Maternal lifetime stress and psychological functioning in pregnancy is associated with preschoolers' temperament: Exploring effect modification by race and ethnicity.

BACKGROUND: Psychosocial stress and psychopathology frequently co-occur, with patterns differing by race and ethnicity. We used statistical mixtures methodology to examine associations between prenatal stress and child temperament in N = 382 racially and ethnically diverse maternal-child dyads to disentangle associations among maternal stressful life events, maternal psychological functioning in pregnancy, childhood neurobehavior, and maternal race and ethnicity. METHODS: This study utilized data from a longitudinal pregnancy cohort, PRogramming of Intergenerational Stress Mechanisms (PRISM). Mothers completed the Lifetime Stressor Checklist-Revised, Edinburgh Postnatal Depression Scale, and Spielberger State-Trait Anxiety Scale during pregnancy. When their children were 3-5 years of age, they completed the Children's Behavior Questionnaire, which yields three temperament dimensions: Negative Affectivity (NA), Effortful Control (EC), and Surgency (S). We used weighted quantile sum regression to derive a weighted maternal stress index encompassing lifetime stress and depression and anxiety symptoms and examined associations between the resulting stress index and child temperament. Differential contributions of individual stress domains by race and ethnicity also were examined. RESULTS: Mothers self-identified as Black/Black Hispanic (46.1 %), non-Black Hispanic (31.9 %), or non-Hispanic White (22 %). A higher maternal stress index was significantly associated with increased child NA (ß = 0.72 95 % CI = 0.35, 1.10). Lifetime stress was the strongest contributor among Hispanic (36.7 %) and White (17.8 %) mothers, whereas depressive symptoms in pregnancy was the strongest contributor among Black (16.7 %) mothers. CONCLUSION: Prenatal stress was most strongly associated with negative affectivity in early childhood. Consideration of multiple stress measures as a mixture accounted for differential contributions of individual stress domains by maternal race and ethnicity. These findings may help elucidate the etiology of racial/ethnic disparities in childhood neurobehavior.

Comparison of maternal venous blood metabolomics collected as dried blood spots, dried blood microsamplers, and plasma for integrative environmental health research.

Use of capillary blood devices for exposome research can deepen our understanding of the intricate relationship between environment and health, and open up new avenues for preventive and personalized medicine, particularly for vulnerable populations. While the potential of these whole blood devices to accurately measure chemicals and metabolites has been demonstrated, how untargeted metabolomics data from these samplers can be integrated with previous and ongoing environmental health studies that have used conventional blood collection approaches is not yet clear. Therefore, we performed a comprehensive comparison between relative-quantitative metabolite profiles measured in venous blood collected with dried whole blood microsamplers (DBM), dried whole blood spots (DBS), and plasma from 54 mothers in an ethnically diverse population. We determined that a majority of the 309 chemicals and metabolites showed similar median intensity rank, moderate correlation, and moderate agreement between participant-quantiled intraclass correlation coefficients (ICCs) for pair-wise comparisons among the three biomatrices. In particular, whole blood sample types, DBM and DBS, were in highest agreement across metabolite comparison metrics, followed by metabolites measured in DBM and plasma, and then metabolites measured in DBS and plasma. We provide descriptive characteristics and measurement summaries as a reference database. This includes unique metabolites that were particularly concordant or discordant in pairwise comparisons. Our results demonstrate that the range of metabolites from untargeted metabolomics data collected with DBM, DBS, and plasma provides biologically relevant information for use in independent exposome investigations. However, before meta-analysis with combined datasets are performed, robust statistical approaches that integrate untargeted metabolomics data collected on different blood matrices need to be developed.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying its risk factors is crucial for developing intervention programs. Many "omics" factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.

Associations between neighborhood characteristics and child well-being before and during the COVID-19 pandemic: A repeated cross-sectional study in the Environmental influences on Child Health Outcomes (ECHO) program.

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship.

Associations of salivary aldosterone levels during pregnancy with maternal blood pressure and birth weight-for-gestational age in a Mexico City birth cohort.

OBJECTIVE: To determine associations of maternal salivary aldosterone with blood pressure (BP) in pregnancy and infant birth weight-for-gestational age (BWGA). METHODS: We measured maternal salivary aldosterone, BP and BWGA z-scores in 471 Mexico City pregnancy cohort participants and performed multivariable linear regression of BP and BWGA on log-aldosterone levels. RESULTS: Log-aldosterone was positively associated with diastolic BP (ß = 0.12 95% CI: 0.04, 0.21). There were no main effects of log-aldosterone on BWGA. However, we detected an interaction between log-aldosterone and BP in association with BWGA; higher log-aldosterone was associated with lower BWGA in the lowest (ß = -0.12, 95% CI: -0.26, 0.02) and highest (ß = -0.12, 95% CI: -0.29, 0.06) BP tertiles. In contrast, in the middle BP tertile the association was positive (ß = 0.09, 95% CI: -0.02, 0.20), p for interaction = 0.03. CONCLUSION: Higher maternal salivary aldosterone is positively associated with diastolic BP and may affect fetal growth differently depending on concurrent maternal blood pressure.

