Prenatal Metal Exposure Research Articles

Prenatal metal(loid) exposure and preterm birth: a systematic review of the epidemiologic evidence.

Preterm birth (PTB) is a common pregnancy complication associated with significant neonatal morbidity. Prenatal exposure to environmental chemicals, including toxic and/or essential metal(loid)s, may contribute to PTB risk. We aimed to summarize the epidemiologic evidence of the associations amonglevels ofarsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), manganese (Mn), lead (Pb), and zinc (Zn) assessed during the prenatal periodandPTB or gestational age at delivery; to assess the quality of the literature and strength of evidence for an effect for each metal; and to provide recommendations for future research. We adapted the Navigation Guide methodology and followed PRISMA guidelines. We searched the MEDLINE/PubMed database for epidemiologic studies from 1995 to 2023. We used a customized risk of bias protocol and evaluated the sufficiency of evidence for an effect of each metal(loid) on PTB risk. A total of 1206 studies were identified and screened. Of these, 139 were assessed for eligibility by reading the full-text, and 92 studies were ultimately included (arsenic: 40, cadmium: 30, chromium: 11, copper: 21, mercury: 27, manganese: 17, lead: 41, zinc: 18, metal(loid) mixtures: 12). We found sufficient evidence that lead increases the risk of PTB and, while the evidence was limited, suggestive evidence that cadmium and chromium increase the risk of PTB. The evidence was deemed inadequate to determine an effect for the other metal(loid)s. Future research would benefit from more precise PTB clinical phenotyping, measuring exposure early and longitudinally throughout pregnancy, using an appropriate media for metal(loid)s under study, and evaluating metal mixtures. Given the strength of evidence linking lead exposure and PTB, active and comprehensive prenatal screening for lead exposure among pregnant individuals is warranted. By summarizing 92 epidemiologic studies that investigated the associations between metal exposure and preterm birth using the rigorous Navigation Guide methodology, our review provides compelling evidence for a strong link between prenatal lead exposure and preterm birth. Additionally, it suggests potential associations between cadmium and chromium exposure and preterm birth. Given the robust nature of this evidence, there is an urgent need for prenatal screening for lead exposure during pregnancy, along with targeted interventions to reduce exposure. These actions are critical for advancing maternal and child health.

Sex-specific associations between maternal exposure to metal mixtures and fetal growth trajectories: A prospective birth cohort study.

The associations of prenatal metals exposure with birth outcomes have been widely assessed. However, evidence on the associations between metal mixtures and fetal intrauterine growth trajectories is scarce. This study aimed to explore the associations of metal mixtures with fetal intrauterine growth trajectories overall and by sex. We analyzed data from the Ma'anshan birth cohort, which included a total of 1041 pregnant woman. The concentrations of 12 metals in maternal blood were measured during early pregnancy, and fetal intrauterine growth indicators were standardized and assessed at 16, 23, 30, 34, and 38weeks of gestation. We used generalized linear regression and linear mixed models to identify the key fetal growth indicator (biparietal diameter (BPD)), and applied GBTM to characterize BPD SD-scores trajectories. To further assess the individual and combined effects of metals, we conducted multivariable logistic regression and repeated holdouts weighted quantile sum (WQS) regression analyses, respectively. Finally, we performed a sex-stratified analysis to explore sex-specific associations. The sex-stratified multivariable logistic regression analysis indicated that in male fetal, cobalt (Co) (OR: 0.60, 95% CI: 0.38, 0.92) was negatively associated with the high-growth BPD-SD scores trajectory. In contrast, Co (OR: 2.39, 95% CI: 1.40, 4.45) showed a positive association in female fetal. Results from the WQS showed that early pregnancy metal mixture exposure was associated with BPD-SD scores at 16, 34, and 38weeks in female fetal. The results highlighted Zn and Co as key metals associated with high-growth BPD SD-scores trajectory. We also identified a significant interaction between early pregnancy metal mixtures and sex on high-growth BPD SD-scores trajectories. The WQS*sex interaction term had a mean odds ratio of 1.271 (95% CI: 1.027, 1.619). This study suggests that exposure to prenatal metal mixtures affects fetal intrauterine growth trajectories with sexual dimorphism.

Prenatal metal exposures and kidney function in adolescence in Project Viva.

