linger from birth up to prepubertal age.

Long-term cadmium exposure and fractures, cardiovascular disease, and mortality in a prospective cohort of women.

BACKGROUND: Cadmium (Cd) is a toxic metal, which the non-smoking population is mainly exposed to through diet. Current health-based guidance values are based on renal toxicity; however, emerging evidence suggests that bone and the cardiovascular system might be more sensitive to Cd exposure. OBJECTIVE: To assess the association of urinary Cd (U-Cd) with incidence of fractures, myocardial infarction, heart failure, ischemic stroke and mortality in postmenopausal women. METHODS: We used data from 4024 women, aged 56-85 in the population-based prospective Swedish Mammography Cohort-Clinical. U-Cd was measured by ICP-MS at baseline (2004-2009) and categorized into tertiles. Incident cases of the outcomes were ascertained via register linkage through 2019. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. RESULTS: The median U-Cd at baseline was 0.33 µg/g creatinine (cr) (5-95 percentiles 0.15-0.77). We ascertained the following incident cases: 903 first fracture of any type, 149 myocardial infarction, 174 heart failure, 162 ischemic stroke and 545 total deaths during the approximately 11 years of follow-up. U-Cd was dose-dependently associated with risk of any fracture (HR: 1.20, 95% CI: 1.01 to 1.43, ptrend: 0.04) and all-cause mortality (HR: 1.38, 95% CI: 1.10 to 1.74, ptrend: <0.01) when comparing the highest tertile of U-Cd (median 0.54 µg/g cr) with the lowest (median 0.20 µg/g cr). No clear associations were observed for myocardial infarction, heart failure or stroke. DISCUSSION: Long-term Cd exposure might be associated with risk of fractures and all-cause mortality at lower levels than previously suggested.

Contribution of household drinking water intake to arsenic and lead exposure among Uruguayan schoolchildren.

BACKGROUND: 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. OBJECTIVE: To assess the extent to which consumption of household drinking water contributes to arsenic and lead exposure among Uruguayan schoolchildren with low-level exposure. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Thyroid hormones in relation to toxic metal exposure in pregnancy, and potential interactions with iodine and selenium.

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.

Environmental metal exposure and growth to 10 years of age in a longitudinal mother-child cohort in rural Bangladesh.

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.

A longitudinal study of rural Bangladeshi children with long-term arsenic and cadmium exposures and biomarkers of cardiometabolic diseases.

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 (ß = 0.80 at 4.5 years; ß = 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.

Lead exposure and indices of height and weight in Uruguayan urban school children, considering co-exposure to cadmium and arsenic, sex, iron status and dairy intake.

Child growth depends on complex factors including diet, nutritional status, socioeconomic, and sanitary conditions, and exposure to environmental chemicals. Lead exposure is known to impair growth in young children but effects in school-age children are less clear. The effects of co-exposure to low-level lead and other toxic metals on child growth are not well understood. We examined cross-sectional associations of blood lead (BLL) with growth indices (Z scores of body mass index for age, BAZ, and height for age, HAZ) in Uruguayan urban school children (n = 259; ~7 y). Potential differences in these associations in children with lower vs. higher urinary inorganic arsenic metabolites (U-As), urinary cadmium (U-Cd), sex (42% girls), iron deficiency (ID, 39% children), or intake of dairy foods below recommended levels were examined. BLL was measured using AAS, U-As using HPLC-HGICP-MS, and U-Cd using ICP-MS. Dietary information was obtained by two 24-h recalls completed by caregivers. Children's linear growth was within age and sex-appropriate reference values. Overweight (BAZ > 1 2 SD) was found in 20.1%, and obesity (BAZ > 2 SD) in 18.5%, of children. Ranges (5th, 95th percentile) of biomarker concentrations were: BLL, 0.8-7.8 µg/dL; U-Cd, 0.01-0.2 µg/L, and U-As, 4.0-27.3 µg/L. BLL was inversely associated with HAZ ([95% CI]: 0.10 [-0.17, -0.03]) in covariate-adjusted models. Although this association was slightly more pronounced in girls, children without ID, and children with lower U-As, there was little evidence of effect modification due to overlapping CIs in stratified models. BLLs were not associated with BAZ, except for a suggestion of a negative relationship in girls (-0.10 [-0.23, 0.02]) but not boys [0.001 [-0.11, 0.12]). Our findings indicate that exposure to low levels of lead was associated with lower HAZ in apparently normally growing urban school children. Larger future studies should help elucidate if these associations persist over time and across populations.