Airborne Lead Exposure and Childhood Cognition: The Environmental Influences on Child Health Outcomes (ECHO) Cohort (2003-2022).

Objectives. To examine whether a previously reported association between airborne lead exposure and children's cognitive function replicates across a geographically diverse sample of the United States. Methods. Residential addresses of children (< 5 years) were spatially joined to the Risk-Screening Environmental Indicators model of relative airborne lead toxicity. Cognitive outcomes for children younger than 8 years were available for 1629 children with IQ data and 1476 with measures of executive function (EF; inhibitory control, cognitive flexibility). We used generalized linear models using generalized estimating equations to examine the associations of lead, scaled by interquartile range (IQR), accounting for individual- and area-level confounders. Results. An IQR increase in airborne lead was associated with a 0.74-point lower mean IQ score (b = -0.74; 95% confidence interval = -1.00, -0.48). The association between lead and EF was nonlinear and was modeled with a knot at the 97.5th percentile of lead in our sample. Lead was significantly associated with lower mean inhibitory control but not with cognitive flexibility. This effect was stronger among males for both IQ and inhibitory control. Conclusions. Early-life exposure to airborne lead is associated with lower cognitive functioning. (Am J Public Health. 2024;114(3):309-318. https://doi.org/10.2105/AJPH.2023.307519).

Sensitive development windows of prenatal air pollution and cognitive functioning in preschool age Mexican children.

Introduction: Neurotoxicity resulting from air pollution is of increasing concern. Considering exposure timing effects on neurodevelopmental impairments may be as important as the exposure dose. We used distributed lag regression to determine the sensitive windows of prenatal exposure to fine particulate matter (PM2.5) on children's cognition in a birth cohort in Mexico. Methods: Analysis included 553 full-term (≥37 weeks gestation) children. Prenatal daily PM2.5 exposure was estimated using a validated satellite-based spatiotemporal model. McCarthy Scales of Children's Abilities (MSCA) were used to assess children's cognitive function at 4-5 years old (lower scores indicate poorer performance). To identify susceptibility windows, we used Bayesian distributed lag interaction models to examine associations between prenatal PM2.5 levels and MSCA. This allowed us to estimate vulnerable windows while testing for effect modification. Results: After adjusting for maternal age, socioeconomic status, child age, and sex, Bayesian distributed lag interaction models showed significant associations between increased PM2.5 levels and decreased general cognitive index scores at 31-35 gestation weeks, decreased quantitative scale scores at 30-36 weeks, decreased motor scale scores at 30-36 weeks, and decreased verbal scale scores at 37-38 weeks. Estimated cumulative effects (CE) of PM2.5 across pregnancy showed significant associations with general cognitive index (CE^ = -0.35, 95% confidence interval [CI] = -0.68, -0.01), quantitative scale (CE^ = -0.27, 95% CI = -0.74, -0.02), motor scale (CE^ = -0.25, 95% CI = -0.44, -0.05), and verbal scale (CE^ = -0.2, 95% CI = -0.43, -0.02). No significant sex interactions were observed. Conclusions: Prenatal exposure to PM2.5, particularly late pregnancy, was inversely associated with subscales of MSCA. Using data-driven methods to identify sensitive window may provide insight into the mechanisms of neurodevelopmental impairment due to pollution.

Prenatal exposure to metal mixtures and childhood temporal processing in the PROGRESS Birth Cohort Study: Modification by childhood obesity.

