Food groups consumption and urinary metal mixtures in women from Northern Mexico.

OBJECTIVE: We aimed to evaluate the association between food groups and mixtures of urinary metal concentrations in a sample of women; as well as identify the most important metals within each mixture. METHODS: This is a cross-sectional analysis between food groups consumption and mixtures of various metals in urine from 439 women, ≥18 years old, from Northen Mexico. We estimated the dietary intake of 20 food groups through a validated semi-quantitative food frequency questionnaire. Urinary metal concentration of aluminum, antimony, arsenic, barium, cadmium, cesium, chromium, cobalt, copper, lead, manganese, magnesium, molybdenum, nickel, selenium, thallium, tin, vanadium, and zinc, were measured by inductively coupled plasma triple quad. We used weighted quantile sum (WQS) regression with binomial family specification to assess the association of food groups and metal mixtures, as well as to identify the most important ones. RESULTS: We identified tin, lead, and antimony as the most important metals, in the metal mixtures that were positively associated with the consumption of eggs, non-starchy vegetables, fruits, seafood, corn, oil seeds, chicken, soda, legumes, red and/or processed meats, as well as negatively with the consumption of alliums, corn tortillas and/or vegetable oils. CONCLUSION: Our findings suggest that food consumption is related to more than one metal in the study sample, and highlights the presence of some of them. Further research is required to identify the possible sources of metals in food, as well as the chronic adverse health effects attributed to their simultaneous presence.

Prenatal Household Air Pollution Exposure and Childhood Blood Pressure in Rural Ghana.

BACKGROUND: The association between prenatal household air pollution (HAP) exposure and childhood blood pressure (BP) is unknown. OBJECTIVE: Within the Ghana Randomized Air Pollution and Health Study (GRAPHS) we examined time-varying associations between a) maternal prenatal and b) first-year-of-life HAP exposure with BP at 4 years of age and, separately, whether a stove intervention delivered prenatally and continued through the first year of life could improve BP at 4 years of age. METHODS: GRAPHS was a cluster-randomized cookstove intervention trial wherein n=1,414 pregnant women were randomized to one of two stove interventions: a) a liquefied petroleum gas (LPG) stove or improved biomass stove, or b) control (open fire cooking). Maternal HAP exposure over pregnancy and child HAP exposure over the first year of life was quantified by repeated carbon monoxide (CO) measurements; a subset of women (n=368) also performed one prenatal and one postnatal personal fine particulate matter (PM2.5) measurement. Systolic and diastolic BP (SBP and DBP) were measured in n=667 4-y-old children along with their PM2.5 exposure (n=692). We examined the effect of the intervention on resting BP z-scores. We also employed reverse distributed lag models to examine time-varying associations between a) maternal prenatal and b) first-year-of-life HAP exposure and resting BP z-scores. Among those with PM2.5 measures, we examined associations between PM2.5 and resting BP z-scores. Sex-specific effects were considered. RESULTS: Intention-to-treat analyses identified that DBP z-score at 4 years of age was lower among children born in the LPG arm (LPG ß=-0.20; 95% CI: -0.36, -0.03) as compared with those in the control arm, and females were most susceptible to the intervention. Higher CO exposure in late gestation was associated with higher SBP and DBP z-score at 4 years of age, whereas higher late-first-year-of-life CO exposure was associated with higher DBP z-score. In the subset with PM2.5 measurements, higher maternal postnatal PM2.5 exposure was associated with higher SBP z-scores. DISCUSSION: These findings suggest that prenatal and first-year-of-life HAP exposure are associated with child BP and support the need for reductions in exposure to HAP, with interventions such as cleaner cooking beginning in pregnancy. https://doi.org/10.1289/EHP13225.

Akkermansia muciniphila modifies the association between metal exposure during pregnancy and depressive symptoms in late childhood.

Emerging research suggests that exposures to metals during pregnancy and gut microbiome (GM) disruptions are associated with depressive disorders in childhood. Akkermansia muciniphila, a GM bacteria, has been studied for its potential antidepressant effects. However, its role in the influence of prenatal metal exposures on depressive symptoms during childhood is unknown. Leveraging a well-characterized pediatric longitudinal birth cohort and its microbiome substudy (n=112) and using a state-of-the-art machine-learning model, we investigated whether the presence of A.muciniphila in GM of 9-11-year-olds modifies the associations between exposure to a specific group of metals (or metal-clique) during pregnancy and concurrent childhood depressive symptoms. Among children with no A.muciniphila, a metal-clique of Zinc-Chromium-Cobalt was strongly associated with increased depression score (P<0.0001), whereas, for children with A.muciniphila, this same metal-clique was weakly associated with decreased depression score(P<0.4). Our analysis provides the first exploratory evidence hypothesizing A. muciniphila as a probiotic intervention attenuating the effect of prenatal metal-exposures-associated depressive disorders in late childhood.