Infant Iodine and Selenium Status in Relation to Maternal Status and Diet During Pregnancy and Lactation.

Iodine and selenium are essential trace elements. Recent studies indicate that pregnant and lactating women often have insufficient intake of iodine and selenium, but the impact on fetal and infant status is unclear. Here, we assessed iodine and selenium status of infants in relation to maternal intake and status of these trace elements in the birth cohort NICE, conducted in northern Sweden (n = 604). Iodine was measured in urine (UIC) in gestational week 29, and in breast milk and infant urine 4 months postpartum, while selenium was measured in maternal plasma and erythrocytes in gestational week 29, and in breast milk and infant erythrocytes 4 months postpartum, in both cases using ICP-MS. Maternal intake was assessed with semi-quantitative food frequency questionnaires in gestational week 34 and at 4 months postpartum. The median intake of iodine and selenium during pregnancy (98 and 40 µg/d, respectively) and lactation (108 and 39 µg/d, respectively) was below recommended intakes, reflected in insufficient status (median UIC of 113 µg/L, median plasma selenium of 65 µg/L). Also, breast milk concentrations (median iodine 77 µg/L, median selenium 9 µg/L) were unlikely to meet infant requirements. Median UIC of the infants was 114 µg/L and median erythrocyte selenium 96 µg/kg, both similar to the maternal concentrations. Infant UIC correlated strongly with breast milk levels (rho = 0.64, p < 0.001). Their erythrocyte selenium correlated with maternal erythrocyte selenium in pregnancy (rho = 0.38, p < 0.001), but not with breast milk selenium, suggesting formation of prenatal reserves. Our results indicate that the transport of iodine and selenium to the fetus and infant is prioritized. Still, it is uncertain whether most infants had sufficient intakes. Further, the results might indicate an involvement of iodine in asthma development during the first year of life, which is essential to follow up. The low maternal and infant dietary intake of both iodine and selenium, especially when the mothers did not use supplements or iodized table salt, suggest a need for a general screening of women and young children.

Associations of dietary intakes and serum levels of folate and vitamin B-12 with methylation of inorganic arsenic in Uruguayan children: Comparison of findings and implications for future research.

BACKGROUND: In the human body, inorganic arsenic (iAs) is methylated via the one-carbon cycle to form monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Lower proportions of iAs and MMA, and higher proportions of DMA in urine indicate efficient methylation; formation of DMA is thought to detoxify iAs and MMA. Studies on folate, vitamin B-12 and iAs methylation yield mixed findings, depending on whether folate and vitamin B-12 were assessed from diet, supplements, or using a blood biomarker. OBJECTIVE: First, to compare the associations of serum concentrations and estimated intake of folate and vitamin B-12 with indicators of iAs methylation. Second, to highlight the implications of these different B-vitamin assessment techniques on the emerging evidence of the impact of dietary modifications on iAs methylation. METHODS: The study was conducted among ~7-year-old children from Montevideo, Uruguay. Serum folate and vitamin B-12 levels were measured on the Horiba ABX Pentra 400 analyzer; urinary arsenic was measured using High-Performance Liquid Chromatography on-line with Inductively Coupled Plasma Mass Spectrometry. Dietary intakes were assessed using the average of two 24-h dietary recalls. Linear regressions assessed the associations of serum levels, and dietary intakes of folate (n = 237) and vitamin B-12 (n = 217) with indicators of iAs methylation. Models were adjusted for age, sex, body mass index, total urinary arsenic, and rice intake. RESULTS: Serum folate and vitamin B-12 levels were above the adequacy threshold for 99% of the participants. No associations were observed between serum folate, serum vitamin B-12, or vitamin B-12 intake and iAs methylation. Folate intake was inversely associated with urinary %MMA [ß (95% confidence interval): -1.04 (-1.89, -0.18)]. CONCLUSION: Additional studies on the role of B-vitamins in iAs methylation are needed to develop a deeper understanding of the implications of assessing folate and vitamin B-12 intake compared to the use of biomarkers. Where possible, both methods should be employed because they reflect different exposure windows and inherent measurement error, and if used individually, will likely continue to contribute to lack of consensus.