Children are frequently exposed to various biological trace metals, some essential for their development, while others can be potent neurotoxicants. Furthermore, the inflammatory and metabolic conditions associated with obesity may interact with and amplify the impact of metal exposure on neurodevelopment. However, few studies have assessed the potential modification effect of body mass index (BMI). As a result, we investigated the role of child BMI phenotype on the relationship between prenatal exposure to metal mixtures and temporal processing. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 563) aged 6-9 years completed a Temporal Response Differentiation (TRD) task where they had to hold a lever down for 10-14 s. Blood and urinary metal (As, Pb, Cd, and Mn) measurements were collected from mothers in the 2nd and 3rd trimesters. Child BMI z-scores were dichotomized to normal (between -2 and +0.99) and high (≥1.00). Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate and examine the combined effect of metal biomarkers (i.e., blood and urine) on TRD measures. Effect modification by the child's BMI was evaluated using 2-way interaction terms. Children with a high BMI and greater exposure to the metal mixture during prenatal development exhibited significant temporal processing deficits compared to children with a normal BMI. Notably, children with increased exposure to the metal mixture and higher BMI had a decrease in the percent of tasks completed (ß = -10.13; 95 % CI: -19.84, -0.42), number of average holds (ß = -2.15; 95 % CI: -3.88, -0.41), longer latency (ß = 0.78; 95 % CI: 0.13, 1.44), and greater variability in the standard deviation of the total hold time (ß = 2.08; 95 % CI: 0.34, 3.82) compared to normal BMI children. These findings implicate that high BMI may amplify the effect of metals on children's temporal processing. Understanding the relationship between metal exposures, temporal processing, and childhood obesity can provide valuable insights for developing targeted environmental interventions.

Association between prenatal and childhood PM2.5 exposure and preadolescent anxiety and depressive symptoms.

Background: Fine particulate matter (PM2.5) exposure has been linked to anxiety and depression in adults; however, there is limited research in the younger populations, in which symptoms often first arise. Methods: We examined the association between early-life PM2.5 exposure and symptoms of anxiety and depression in a cohort of 8-11-year-olds in Mexico City. Anxiety and depressive symptoms were assessed using the Spanish versions of the Revised Children's Manifest Anxiety Scale and Children's Depression Inventory. Daily PM2.5 was estimated using a satellite-based exposure model and averaged over several early and recent exposure windows. Linear and logistic regression models were used to estimate the change in symptoms with each 5-µg/m3 increase in PM2.5. Models were adjusted for child's age, child's sex, maternal age, maternal socioeconomic status, season of conception, and temperature. Results: Average anxiety and depressive symptom T-scores were 51.0 (range 33-73) and 53.4 (range 44-90), respectively. We observed consistent findings for exposures around the fourth year of life, as this was present for both continuous and dichotomized anxiety symptoms, in both independent exposure models and distributed lag modeling approaches. This window was also observed for elevated depressive symptoms. An additional consistent finding was for PM2.5 exposure during early pregnancy in relation to both clinically elevated anxiety and depressive symptoms, this was seen in both traditional and distributed lag modeling approaches. Conclusion: Both early life and recent PM2.5 exposure were associated with higher mental health symptoms in the child highlighting the role of PM2.5 in the etiology of these conditions.

Associations of prenatal one-carbon metabolism nutrients and metals with epigenetic aging biomarkers at birth and in childhood in a US cohort.

Epigenetic gestational age acceleration (EGAA) at birth and epigenetic age acceleration (EAA) in childhood may be biomarkers of the intrauterine environment. We investigated the extent to which first-trimester folate, B12, 5 essential, and 7 non-essential metals in maternal circulation are associated with EGAA and EAA in early life. Bohlin EGAA and Horvath pan-tissue and skin and blood EAA were calculated using DNA methylation measured in cord blood (N=351) and mid-childhood blood (N=326; median age = 7.7 years) in the Project Viva pre-birth cohort. A one standard deviation increase in individual essential metals (copper, manganese, and zinc) was associated with 0.94-1.2 weeks lower Horvath EAA at birth, and patterns of exposures identified by exploratory factor analysis suggested that a common source of essential metals was associated with Horvath EAA. We also observed evidence nonlinear associations of zinc with Bohlin EGAA, magnesium and lead with Horvath EAA, and cesium with skin and blood EAA at birth. Overall, associations at birth did not persist in mid-childhood; however, arsenic was associated with greater EAA at birth and in childhood. Prenatal metals, including essential metals and arsenic, are associated with epigenetic aging in early life, which might be associated with future health.

An Industry-Relevant Metal Mixture, Iron Status, and Reported Attention-Related Behaviors in Italian Adolescents.

BACKGROUND: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. METHODS: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10-14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale-Long Form, Parent Rating Scales Revised-Short Form, and Teacher Rating Scales Revised-Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. RESULTS: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [ß=0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% (ß=0.04; 95% CrI: 0.00, 0.08), and 4.1% (ß=0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale. CONCLUSIONS: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. https://doi.org/10.1289/EHP12988.

Individual and joint effects of prenatal PM2.5 and maternal stress on child temperament.