The developing kidney is vulnerable to prenatal environmental factors such as metal exposure, potentially altering the risk of later-life kidney dysfunction. This study examines the relationship between prenatal metal exposures, individually and as mixtures, and adolescent kidney function in Project Viva, a prospective longitudinal birth cohort in Massachusetts, USA. We used data on metals measured in blood during pregnancy including 15 in the first trimester and four in the second trimester. We calculated estimated glomerular filtration rate (eGFR) in adolescents (mean: 17.7 years) using cystatin C- (eGFRcys) and creatinine-based (eGFRcreat) equations for children. We used linear regression for single metal analyses, and Bayesian kernel machine regression and quantile-based g-computation for mixture analyses, adjusting for relevant covariates. To account for multiple comparisons in the single metal analyses, we applied the Holm-Bonferroni procedure to control the false discovery rate. This study included 371 participants with first trimester metals and adolescent eGFR, and 256 with second trimester metals. Each doubling in first trimester cadmium concentration was associated with lower adolescent eGFRcys (β:-1.51; 95% CI:-2.83, -0.18). Each doubling in first trimester chromium (β:-1.45; 95% CI:-2.71, -0.19), nickel (β:-1.91; 95% CI:-3.65, -0.16), and vanadium (β:-1.69; 95% CI:-3.21, -0.17) was associated with lower adolescent eGFRcreat. After adjusting for multiple comparisons, p-values for associations between adolescent eGFR and chromium, nickel, vanadium and cadmium did not meet the criteria for significance. Metal mixture analyses did not identify statistically significant associations with adolescent eGFR. These findings have important implications for future studies investigating the potential mechanisms through which prenatal metal exposures affect long-term kidney health in children.

Associations between prenatal metal and metalloid mixtures in teeth and reductions in childhood lung function

BackgroundMetal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects. ObjectiveExamine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex. MethodsAnalyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8–14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex. ResultsWe identified a window of susceptibility at 12–15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8–14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association. ConclusionsPrenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.

Associations between maternal exposure to multiple metals and metalloids and blood pressure in preschool children: A mixture-based approach

BackgroundExposure to metals during pregnancy can potentially influence blood pressure (BP) in children, but few studies have examined the mixed effects of prenatal metal exposure on childhood BP. We aimed to assess the individual and combined effects of prenatal metal and metalloid exposure on BP in preschool children. MethodsA total of 217 mother–child pairs were selected from the Zhuang Birth Cohort in Guangxi, China. The maternal plasma concentrations of 20 metals [e.g. lead (Pb), rubidium (Rb), cesium (Cs), and zinc (Zn)] in early pregnancy were measured by inductively coupled plasmamass spectrometry. Childhood BP was measured in August 2021. The effects of prenatal metal exposure on childhood BP were explored by generalized linear models, restricted cubic spline and Bayesian kernel machine regression (BKMR) models. ResultsIn total children, each unit increase in the log10-transformed maternal Rb concentration was associated with a 10.82-mmHg decrease (95% CI: −19.40, −2.24) in childhood diastolic BP (DBP), and each unit increase in the log10-transformed maternal Cs and Zn concentrations was associated with a 9.67-mmHg (95% CI: −16.72, −2.61) and 4.37-mmHg (95% CI: −8.68, −0.062) decrease in childhood pulse pressure (PP), respectively. The log10-transformed Rb and Cs concentrations were linearly related to DBP (P nonlinear=0.603) and PP (P nonlinear=0.962), respectively. Furthermore, an inverse association was observed between the log10-transformed Cs concentration and PP (β =-12.18; 95% CI: −22.82, −1.54) in girls, and between the log10-transformed Rb concentration and DBP (β =-12.54; 95% CI: −23.87, −1.21) in boys, while there was an increasing association between the log10-transformed Pb concentration and DBP there was an increasing in boys (β =6.06; 95% CI: 0.36, 11.77). Additionally, a U-shaped relationship was observed between the log10-transformed Pb concentration and SBP (P nonlinear=0.015) and DBP (P nonlinear=0.041) in boys. Although there was no statistically signiffcant difference, there was an inverse trend in the combined effect of maternal metal mixture exposure on childhood BP among both the total children and girls in BKMR. ConclusionsPrenatal exposure to both individual and mixtures of metals and metalloids influences BP in preschool children, potentially leading to nonlinear and sex-specific effects.