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.

EDC mixtures during pregnancy and body fat at 7 years of age in a Swedish cohort, the SELMA study.

BACKGROUND: Some endocrine disrupting chemicals (EDC), are "obesogens" and have been associated with overweight and obesity in children. Daily exposure to different classes of EDCs demands for research with mixtures approach. OBJECTIVES: This study evaluates the association, considering sex-specific effects, between prenatal exposure to EDC mixture and children's body fat at seven years of age. METHODS: A total of 26 EDCs were assessed in prenatal urine and serum samples from first trimester in pregnancy from 737 mother-child pairs participating in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. An indicator for children's "overall body fat" was calculated, using principal component analysis (PCA), based on BMI, percent body fat, waist, and skinfolds measured at seven years of age. Weighted quantile sum (WQS) regression was used to assess associations between EDC mixture and children's body fat. RESULTS: Principal component (PC1) represented 83.6 % of the variance, suitable as indicator for children's "overall body fat", with positive loadings of 0.40-0.42 for each body fat measure. A significant interaction term, WQS*sex, confirmed associations in the opposite direction for boys and girls. Higher prenatal exposure to EDC mixture was borderline significant with more "overall body fat" for boys (Mean ß = 0.20; 95 % CI: -0.13, 0.53) and less for girls (Mean ß = -0.23; 95 % CI: -0.58, 0.13). Also, higher prenatal exposure to EDC mixture was borderline significant with more percent body fat (standardized score) for boys (Mean ß = 0.09; 95 % CI: -0.04, 0.21) and less for girls (Mean ß = -0.10 (-0.26, 0.05). The chemicals of concern included bisphenols, phthalates, PFAS, PAH, and pesticides with different patterns for boys and girls. DISCUSSION: Borderline significant associations were found between prenatal exposure to a mixture of EDCs and children's body fat. The associations in opposite directions suggests that prenatal exposure to EDCs may present sex-specific effects on children's body fat.

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.

Predictors of Phthalate Metabolites Exposure among Healthy Pregnant Women in the United States, 2010-2015.

Phthalate use and the concentrations of their metabolites in humans vary by geographic region, race, ethnicity, sex, product use and other factors. Exposure during pregnancy may be associated with detrimental reproductive and developmental outcomes. No studies have evaluated the predictors of exposure to a wide range of phthalate metabolites in a large, diverse population. We examined the determinants of phthalate metabolites in a cohort of racially/ethnically diverse nulliparous pregnant women. We report on urinary metabolites of nine parent phthalates or replacement compounds-Butyl benzyl phthalate (BBzP), Diisobutyl phthalate (DiBP), Diethyl phthalate (DEP), Diisononyl phthalate (DiNP), D-n-octyl phthalate (DnOP), Di-2-ethylhexyl terephthalate (DEHTP), Di-n/i-butyl phthalate (DnBP), Di-isononyl phthalate (DiNP) and Di-(2-ethylhexyl) phthalate (DEHP) from urine collected up to three times from 953 women enrolled in the Nulliparous Mothers To Be Study. Phthalate metabolites were adjusted for specific gravity. Generalized estimating equations (GEEs) were used to identify the predictors of each metabolite. Overall predictors include age, race and ethnicity, education, BMI and clinical site of care. Women who were Non-Hispanic Black, Hispanic or Asian, obese or had lower levels of education had higher concentrations of selected metabolites. These findings indicate exposure patterns that require policies to reduce exposure in specific subgroups.

Household Air Pollution and Child Lung Function: The Ghana Randomized Air Pollution and Health Study.