Prenatal fine particulate matter (PM2.5) and maternal psychological functioning have been associated with child cognitive outcomes, though their independent and joint impacts on earlier behavioral outcomes remains less studied. We used data from 382 mother-child pairs from a prospective birth cohort in Mexico City. Temperament was measured at 24 months using the Carey Toddler Temperament Scale (TTS). Exploratory factor analysis (EFA) was used to update the factor structure of the TTS. During pregnancy, mothers completed the Crisis in Family Systems-Revised, Edinburgh Depression Scale, pregnancy-specific anxiety scale, and the Perceived Stress Scale. Pregnancy PM2.5 was assessed using estimates from a satellite-based exposure model. We assessed the association between prenatal maternal stress and PM2.5 on temperament, in both independent and joint models. Quantile g-computation was used to estimate the joint associations. Models were adjusted for maternal age, SES, education, child sex, and child age. In EFA, we identified three temperament factors related to effortful control, extraversion, and negative affect. Our main results showed that higher levels of PM2.5 and several of the maternal psychological functioning measures were related to both effortful control and negative affect in the child, both individually and as a mixture. For instance, a one quartile increase in the prenatal mixture was associated with higher negative affect scores in the child (0.34, 95% CI: 0.16, 0.53). We observed modification of these associations by maternal SES, with associations seen only among lower SES participants for both effortful control (-0.45, 95% CI: -0.70, -0.20) and negative affect outcomes (0.60, 95% CI: 0.35, 0.85). Prenatal PM2.5 and maternal psychological functioning measures were associated with toddler temperament outcomes, providing evidence for impacts of chemical and non-chemical stressors on early child health.

Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood.

Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (ß = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms.

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

BACKGROUND: Childhood 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. OBJECTIVES: Using 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. METHODS: We 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. RESULTS: We 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 (ß = 0.14, 95%CI = [0.05,0.23], P < 0.01 for the four-component clique). SIGNIFICANCE: This 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.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying risk factors is crucial for developing intervention programs. Many 'omics' factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.

Associations between a metal mixture and infant negative affectivity: Effect modification by prenatal cortisol and infant sex.

In-utero exposures interact in complex ways that influence neurodevelopment. Animal research demonstrates that fetal sex moderates the impact of joint exposure to metals and prenatal stress measures, including cortisol, on offspring socioemotional outcomes. Further research is needed in humans. We evaluated the joint association of prenatal exposures to a metal mixture and cortisol with infant negative affectivity, considering sex differences. Analyses included 226 (29% White, Non-Hispanic) mother-infant pairs with data on exposures and negative affectivity assessed using the Infant Behavior Questionnaire-Revised in 6-month-olds. Results showed that girls whose mothers had higher cortisol had significantly higher scores of Fear and Sadness with greater exposure to the mixture. Examining higher-order interactions may better elucidate the effects of prenatal exposure to metals and cortisol on socioemotional functioning.

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 (ß = -3.67, 95% credible interval (CrI): -7.61, -0.01) and FTDL (ß = -3.76, 95% CrI: -7.66, -0.24) samples, with a similar trend in the PRISM Boston sample (ß = -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.

Longitudinal associations between early-life fluoride exposures and cardiometabolic outcomes in school-aged children.

BACKGROUND/AIM: Fluoride is a natural mineral present in food, water, and dental products, constituting ubiquitous long-term exposure in early childhood and across the lifespan. Experimental evidence shows fluoride-induced lipid disturbances with potential implications for cardiometabolic health. However, epidemiological studies are scarce. For the first time, we evaluated associations between repeated fluoride measures and cardiometabolic outcomes in children. METHODS: We studied âˆ¼ 500 Mexican children from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort with measurements on urinary fluoride at age 4, and dietary fluoride at ages 4, 6, and 8 years approximately. We used covariate-adjusted linear mixed-effects and linear regression models to assess fluoride associations with multiple cardiometabolic outcomes (ages 4-8): lipids (total cholesterol, HDL, LDL, and triglycerides), glucose, HbA1c, adipokines (leptin and adiponectin), body fat, and age- and sex-specific z-scores of body mass index (zBMI), waist circumference, and blood pressure. RESULTS: Dietary fluoride intake at age 4 was associated with annual increases in triglycerides [ß per-fluoride-doubling = 2.02 (95 % CI: 0.37, 3.69)], cholesterol [ß = 1.46 (95 % CI: 0.52, 2.39)], HDL [ß = 0.39 (95 % CI: 0.02, 0.76)], LDL [ß = 0.87 (95 % CI: 0.02, 1.71)], and HbA1c [ß = 0.76 (95 % CI: 0.28, 1.24)], and decreased leptin [ß = -3.58 (95 % CI: -6.34, -0.75)] between the ages 4 and 8. In cross-sectional analyses at age 8, higher tertiles of fluoride exposure were associated with increases in zBMI, triglycerides, glucose, and leptin (p-tertile trend < 0.05). Stronger associations were observed in boys at year 8 and in girls prior to year 8 (p-sex interaction < 0.05). Fewer but consistent associations were observed for urinary fluoride at age 4, indicating increased annual changes in HDL and HbA1c with higher fluoride levels. CONCLUSION: Dietary fluoride exposures in early- and mid-childhood were associated with adverse cardiometabolic outcomes in school-aged children. Further research is needed to elucidate whether these associations persist at later ages.