Prenatal metal exposures and childhood gut microbial signatures are associated with depression score in late childhood

BackgroundChildhood depression is a major public health issue worldwide. Previous studies have linked both prenatal metal exposures and the gut microbiome to depression in children. However, few, if any, have studied their interacting effect in specific subgroups of children. ObjectivesUsing an interpretable machine-learning method, this study investigates whether children with specific combinations of prenatal metals and childhood microbial signatures (cliques or groups of metals and microbes) were more likely to have higher depression scores at 9–11 years of age. MethodsWe leveraged data from a well-characterized pediatric longitudinal birth cohort in Mexico City and its microbiome substudy (n = 112). Eleven metal exposures were measured in maternal whole blood samples in the second and third trimesters of pregnancy. The gut microbial abundances were measured at 9–11-year-olds using shotgun metagenomic sequencing. Depression symptoms were assessed using the Child Depression Index (CDI) t-scores at 9–11 years of age. We used Microbial and Chemical Exposure Analysis (MiCxA), which combines interpretable machine-learning into a regression framework to identify and estimate joint associations of metal-microbial cliques in specific subgroups. Analyses were adjusted for relevant covariates. ResultsWe identified a subgroup of children (11.6 % of the sample) characterized by a four-component metal-microbial clique that had a significantly high depression score (15.4 % higher than the rest) in late childhood. This metal-microbial clique consisted of high Zinc in the second trimester, low Cobalt in the third trimester, a high abundance of Bacteroides fragilis, a high abundance of Faecalibacterium prausnitzii. All combinations of cliques (two-, three-, and four-components) were significantly associated with increased log-transformed t-scored CDI (β = 0.14, 95%CI = [0.05,0.23], P < 0.01 for the four-component clique). SignificanceThis study offers a new approach to chemical-microbial analysis and a novel demonstration that children with specific gut microbiome cliques and metal exposures during pregnancy may have a higher likelihood of elevated depression scores.

Associations between prenatal metal exposure and growth rate in children: Based on Hangzhou Birth Cohort Study

BackgroundIt has been reported that prenatal metal exposure is associated with child anthropometry. However, studies focusing on the growth rate of anthropometry among children have not been conducted. This study aimed to examine associations between the exposure of multiple metals during pregnancy and the growth rate of anthropometry among offspring. Methods743 mother-child pairs from the Hangzhou Birth Cohort Study (HBCS) were included. Levels of eleven metals in mother's blood during pregnancy were measured. Offspring had a mean of 5.7 measurements on anthropometric indicators including weight, length/height, head circumference, and body mass index (BMI) within 1.5 years of birth. Generalized estimating equation (GEE) model was used to investigate the associations between maternal metal exposure and growth rate of anthropometric indicators in children. Stratification analysis by sex was also examined. ResultsLevels of selenium (Se, β = 0.213, 95 % CI = 0.017 to 0.409, P = 0.033) were positively associated with length/height gain per month in children. Levels of chromium (Cr, β = 0.025, 95 % CI = 0.018 to 0.033, P < 0.001) were positively associated with the rate of weight gain. Levels of manganese (Mn, β = −0.030, 95 % CI = −0.052 to −0.008, P = 0.009) and cobalt (Co, β = −0.012, 95 % CI = −0.024 to −0.000, P = 0.044) were inversely associated with growth rate of head circumference. Children with higher maternal Mn levels had a lower BMI change rate. Associations between metals and growth rate were stronger in girls than in boys. Besides, significant associations between metal mixtures and growth rate were found. ConclusionPrenatal exposure to Se, Cr, Mn, and Co was associated with growth rate in children, with sex-specific disparities. Our results suggested important effects of maternal exposure to multiple metals on development in offspring.

Prenatal Metal Exposures and Child Social Responsiveness Scale Scores in 2 Prospective Studies.