RATIONALE: The impact of a household air pollution (HAP) stove intervention on child lung function is poorly described. OBJECTIVES: To assess the effect of a prenatal to age one HAP stove intervention on, and exposure-response associations with, age four lung function. METHODS: The Ghana Randomized Air Pollution and Health Study (GRAPHS) randomized pregnant women to a liquefied petroleum gas (LPG), improved biomass, or open fire (control) stove through child age one. We quantified HAP exposure by repeated maternal and child personal carbon monoxide (CO) exposure measurements. Children performed oscillometry, an effort-independent lung function measurement, at age four. We examined associations between GRAPHS stove assignment and prenatal and infant CO measurements and oscillometry via generalized linear regression models. We used reverse distributed lag models (rDLMs) to examine time-varying associations between prenatal CO and oscillometry. MEASUREMENTS AND MAIN RESULTS: The primary oscillometry measure was reactance at 5 Hertz, X5, a measure of elastic and inertial lung properties. Secondary measures included total, large and small airway resistance (R5, R20, R5-20), area of reactance (AX) and resonant frequency (Fres). Of the 683 children who attended the lung function visit, 567 (83%) performed acceptable oscillometry. Two hundred and twenty-one, 106, and 240 children were from the LPG, improved biomass and control arms, respectively. Compared to control, the improved biomass stove was associated with lower reactance at 5 Hertz (X5 z-score, beta=-0.25, 95% CI -0.39, -0.11), higher large airway resistance (R20 z-score, beta=0.34, 95% CI 0.23, 0.44) and higher area of reactance (AX z-score, beta=0.16, 95% CI 0.06, 0.26) suggestive of overall worse lung function. The LPG stove was associated with higher X5 (beta=0.16, 95% CI 0.01, 0.31) and lower small airway resistance (R5-20 z-score, beta=-0.15, 95% CI -0.30, 0.0) suggestive of better small airway function. Higher average prenatal CO exposure was associated with higher R5 and R20 and DLMs identified sensitive windows of exposure between CO and X5, R5, R20 and R5-20. CONCLUSIONS: These data support the importance of prenatal HAP exposure on child lung function. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT01335490.

Prenatal Lead Exposure Is Associated with Reduced Abundance of Beneficial Gut Microbial Cliques in Late Childhood: An Investigation Using Microbial Co-Occurrence Analysis (MiCA).

Many analytical methods used in gut microbiome research focus on either single bacterial taxa or the whole microbiome, ignoring multibacteria relationships (microbial cliques). We present a novel analytical approach to identify microbial cliques within the gut microbiome of children at 9-11 years associated with prenatal lead (Pb) exposure. Data came from a subset of participants (n = 123) in the Programming Research in Obesity, Growth, Environment and Social Stressors cohort. Pb concentrations were measured in maternal whole blood from the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the gut microbiome. Using a novel analytical approach, Microbial Co-occurrence Analysis (MiCA), we paired a machine learning algorithm with randomization-based inference to first identify microbial cliques that were predictive of prenatal Pb exposure and then estimate the association between prenatal Pb exposure and microbial clique abundance. With second-trimester Pb exposure, we identified a two-taxa microbial clique that included Bifidobacterium adolescentis and Ruminococcus callidus and a three-taxa clique that also included Prevotella clara. Increasing second-trimester Pb exposure was associated with significantly increased odds of having the two-taxa microbial clique below the median relative abundance (odds ratio (OR) = 1.03, 95% confidence interval (CI) [1.01-1.05]). Using a novel combination of machine learning and causal inference, MiCA identified a significant association between second-trimester Pb exposure and the reduced abundance of a probiotic microbial clique within the gut microbiome in late childhood.

Prenatal exposures to mixtures of endocrine disrupting chemicals and sex-specific associations with children's BMI and overweight at 5.5 years of age in the SELMA study.

BACKGROUND: Prenatal exposure to mixtures of endocrine disrupting chemicals (EDC) has the potential to disrupt human metabolism. Prenatal periods are especially sensitive as many developmental processes are regulated by hormones. Prenatal exposure to EDCs has inconsistently been associated with children's body mass index (BMI) and obesity. The objective of this study was to investigate if prenatal exposure to a mixture of EDCs was associated with children's BMI and overweight (ISO-BMI ≥ 25) at 5.5 years of age, and if there were sex-specific effects. METHODS: A total of 1,105 mother-child pairs with complete data on prenatal EDCs concentrations (e.g., phthalates, non-phthalate plasticizers, phenols, PAH, pesticides, PFAS, organochlorine pesticides, and PCBs), children's measured height and weight, and selected covariates in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study were included in this analysis. The mixture effect of EDCs with children's BMI and overweight was assessed using WQS regression with 100 repeated holdouts. A positively associated WQS index with higher BMI and odds of overweight was derived. Models with interaction term and stratified weights by sex was applied in order to evaluate sex-specific associations. RESULTS: A significant WQS*sex interaction term was identified and associations for boys and girls were in opposite directions. Higher prenatal exposure to a mixture of EDCs was associated with lower BMI (Mean ß = -0.19, 95%CI: -0.40, 0.01) and lower odds of overweight (Mean OR = 0.72, 95%CI: 0.48, 1.04) among girls with borderline significance. However, the association among boys did not reach statistical significance. Among girls, the possible chemicals of concern were MEP, 2-OHPH, BPF, BPS, DPP and PFNA. CONCLUSION: Prenatal exposure to a mixture of EDCs was associated with lower BMI and overweight among girls, and non-significant associations among boys. Chemicals of concern for girls included phthalates, non-phthalate plasticizers, bisphenols, PAHs, and PFAS.