Cross-sectional and prospective associations of early childhood circulating metals with early and mid-childhood cognition in the Project Viva cohort.

BACKGROUND: Relatively little is known about the immediate and prospective neurodevelopmental impacts of joint exposure to multiple metals (i.e., metal mixtures) in early childhood. OBJECTIVES: To estimate associations of early childhood (∼3 years of age) blood metal concentrations with cognitive test scores at early and mid-childhood (∼8 years of age). METHODS: We studied children from the Project Viva cohort. We measured erythrocyte concentrations of seven essential (Co, Cu, Mg, Mn, Mo, Se, and Zn) and eight non-essential metals (As, Ba, Cd, Cs, Hg, Pb, Sn, and Sr) in early childhood blood samples. Trained research assistants administered cognitive tests assessing vocabulary, visual-motor ability, memory, and general intelligence (standard deviations: ∼10 points), in early and mid-childhood. We employed multivariable linear regression to examine associations of individual metals with test scores adjusting for confounders, other concurrently measured metals, and first-trimester maternal blood metals. We also estimated joint associations and explored interaction between metals in mixture analyses. RESULTS: We analyzed 349 children (median whole blood Pb ∼1 µg/dL). In cross-sectional analyses, each doubling of Pb was associated with lower visual-motor function (mean difference: -2.43 points, 95% confidence interval (CI): -4.01, -0.86) and receptive vocabulary, i.e., words understood (-1.45 points, 95% CI: -3.26, 0.36). Associations of Pb with mid-childhood cognition were weaker and less precise by comparison. Mg was positively associated with cognition in cross-sectional but not prospective analyses, and cross-sectional associations were attenuated in a sensitivity analysis removing adjustment for concurrent metals. We did not observe joint associations nor interactions. DISCUSSION: In this cohort with low blood Pb levels, increased blood Pb was robustly associated with lower cognitive ability in cross-sectional analyses, even after adjustment for prenatal Pb exposure, and regardless of adjustment for metal co-exposures. However, associations with mid-childhood cognition were attenuated and imprecise, suggesting some buffering of Pb neurotoxicity in early life. WHAT THIS STUDY ADDS: Relatively few studies have comprehensively separated the effects of neurotoxic metals such as lead (Pb) from pre- and postnatal co-occurring metals, nor examined persistence of associations across childhood. In a cohort of middle-class children, we found higher early childhood (∼3 y) blood Pb was associated with lower scores on cognitive tests, independent of other metals and prenatal blood Pb. However, early childhood Pb was only weakly associated with cognition in mid-childhood (∼8 y). Our results suggest the effects of low-level Pb exposure may attenuate over time in some populations, implying the presence of factors that may buffer Pb neurotoxicity in early life.

Effects of storage temperature and time on metabolite profiles measured in dried blood spots, dried blood microsamplers, and plasma.

The practical advantages of capillary whole blood collection over venipuncture plasma collection for human exposome research are well known. However, before epidemiologists, clinicians, and public health researchers employ these microvolume sample collections, a rigorous evaluation of pre-analytical storage conditions is needed to develop protocols that maximize sample stability and reliability over time. Therefore, we performed a controlled experiment of dried whole blood collected on 10 µL Mitra microsamplers (DBM), 5-mm punches of whole blood from a dried blood spot (DBS), and 10 µL of plasma, and evaluated the effects of storage conditions at 4 °C, -20 °C, or -80 °C for up to 6 months on the resulting metabolite profiles measured with untargeted liquid chromatography-high resolution mass spectrometry (LC-HRMS). At -80 °C storage conditions, metabolite profiles from DBS, DBM, and plasma showed similar stability. While DBS and DBM metabolite profiles remained similarly stable at -20 °C storage, plasma profiles showed decreased stability at -20 °C compared to -80 °C storage. At refrigerated temperatures (4 °C), metabolite profiles collected on DBM were more stable than plasma or DBS, particularly for lipid classes. These results inform robust capillary blood sample storage protocols for DBM and DBS at potentially warmer temperatures than -80 °C, which may facilitate blood collections for populations outside of a clinical setting.