Prenatal exposure to metals is hypothesized to be associated with child autism. We aim to investigate the joint and individual effects of prenatal exposure to urine metals including lead (Pb), mercury (Hg), manganese (Mn), and selenium (Se) on child Social Responsiveness Scale (SRS) scores. We used data from 2 cohorts enriched for likelihood of autism spectrum disorder (ASD): Early Autism Risk Longitudinal Investigation (EARLI) and the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) studies. Metal concentrations were measured in urine collected during pregnancy. We used Bayesian Kernel Machine Regression and linear regression models to investigate both joint and independent associations of metals with SRS Z-scores in each cohort. We adjusted for maternal age at delivery, interpregnancy interval, maternal education, child race/ethnicity, child sex, and/or study site. The final analytic sample consisted of 251 mother-child pairs. When Pb, Hg, Se, and Mn were at their 75th percentiles, there was a 0.03 increase (95% credible interval [CI]: -0.11, 0.17) in EARLI and 0.07 decrease (95% CI: -0.29, 0.15) in MARBLES in childhood SRS Z-scores, compared to when all 4 metals were at their 50th percentiles. In both cohorts, increasing concentrations of Pb were associated with increasing values of SRS Z-scores, fixing the other metals to their 50th percentiles. However, all the 95% credible intervals contained the null. There were no clear monotonic associations between the overall prenatal metal mixture in pregnancy and childhood SRS Z-scores at 36 months. There were also no clear associations between individual metals within this mixture and childhood SRS Z-scores at 36 months. The overall effects of the metal mixture and the individual effects of each metal within this mixture on offspring SRS Z-scores might be heterogeneous across child sex and cohort. Further studies with larger sample sizes are warranted.

Prenatal exposure to environmental heavy metals and newborn telomere length: A systematic review and meta-analysis

Exposure to environmental heavy metals is associated with telomere length (TL) alteration. Available information regarding the effect of prenatal exposure to environmental pollutants on newborn TL is controversial. The aim of this study is to systematically review and conduct a meta-analysis of the existing epidemiological studies on the associations between prenatal metal exposure and newborn TL. A comprehensive literature search was performed using the online databases of PubMed, Web of Science, and ScienceDirect from their inception to December 1, 2023. Thirteen eligible studies were included from the overall initial identification of 3559 records. The effect size was expressed as standardized beta coefficients with 95% confidence intervals (CIs) by the restricted maximum-likelihood approach with a weighted random-effects model. Prenatal exposure to environmental heavy metals was associated with a shorter newborn TL (standardized beta = −0.04; 95% CI: −0.08, 0.00; p = 0.05). Subgroup analysis showed that prenatal exposure to cadmium was significantly, negatively associated with TL in newborns (standardized beta = −0.05; 95% CI: −0.10, −0.01; p = 0.021). Heavy metal exposure during the third trimester was significantly associated with a shorter TL in newborns (standardized beta = −0.05; 95% CI: −0.11, −0.01; p = 0.045). No significant association was found between the newborn's sex and exposure sample type. This study provides evidence for the negative effect of prenatal exposure to heavy metals on newborn TL. In particular, cadmium exposure and exposure during the third trimester of pregnancy are critical factors associated with heavy metal-induced TL shortening.

Integrating Data Across Multiple Sites in the Northeastern United States to Examine Associations Between a Prenatal Metal Mixture and Child Cognition.

We applied a novel hierarchical Bayesian weighted quantile sum (HBWQS) regression to combine data across 3 study sites to examine associations between prenatal exposure to metals and cognitive functioning in childhood. Data from 326 mother-child dyads enrolled in an ongoing cohort study, the Programming of Intergenerational Stress Mechanisms (PRISM) Study, based in New York, New York (recruitment in 2013-2020) and Boston, Massachusetts (recruitment 2011-2013), and the First Thousand Days of Life (FTDL) cohort study (recruitment 2012-2019), based in northern Virginia, were used. Arsenic, cadmium, manganese, lead, and antimony were measured in urine collected during pregnancy. Cognitive functioning was assessed in children aged 3-11 years using the National Institutes of Health Toolbox Cognition Battery. The HBWQS regression showed a negative association between the urinary metal mixture and the Cognition Early Childhood Composite Score in the PRISM New York City (β = -3.67, 95% credible interval (CrI): -7.61, -0.01) and FTDL (β = -3.76, 95% CrI: -7.66, -0.24) samples, with a similar trend in the PRISM Boston sample (β = -3.24, 95% CrI: -6.77, 0.144). We did not detect these associations in traditionally pooled models. HBWQS regression allowed us to account for site heterogeneity and detect associations between prenatal metal-mixture exposure and cognitive outcomes in childhood. Given the ubiquity of metals exposure, interventions aimed at reducing prenatal exposure may improve cognitive outcomes in children. This article is part of a Special Collection on Environmental Epidemiology.

Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children's Study.