PFAS Exposures and the Human Metabolome: A Systematic Review of Epidemiological Studies.

Purpose of Review: There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines. Recent Findings: We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional (n = 25), including four with prospective analyses of PFAS measured prior to metabolomics. Summary: Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.

Machine Learning Assisted Discovery of Interactions between Pesticides, Phthalates, Phenols, and Trace Elements in Child Neurodevelopment.

A growing body of literature suggests that developmental exposure to individual or mixtures of environmental chemicals (ECs) is associated with autism spectrum disorder (ASD). However, investigating the effect of interactions among these ECs can be challenging. We introduced a combination of the classical exposure-mixture Weighted Quantile Sum (WQS) regression and a machine-learning method termed Signed iterative Random Forest (SiRF) to discover synergistic interactions between ECs that are (1) associated with higher odds of ASD diagnosis, (2) mimic toxicological interactions, and (3) are present only in a subset of the sample whose chemical concentrations are higher than certain thresholds. In a case-control Childhood Autism Risks from Genetics and Environment (CHARGE) study, we evaluated multiordered synergistic interactions among 62 ECs measured in the urine samples of 479 children in association with increased odds for ASD diagnosis (yes vs no). WQS-SiRF identified two synergistic two-ordered interactions between (1) trace-element cadmium (Cd) and the organophosphate pesticide metabolite diethyl-phosphate (DEP); and (2) 2,4,6-trichlorophenol (TCP-246) and DEP. Both interactions were suggestively associated with increased odds of ASD diagnosis in the subset of children with urinary concentrations of Cd, DEP, and TCP-246 above the 75th percentile. This study demonstrates a novel method that combines the inferential power of WQS and the predictive accuracy of machine-learning algorithms to discover potentially biologically relevant chemical-chemical interactions associated with ASD.

A weighted quantile sum regression with penalized weights and two indices.

Background: New statistical methodologies were developed in the last decade to face the challenges of estimating the effects of exposure to multiple chemicals. Weighted Quantile Sum (WQS) regression is a recent statistical method that allows estimating a mixture effect associated with a specific health effect and identifying the components that characterize the mixture effect. Objectives: In this study, we propose an extension of WQS regression that estimates two mixture effects of chemicals on a health outcome in the same model through the inclusion of two indices, one in the positive direction and one in the negative direction, with the introduction of a penalization term. Methods: To evaluate the performance of this new model we performed both a simulation study and a real case study where we assessed the effects of nutrients on obesity among adults using the National Health and Nutrition Examination Survey (NHANES) data. Results: The method showed good performance in estimating both the regression parameter and the weights associated with the single elements when the penalized term was set equal to the magnitude of the Akaike information criterion of the unpenalized WQS regression. The two indices further helped to give a better estimate of the parameters [Positive direction Median Error (PME): 0.022; Negative direction Median Error (NME): -0.044] compared to the standard WQS without the penalization term (PME: -0.227; NME: 0.215). In the case study, WQS with two indices was able to find a significant effect of nutrients on obesity in both directions identifying sodium and magnesium as the main actors in the positive and negative association, respectively. Discussion: Through this work, we introduced an extension of WQS regression that improved the accuracy of the parameter estimates when considering a mixture of elements that can have both a protective and a harmful effect on the outcome; and the advantage of adding a penalization term when estimating the weights.

Identifying sensitive windows of prenatal household air pollution on birth weight and infant pneumonia risk to inform future interventions.

