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Background and Objective: Very preterm infants are susceptible to neurodevelopmental impairments, necessitating early detection of prognostic biomarkers for timely intervention. The study aims to explore possible functional biomarkers for very preterm infants at born that relate to their future cognitive and motor development using resting-state fMRI. Prior studies are limited by the sample size and suffer from efficient functional connectome (FC) construction algorithms that can handle the noisy data contained in neonatal time series, leading to equivocal findings. Therefore, we first propose an enhanced functional connectome construction algorithm as a prerequisite step. We then apply the new FC construction algorithm to our large prospective very preterm cohort to explore multi-level neurodevelopmental biomarkers., Methods: There exists an intrinsic relationship between the structural connectome (SC) and FC, with a notable coupling between the two. This observation implies a putative property of graph signal smoothness on the SC as well. Yet, this property has not been fully exploited for constructing intrinsic dFC. In this study, we proposed an advanced dynamic FC (dFC) learning model, dFC-Igloo, which leveraged SC information to iteratively refine dFC estimations by applying graph signal smoothness to both FC and SC. The model was evaluated on artificial small-world graphs and simulated graph signals., Results: The proposed model achieved the best and most robust recovery of the ground truth graph across different noise levels and simulated SC pairs from the simulation. The model was further applied to a cohort of very preterm infants from five Neonatal Intensive Care Units, where an enhanced dFC was obtained for each infant. Based on the improved dFC, we identified neurodevelopmental biomarkers for neonates across connectome-wide, regional, and subnetwork scales., Conclusion: The identified markers correlate with cognitive and motor developmental outcomes, offering insights into early brain development and potential neurodevelopmental challenges., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Evidence from toxicological studies indicate organophosphate esters (OPEs) are neurotoxic, but few epidemiological studies investigated associations between gestational OPEs and executive function., Objective: To examine the associations between gestational concentrations of OPE urinary metabolites and executive function at 12 years., Methods: We used data from 223 mother-adolescent dyads from the Health Outcomes of Measures of the Environment (HOME) Study. Women provided spot urine samples at 16 weeks gestation, 26 weeks gestation, and at delivery for quantification of bis(1,3-dichloro-2-propyl) phosphate, bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP). Executive function was assessed at age 12 years using the parent- and self-report Behavior Rating Inventory of Executive Function (BRIEF2). Covariate-adjusted associations between specific gravity-corrected OPEs and BRIEF2 scores were estimated using multiple informant models. Bayesian Kernel Machine Regression (BKMR) was used to assess the impact of all OPEs simultaneously., Results: Parent- and self-report BRIEF2 indices and composite scores were weakly to moderately correlated (r s  = 0.32-0.41). A natural-log unit increase in BCEP at 26 weeks was associated with approximately a 1-point increase on the self-report Cognitive Regulation Index [CRI] (95% CI 0.4, 2.3), the Emotion Regulation Index [ERI] (95% CI 0.3, 2.2), and the Global Executive Composite [GEC] (95% CI 0.4, 2.2), indicating poorer performance. Higher DPHP at 16 weeks was associated with lower parent-report GEC score (β = -1.1, 95% CI -2.3, -0.003). BKMR identified BCEP and DNBP at 26 weeks as important contributors to CRI and ERI, respectively., Conclusion: OPE metabolites during gestational development, particularly BCEP, may influence adolescent executive function. However, since the FDR p-values failed to reach statistical significance, additional studies would benefit from using larger cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ann M Vuong reports financial support was provided by National Institute of Environmental Health Sciences. Bruce Lanphear reports financial support was provided by National Institute of Environmental Health Sciences. Aimin Chen reports financial support was provided by National Institute of Environmental Health Sciences. Kimberly Yolton reports financial support was provided by National Institute of Environmental Health Sciences. Joseph Bruan reports financial support was provided by National Institute of Environmental Health Sciences. Kim Cecil reports financial support was provided by National Institute of Environmental Health Sciences. Aimin Chen reports financial support was provided