The association between prenatal metal exposure and congenital anomalies is unclear. We aimed to examine the association between exposure to cadmium, lead, mercury, selenium, and manganese and physical abnormalities. Data from 89,887 pregnant women with singleton pregnancies who participated in the Japan Environment and Children's Study (JECS) were used. The correlation between maternal blood metal concentrations and physical abnormalities during the second or third trimester was investigated using logistic regression models. Physical anomalies included those observed at birth or at 1 month, primarily from ICD-10 Chapter 17, particularly congenital anomalies associated with environmental factors (e.g., hypospadias, cryptorchidism, cleft lip and palate, digestive tract atresia, congenital heart disease, and chromosomal abnormalities) and minor abnormalities. After adjusting for covariates, the OR (95% CIs) of physical abnormalities for a one-unit rise in Mn concentrations in all individuals were 1.26 (1.08, 1.48). The OR (95% CIs) of physical abnormalities in the 4th quartile (≥18.7 ng/g) were 1.06 (1.01, 1.13) (p-value for the trend = 0.034) compared with those in the 1st quartile (≤12.5 ng/g). In Japan, maternal blood Mn concentrations above threshold during pregnancy may slightly increase the incidence of physical abnormalities. Physical abnormalities (including minor anomalies and congenital anomalies) are associated with prenatal manganese concentrations. They are not associated with cadmium, lead, mercury, and selenium concentrations.

Prenatal Metal Exposure Alters the Placental Proteome in a Sex-Dependent Manner in Extremely Low Gestational Age Newborns: Links to Gestational Age.

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, such as neurological impairment. It is often the case that these adverse outcomes show sex-specific responses in relation to toxicant exposures. While the precise molecular mechanisms linking in utero toxic metal exposures with later-in-life health are unknown, placental inflammation is posited to play a critical role. Here, we sought to understand whether in utero metal exposure is associated with alterations in the expression of the placental proteome by identifying metal associated proteins (MAPs). Within the Extremely Low Gestational Age Newborns (ELGAN) cohort (n = 230), placental and umbilical cord tissue samples were collected at birth. Arsenic (As), cadmium (Cd), lead (Pb), selenium (Se), and manganese (Mn) concentrations were measured in umbilical cord tissue samples via ICP-MS/MS. Protein expression was examined in placental samples using an LC-MS/MS-based, global, untargeted proteomics analysis measuring more than 3400 proteins. MAPs were then evaluated for associations with pregnancy and neonatal outcomes, including placental weight and gestational age. We hypothesized that metal levels would be positively associated with the altered expression of inflammation/immune-associated pathways and that sex-specific patterns of metal-associated placental protein expression would be observed. Sex-specific analyses identified 89 unique MAPs expressed in female placentas and 41 unique MAPs expressed in male placentas. Notably, many of the female-associated MAPs are known to be involved in immune-related processes, while the male-associated MAPs are associated with intracellular transport and cell localization. Further, several MAPs were significantly associated with gestational age in males and females and placental weight in males. These data highlight the linkage between prenatal metal exposure and an altered placental proteome, with implications for altering the trajectory of fetal development.

Prenatal Metals Exposure and pre-adolescents’ Emotional and Behavioral Problems

Emotional and behavioral problems during childhood raise the risk of subsequent developmental of mental disorders. Our aim was to study the association between maternal metal and trace element concentrations during gestation and these problems in 9 year-old children. The study sample comprised Spanish mother-child pairs in the INMA project (n = 1003). Metals and trace elements (As, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Tl and Zn) were measured in urine samples collected during pregnancy. Inorganic As metabolites were speciated in a subsample (n = 729). Emotional and behavioral problems were assessed using the Child Behavior Checklist (CBCL) composed of three scales: internalizing, externalizing and total problems. Sociodemographic, dietary and exposure to other environmental pollutants were obtained through questionnaires. Single nucleotide polymorphisms in brain- and metabolism-related genes APOE, BDNF, GSTP1, and PON1 were determined in cord blood. Multivariate negative binomial models were used. The interaction with sex and genotypes was evaluated including interaction terms. A multi-element analysis was carried out by a principal component analysis. Higher concentrations of Cu, monomethylarsonic acid, and Pb during pregnancy were associated with an increased incidence ratio risk (IRR) between 4.6 and 7.5% for internalizing and externalizing problems for all three CBCL scales in the children. Increasing Mo, Ni and Co concentrations were associated with higher IRR for internalizing problems (up to 8%), and Cd for externalizing problems (6.7%). Modifications by sex and genotypes were found for several associations. Multi-element analysis associated multiple metals and trace elements (Ni, Cu, Se, Cd and Pb) with higher internalizing problems.