BACKGROUND: Prenatal household air pollution impairs birth weight and increases pneumonia risk however time-varying associations have not been elucidated and may have implications for the timing of public health interventions. METHODS: The Ghana Randomized Air Pollution and Health Study (GRAPHS) enrolled 1,414 pregnant women from Kintampo, Ghana and measured personal carbon monoxide (CO) exposure four times over pregnancy. Birth weight was measured within 72-hours of birth. Fieldworkers performed weekly pneumonia surveillance and referred sick children to study physicians. The primary pneumonia outcome was one or more physician-diagnosed severe pneumonia episode in the first year of life. We employed reverse distributed lag models to examine time-varying associations between prenatal CO exposure and birth weight and infant pneumonia risk. RESULTS: Analyses included n = 1,196 mother-infant pairs. In models adjusting for child sex; maternal age, body mass index (BMI), ethnicity and parity at enrollment; household wealth index; number of antenatal visits; and evidence of placental malaria, prenatal CO exposures from 15 to 20 weeks gestation were inversely associated with birth weight. Sex-stratified models identified a similar sensitive window in males and a window at 10-weeks gestation in females. In models adjusting for child sex, maternal age, BMI and ethnicity, household wealth index, gestational age at delivery and average postnatal child CO exposure, CO exposure during 34-39 weeks gestation were positively associated with severe pneumonia risk, especially in females. CONCLUSIONS: Household air pollution exposures in mid- and late- gestation are associated with lower birth weight and higher pneumonia risk, respectively. These findings support the urgent need for deployment of clean fuel stove interventions beginning in early pregnancy.

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

Background: 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. Objectives: This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Methods: 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. Results: 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 (2Tß = -0.17, 95%CI = [-0.46,0.11]; 3Tß = -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. Discussion: Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

Phthalate exposure in the neonatal intensive care unit is associated with development of bronchopulmonary dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious yet common morbidity of preterm birth. Although prior work suggests a possible role for phthalate exposure in the development of BPD, no study has rigorously evaluated this. Our objective was to determine whether hospital-based phthalate exposure is associated with the development of BPD and to identify developmental windows sensitive to exposure. STUDY DESIGN: This is a prospective multicenter cohort study of 360 preterm infants born at 23-33 weeks gestation participating in the Developmental Impact of NICU Exposures (DINE) cohort. 939 urine specimens collected during the NICU stay were analyzed for biomarkers of phthalate exposure by liquid chromatography with tandem mass spectrometry. The modified Shennan definition was used to diagnose bronchopulmonary dysplasia. Reverse distributed-lag modeling identified developmental windows sensitive to specific phthalate exposure, controlling for relevant covariates including sex and respiratory support. RESULTS: Thirty-five percent of participants were diagnosed with BPD. Exposure to specific phthalate mixtures at susceptible points in preterm infant development are associated with later diagnosis of BPD in models adjusted for use of respiratory support. The weighted influence of specific phthalate metabolites in the mixtures varied by sex. Metabolites of di(2-ethylhexyl) phthalate, a phthalate previously linked to neonatal respiratory support equipment, drove this association, particularly among female infants, at 26- to 30-weeks post-menstrual age. CONCLUSIONS: This is the largest and only multi-site study of NICU-based phthalate exposure and clinical impact yet reported. In well-constructed models accounting for infant sex and respiratory support, we found a significant positive association between ultimate diagnosis of BPD and prior exposure to phthalate mixtures with DEHP predominance at 26- to 30-weeks PMA or 34-36-weeks PMA. This information is critically important as it identifies a previously unrecognized and modifiable contributing factor to BPD.

Prenatal exposure to phthalates and gender-specific play behavior at seven years of age in the SELMA study.

BACKGROUND: A growing body of evidence shows that prenatal exposure to phthalates affects child development. Since many phthalates have been shown to alter endocrine signaling, they may influence reproductive development, neurodevelopment, and child behavior. Indeed, a few studies reported associations between prenatal phthalate exposure and gender-specific play behavior. However, evidence for this relationship is limited, and previous findings are based on single phthalates, while human exposure entails mixtures of chemicals. OBJECTIVE: We aimed to investigate the associations between prenatal exposure to single phthalates, as well as a phthalate mixture, and gender-specific play behavior. METHODS: A total of 715 mother-child pairs from the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study were included. In the median week 10 of pregnancy, phthalate metabolites were measured in urine. Gender-specific play behavior was measured with Preschool Activities Inventory at the age of seven years. Linear and weighted quantile sum regressions were used; data was stratified by sex. Models were adjusted for child and maternal age, maternal education, parental attitudes toward play behavior, and urinary creatinine concentration. RESULTS: For boys, single compound analyses revealed negative associations of prenatal exposure to di-isononyl phthalate (DINP) concentrations with masculine (ß = -1.44; 95% CI = -2.72, -0.16) and composite (ß = -1.43; 95% CI = -2.72, -0.13) scores. Suggestive associations were also observed with a mixture approach identifying DINP as the main contributor of the association of decreased masculine play. Among girls, higher urinary concentrations of 2,4-methyl-7-oxyooctyl-oxycarbonyl-cyclohexane carboxylic acid (MOiNCH) was associated with decreased feminine (ß = -1.59; 95% CI = -2.62, -0.57) and masculine scores (ß = -1.22; 95% CI = -2.14, -0.29), whereas the mixture analyses did not yield conclusive results for girls. CONCLUSION: Our findings suggest associations of prenatal exposure to DINP with decreased masculine play behavior in boys while the results for girls were not fully conclusive.