by Environmental Protection Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous chemicals routinely detected in personal care products (PCPs). However, few studies have evaluated the impact of PCP use on PFAS concentrations in pregnant and lactating populations., Objective: We investigated associations between PCP use and PFAS concentrations in prenatal plasma and human milk., Methods: We leveraged the Maternal-Infant Research on Environmental Chemicals (MIREC) Study to evaluate the contribution of PCP use on PFAS concentrations in prenatal plasma (6 to 13 weeks' gestation; n = 1,940) and human-milk (2 to 10 weeks' postpartum; n = 664). Participants reported frequency of use across 8 PCP categories during the 1st and 3rd trimesters, 1 to 2 days postpartum, and 2 to 10 weeks' postpartum. We used adjusted linear regression models to quantify percent differences and corresponding 95 % confidence intervals., Results: In 1st trimester pregnant people, we found higher use of nailcare products (≥once a week vs. never: perfluorooctanoic acid (PFOA): 21 % [9.7 %, 32 %]; perfluorooctane-sulfonic acid (PFOS): 11 % [0.3 %, 23 %]), fragrances (daily vs. never: PFOA: 14 % [7.8 %, 21 %]; PFOS: 7.8 % [1.3 %, 15 %]), makeup (daily vs. never: PFOA: 14 % [5.8 %, 23 %]), hair dyes (never vs. 1-2 times during pregnancy: PFOA: 8.3 % [2.4 %, 15 %]), and hair sprays or gels (daily vs. never: PFOA: 12 % [5.0 %, 19 %], PFOS: 7.1 % [0.2 %, 15 %]) were associated with higher plasma PFAS concentrations. Similar results were observed for 3rd trimester PCP use and 2 to 10 weeks' postpartum human-milk PFAS concentrations. In addition, we also found that people using colored-permanent dye 1 to 2 days postpartum had higher Sm-PFOS (18 % [2.7 %, 35 %]), PFOA (16 % [4.3 %, 29 %]), and perfluorononanoic acid (17 % [3.6 %, 33 %]) postpartum human-milk concentrations., Conclusions: Our results show that PCP use may be a modifiable source of PFAS exposure in pregnant and lactating populations. These results along with growing scientific evidence can help inform PFAS regulation and guide individual choices to reduce PFAS exposure., Competing Interests: Declaration of competing interest Dr. Joseph Braun was compensated for serving as an expert witness on behalf of plaintiffs in litigation related to PFAS-contaminated drinking water. No other authors have any conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exposure to fluoride in early childhood has been associated with altered cognition, intelligence, attention, and neurobehavior. Fluoride-related neurodevelopment effects have been shown to vary by sex and very little is known about the mechanistic processes involved. There is limited research on how fluoride exposure impacts the epigenome, potentially leading to changes in DNA methylation of specific genes regulating key developmental processes. In the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), urine samples were analyzed using a microdiffusion method to determine childhood urinary fluoride adjusted for specific gravity (CUFsg) concentrations. Whole blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip 850 k Array. In a cross-sectional analysis, we interrogated epigenome-wide DNA methylation at 775,141 CpG loci across the methylome in relation to CUFsg concentrations in 272 early adolescents at age 12 years. Among all participants, higher concentrations of CUF were associated with differential methylation of one CpG (p < 6 × 10 -8 ) located in the gene body of GBF1 (cg25435255). Among females, higher concentrations of CUFsg were associated with differential methylation of 7 CpGs; only three CpGs were differentially methylated among males with no overlap of significant CpGs observed among females. Secondary analyses revealed several differentially methylated regions (DMRs) and CpG loci mapping to genes with key roles in psychiatric outcomes, social interaction, and cognition, as well as immunologic and metabolic phenotypes. While fluoride exposure may impact the epigenome during early adolescence, the functional consequences of these changes are unclear warranting further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The integration of different imaging modalities, such as structural, diffusion tensor, and functional magnetic resonance imaging, with deep learning models has yielded promising outcomes in discerning phenotypic characteristics and enhancing disease diagnosis. The development of such a technique hinges on the efficient fusion of heterogeneous multimodal features, which initially reside within distinct representation spaces. Naively fusing the multimodal features does not adequately capture the complementary information and could even produce redundancy. In this work, we present a novel joint self-supervised and supervised contrastive learning method to learn the robust latent feature representation