Prenatal lead exposure is negatively associated with the gut microbiome in childhood.

Metal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood. This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Data come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders. Of the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6 (SE = 2.1) ug/L and 34.9 (SE = 2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2Tβ = -0.17, 95%CI = [-0.46,0.11]; 3Tβ = -0.17, 95%CI = [-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure. Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

Abstract P168: Early Life Metal Profiles and Kidney Function in Mid-Adolescence: A Preliminary Study in Project Viva

Introduction: The developing kidney is vulnerable to pre- and postnatal environmental stressors. Suboptimal environmental conditions during early life, such as exposure to toxic metals and deficiency in essential metals, can alter the risk of kidney dysfunction later in life. In this pilot study, we aimed to examine the relationship between prenatal exposure to metals and adolescent kidney function using data from Project Viva, a Boston-area prospective pre-birth cohort. Hypothesis: Prenatal exposure to higher metal concentrations, both individually and as mixtures, will be associated with altered kidney function in mid-adolescence. Methods: We assessed the following metals in erythrocyte samples collected during pregnancy: 1 st -trimester [arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb), copper (Cu), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)]; 2 nd -trimester (Pb, Mn, Hg, and Se). We measured plasma cystatin C and creatinine from blood samples collected in mid-adolescence (mean age 18 years) in a sub-sample of Project Viva participants. We calculated the estimated glomerular filtrate rate (eGFR) using a cystatin C-based equation for children. We examined associations of prenatal metal exposure and mid-adolescent eGFR using linear regression for single metal analyses, and Bayesian kernel machine regression and quantile-based g-computation for mixture analyses. In all models, we adjusted for maternal education level, annual household income, race/ethnicity, child sex, and age at eGFR assessment. Results: A total of 146 participants had complete data for 1 st -trimester erythrocyte metals and mid-adolescent eGFR, and 105 participants had complete data for 2 nd -trimester blood metals and mid-adolescent eGFR. All children had eGFR values in the normal range (i.e., &gt;60 mL/min/1.73m 2 ); the mean (SD) eGFR was 92.0 (13.7) mL/min/1.73m 2 . Most pairwise metal-eGFR relationships were statistically null; however, a 2-fold increase in 1 st -trimester Zn was associated with higher eGFR (β 7.25 mL/min/1.73m 2 ; 95% CI 0.33, 14.16), while a 2-fold increase in 2 nd -trimester Pb was associated with lower eGFR (β -4.90 mL/min/1.73m 2 ; 95% CI -8.32, -1.48). Mixture analyses did not identify statistically significant findings but suggested some non-linear associations and interactions between metals. Conclusions: Preliminary evidence suggests that prenatal Zn exposure is associated with higher kidney function while prenatal Pb exposure is associated with lower kidney function in mid-adolescence. We plan to assess eGFR in additional participants to increase the power of the analyses.

Associations between biomarkers of prenatal metals exposure and non-nutritive suckamong infants from the PROTECT birth cohort in Puerto Rico.