Maternal nutrition during mid-pregnancy and children's body composition at 7 years of age in the SELMA study.

Optimal nutrition during pregnancy is vital for both maternal and child health. Our objective was to explore if prenatal diet is associated with children's height and body fat. Nutrient intake was assessed through a FFQ from 808 pregnant women and summarised to a nutrition index, 'My Nutrition Index' (MNI). The association with children's height and body fat (bioimpedance) was assessed with linear regression models. Secondary analysis was performed with BMI, trunk fat and skinfolds. Overall, higher MNI score was associated with greater height (ß = 0·47; (95 % CI 0·00, 0·94), among both sexes. Among boys, higher MNI was associated with 0·15 higher BMI z-scores, 0·12 body fat z-scores, 0·11 trunk fat z-scores, and larger triceps, and triceps + subscapular skinfolds (ß = 0·05 and ß = 0·06; on the log2 scale) (P-value < 0·05). Among girls, the opposite associations were found with 0·12 lower trunk fat z-scores, and smaller subscapular and suprailiac skinfolds (ß = -0·07 and ß = -0·10; on the log2 scale) (P-value < 0·05). For skinfold measures, this would represent a ± 1·0 millimetres difference. Unexpectedly, a prenatal diet in line with recommended nutrient intake was associated with higher measures of body fat for boys and opposite to girls at a pre-pubertal stage of development.

Prenatal Lead Exposure is Negatively Associated with the Gut Microbiome in Childhood.

Background: 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. Objectives: This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old. Methods: 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. Results: 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 (2Tß=-0.17,95%CI=[-0.46,0.11]; 3Tß=-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. Discussion: Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

Interrogating Components of 2 Diet Quality Indices in Pregnancy using a Supervised Statistical Mixtures Approach.

BACKGROUND: The Healthy Eating Index (HEI)-2015 and Alternative Healthy Eating Index (AHEI)-2010 evaluate diet holistically in pregnancy. However, it remains unclear how individual index components interact to contribute to health. OBJECTIVES: To evaluate associations of HEI-2015 and AHEI-2010 components with gestational length using traditional and novel statistical methods in a prospective cohort. METHODS: Pregnant women completed a 3-mo food-frequency questionnaire (FFQ) at median 13 wk gestation to calculate the HEI-2015 or AHEI-2010. Covariate-adjusted linear regression models evaluated associations of HEI-2015 and AHEI-2010 total scores and individual components (one at a time and simultaneously adjusted) with gestational length. Covariate-adjusted weighted quantile sum regression models evaluated 1) associations of HEI-2015 or AHEI-2010 components as mixtures with gestational length and 2) contributions of components to these associations. RESULTS: Each 10-point increase in HEI-2015 and AHEI-2010 total score was associated with 0.11 (95% CI: -0.05, 0.27) and 0.14 (95% CI: 0.00, 0.28) wk longer gestation, respectively. In individual or simultaneously adjusted HEI-2015 models, higher intakes of seafood/plant proteins, total protein foods, greens/beans, and saturated fats but lower intakes of added sugars and refined grains were associated with longer gestational length. For the AHEI-2010, higher intake of nuts/legumes and lower intake of sugar-sweetened beverages (SSBs)/fruit juice were associated with longer gestational length. Jointly, 10% increases in HEI-2015 or AHEI-2010 mixtures were associated with 0.17 (95% CI: 0.001, 0.34) and 0.18 (95% CI: 0.05, 0.30) wk longer gestational length, respectively. Seafood/plant protein, total protein foods, dairy, greens/beans, and added sugars were the largest contributors to the HEI-2015 mixture. Nuts/legumes, SSBs/fruit juice, sodium, and DHA/EPA were the largest contributors to the AHEI-2010 mixture. Associations were less precise but consistent in women with spontaneous labors. CONCLUSIONS: Compared to traditional methods, associations of diet index mixtures with gestational length were more robust and identified unique contributors. Additional studies could consider interrogating these statistical approaches using other dietary indices and health outcomes.