Infant non-nutritive suck (NNS) has been used as an early marker of neonatal brain function. Although there is an established relationship between prenatal exposure to certain metals and brain development, the association between metal exposure and NNS has not been explored. Therefore, in this study we assessed associations between maternal urinary metal(loid) concentrations and NNS measurements among infants from the Puerto Rico PROTECT birth cohort. We hypothesized that maternal urinary metal(loid) concentrations are significantly associated with infant NNS measures in a sex-dependent manner. We measured urinary concentrations of 14 metal(loid)s in pregnant women at up to three time points in pregnancy. The geometric mean of each metal(loid) for each pregnant woman was calculated and used as an exposure measurement across gestation. NNS measurements (duration, frequency, amplitude, bursts/min, cycles/burst, cycles/min) were collected from infants between 4 and 6 (±2 weeks) weeks of age using our custom research pacifier. Linear regression was used to estimate associations between urinary metal(loid) concentrations across pregnancy and continuous NNS variables. Sex-specific effects were estimated using interaction terms between NNS variables and infant sex. We observed significant positive associations between mercury, manganese, and tin with NNS duration (mercury: %Δ = 1.08, 95% CI: 0.42, 1.74; manganese: %Δ = 0.67, 95% CI: 0.15, 1.20; tin: %Δ = 0.83, 95% CI: 0.17, 1.49) and NNS cycles/burst (mercury: %Δ = 1.85, 95% CI: 0.58, 3.11; manganese: (%Δ = 1.37, 95% CI: 0.40, 2.34; tin: %Δ = 1.68, 95% CI: 0.46, 2.91). Furthermore, the association between NNS cycles/min with cadmium (%Δ = 8.06, 95% CI: 3.33, 12.78), manganese (%Δ = 4.44, 95% CI: 1.40, 7.47), and tin (%Δ = 4.50, 95% CI: 0.81, 8.18) were in the opposite direction from its association with zinc (%Δ = -9.30, 95% CI: -14.71, -3.89), as well as with copper (%Δ = -6.58, 95% CI: -12.06, -1.10). For the sex-stratified analysis, the negative associations between metal(loid)s and NNS duration were predominantly driven by male infants; however, the negative associations between metal(loid)s and NNS bursts/min were mainly driven by female infants. We observed significant associations between prenatal metal(loid) exposure and NNS measurements among infants from the ongoing Puerto Rico PROTECT cohort. Similar to previous studies that have demonstrated associations between NNS and subsequent neurodevelopment, this study highlights the potential of NNS as a quantitative index to measure altered neurodevelopment from prenatal metal(loid) exposures. We believe this study will inform future efforts aimed at reducing health risks related to early life metal exposures, such as developing early identification of metal-induced adverse outcomes in child neurodevelopment.

Association between prenatal metals exposure and blood pressure in 5–6 years children: A birth cohort study

BackgroundThe trajectory of blood pressure (BP) from childhood to early middle age suggested that individuals with elevated BP in early childhood were more likely to be affected by cardiovascular disease in adulthood. Exposure to metals may affect BP in children, and pregnancy is a sensitive time for metal exposure. This study assessed the relationship between different stages of prenatal exposure to metals or metal mixtures and BP in children aged 5–6 years. MethodsThe study included 2535, 2680, 2534 mother-child pairs in three trimesters, from the Ma'anshan birth cohort study (MABC). We collected maternal blood samples during pregnancy and measured the serum levels of four metals (arsenic, selenium, cadmium, and mercury). BP was measured in children aged 5–6 years. A linear regression model and Bayesian kernel machine regression (BKMR) were used to explore associations between prenatal exposure to metals at different stages and multiple metal exposure with BP in children aged 5–6 years. ResultsAssociations were observed between the arsenic in the third trimester and children's diastolic blood pressure (DBP) (β = 0.88, 95% CI: 0.44, 1.33), systolic blood pressure (SBP) (β = 0.72, 95% CI: 0.19, 1.24) and mean arterial pressure (MAP) (β = 0.83, 95% CI: 0.42, 1.23), as well as between the mercury and children's DBP (β = 0.65, 95% CI: 0.13, 1.16) and MAP (β = 0.60, 95% CI: 0.14, 1.07). The BKMR analysis showed that multiple metals had a significant positive joint effect on children's DBP, SBP and MAP. A potential interaction between arsenic and mercury was observed (β = −0.85, 95% CI: −1.62, −0.08). ConclusionsExposure to arsenic and mercury during pregnancy was associated with altered BP in children. The third trimester may represent an important window of opportunity to reduce the effects of metal exposure on children's blood pressure and long-term health.

Prenatal Metal Exposures and Associations with Kidney Injury Biomarkers in Children.

Prenatal exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) may be nephrotoxic, yet limited studies have examined subclinical kidney injury biomarkers in children. We assessed whether metal exposure in the second trimester (2T), a crucial time of kidney development, is associated with altered urine kidney injury and function biomarkers in preadolescent children. Analyses included 494 children participating in a birth cohort study in Mexico City. Concentrations of As, Cd, and Pb were measured from pregnant women in 2T blood and urine, and Hg in urine only. Kidney biomarkers were measured from children in urine at age 8-12 years. We assessed the associations between individual metals and (1) kidney biomarkers using linear regression and (2) a multi-protein kidney mixture using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney biomarkers were assessed via WQS. Within the multi-protein mixture, the association with increased urinary As was predominated by urine alpha-1-microglobulin (A1M), interferon gamma-induced protein 10 (IP10), and fatty acid binding protein 1; the association with increased urinary Cd was predominated by A1M, clusterin, and albumin. The urine metal mixture was associated with increased albumin (0.23 ng/mL; 95% confidence interval (CI): 0.10, 0.37), IP10 (0.15 ng/mL; 95% CI: 0.02, 0.28), and cystatin C (0.17 ng/mL; 95% CI: 0.04, 0.31); these associations were mainly driven by urinary As and Cd. We observed null associations between prenatal blood or urine metal mixtures and estimated glomerular filtration rate. Higher prenatal urinary metals, individually and as a mixture were associated with altered kidney injury biomarkers in children. Further research and longer participant follow-up are required to ascertain the risk of kidney disease later in life.

Impact of prenatal exposure to mercury and selenium on neurodevelopmental delay in children in the Japan environment and Children's study using the ASQ-3 questionnaire: A prospective birth cohort.

Neurodevelopmental delay is associated with neurodevelopmental disorders. Prenatal metal exposure can potentially cause neurodevelopmental delays in children. This study examines whether prenatal exposure to mercury (Hg) and selenium (Se) is associated with the risk of neurodevelopmental delays in children up to 4years of age. Children enrolled in a prospective birth cohort of the Japan Environment and Children's Study were examined. Hg and Se levels in maternal (nchild=48,731) and cord (nchild=3,083) blood were analyzed by inductively coupled plasma-mass spectrometry. Neurodevelopmental delays were assessed in children between the ages of 0.5 to 4years using the Ages and Stages Questionnaires, Third Edition. The association between exposure and outcomes was examined using the generalized estimation equation models. In maternal blood, compared to participants with Se levels in the first quartile (83.0 to<156ng/g), the odds ratio (95% confidence intervals) for problem-solving ability in children of mothers in the third (168 to<181ng/g) and fourth quartiles (181 to 976ng/g) were 1.08 (1.01 to 1.14) and 1.10 (1.04 to 1.17), respectively. Furthermore, communication, gross and fine motor skills, and problem-solving delays were also observed. However, prenatal Hg levels in maternal and cord blood and Se levels in the latter were not associated with neurodevelopmental delays in children. Thus, the findings of this study suggest an association between Se levels in maternal blood and slightly increased risks of neurodevelopmental delays in children up to the age of 4years.

Associations of Prenatal Metals Exposure with Kidney Injury Biomarkers in Children

Background and Aim: Prenatal exposure to toxic metal(loid)s, including arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) during development may have nephrotoxic effects in children. We assessed associations between prenatal metal exposure and urinary kidney injury biomarkers in children. Methods: Analyses included 418 children participating in the PROGRESS birth cohort study in Mexico City. Concentrations of As, Cd, Pb, and Hg (urine only) were quantified in maternal second trimester (2T) blood and urine. Kidney parameters were assessed at 8-10 years of age. We examined associations between individual metals and 1) kidney injury biomarkers using linear regression and 2) a multi-protein kidney index using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney injury biomarkers were assessed via WQS. Covariates included child’s age, sex, body mass index z-score, urine creatinine, 2T socioeconomic status, and 2T smoking exposure. Results: In single metal analyses, doubling of urine Cd was associated with higher urinary TIMP metallopeptidase inhibitor 1 (TIMP1), alpha-1-microglobulin (A1M), clusterin, and cystatin C. Within the multi-protein index, the association with increased urinary As was predominated by albumin, fatty acid binding protein 1 (FABP1), and interferon gamma-induced protein 10 (IP10), and the association with increased urinary Cd was predominated by albumin, A1M, TIMP1, lipocalin, and FABP1. Decile increases in urine metal mixture was associated with increased urinary albumin, IP10, and cystatin C. Urinary As and Cd comprised 60-96% of the metal mixture weights contributing to the associations. Conclusions: Prenatal urinary metals, individually and as a mixture were associated with increased urinary kidney injury biomarkers in healthy children. Prenatal metals exposure may lead to subclinical glomerular or tubular injury in school age children. Further research is required to ascertain resolution or worsening of subclinical kidney injury at later life stages. Keywords: Heavy metals; Renal health; Mixtures