from multimodal MRI data, allowing the projection of heterogeneous features into a shared common space, and thereby amalgamating both complementary and analogous information across various modalities and among similar subjects. We performed a comparative analysis between our proposed method and alternative deep multimodal learning approaches. Through extensive experiments on two independent datasets, the results demonstrated that our method is significantly superior to several other deep multimodal learning methods in predicting abnormal neurodevelopment. Our method has the capability to facilitate computer-aided diagnosis within clinical practice, harnessing the power of multimodal data. The source code of the proposed model is publicly accessible on GitHub: https://github.com/leonzyzy/Contrastive-Network., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: While changes in brain metabolites after injury have been reported, relationships between metabolite changes and head impacts are less characterized., Purpose: To investigate alterations in neurochemistry in high school athletes as a function of head impacts, concussion, and the use of a jugular vein compression (JVC) collar., Study Type: Prospective controlled trial., Subjects: A total of 284 male American football players, divided into JVC collar and noncollar groups; 215 included in final analysis (age = 15.9 ± 1.0 years; 114 in collar group)., Field Strength/sequence: 3 Tesla/T 1 -weighted gradient echo, 1 H point resolved spectroscopy, acquired between August and November 2018., Assessment: Head impacts were quantified using accelerometers. Concussion was diagnosed by medical professionals for each team. Pre- to postseason differences in total N-acetylaspartate (tNAA), total choline (tCho), myo-inositol (myoI), and glutamate + glutamine (Glx), in primary motor cortex (M1) and anterior cingulate cortex (ACC), relative to total creatine (tCr), were determined., Statistical Tests: Group-wise comparisons were performed using Wilcoxon signed-rank, Friedman's, and Mann-Whitney U tests. Relationships between ∆metabolite/tCr and mean g-force were analyzed using linear regressions accounting for concussion and JVC collar. Significance was set at P ≤ 0.05., Results: In participants without concussion, a significant decrease in tCho/tCr (0.233 ± 1.40 × 10 -3 to 0.227 ± 1.47 × 10 -7 ) and increase in Glx/tCr (1.60 ± 8.75 × 10 -3 to 1.63 ± 1.08 × 10 -2 ) in ACC were observed pre- to postseason. The relationship between ∆tCho/tCr in M1 and ACC and mean g-force from >80 g to >140 g differed significantly between participants with and without concussion (M1 β ranged from 3.9 × 10 -3 to 2.1 × 10 -3 ; ACC β ranged from 2.7 × 10 -3 to 2.1 × 10 -3 ). Posthoc analyses revealed increased tCho/tCr in M1 was positively associated with mean g-force >100 g (β = 3.6 × 10 -3 ) and >110 g (β = 2.9 × 10 -3 ) in participants with concussion. Significant associations between ∆ myoI / tCr $$ \Delta \mathrm{myoI}/\mathrm{tCr} $$ in ACC and mean g-force >110 g (β = -1.1 × 10 -3 ) and >120 g (β = -1.1 × 10 -3 ) were observed in the collar group only., Data Conclusion: Diagnosed concussion and the use of a JVC collar result in distinct neurochemical trends after repeated head impacts., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

X-linked creatine transporter deficiency is caused by hemizygous or heterozygous pathogenic variants in SLC6A8 that cause neuropsychiatric symptoms because of impaired uptake of creatine into tissues throughout the body. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males, but only six cases of supplementation in females have been published. Here, we present a female with a de-novo pathogenic SLC6A8 variant who had ongoing weight loss, mild intellectual disability, and neuropsychiatric symptoms. Magnetic resonance spectroscopy of the brain showed reduced creatine on all acquired spectra. The patient was started on creatine-monohydrate, l -arginine, and l -glycine supplementation, and she had significant symptomatic improvement within the following 3 weeks. After 8 months of supplementation, magnetic resonance spectroscopy showed improved creatine concentrations with normalizing semiquantitative ratios with other brain metabolites. Current data supports clinicians trialing creatine, arginine, and glycine supplements for female patients with creatine transporter deficiency., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substance (PFAS) exposures may negatively impact bone mineral accrual, but little is known about potential mitigators of this relation. We assessed whether associations of PFAS and their mixture with bone mineral content (BMC) in adolescence were modified by diet and physical activity., Methods: We included 197 adolescents enrolled in a prospective pregnancy and birth cohort in Cincinnati, Ohio (2003-2006). At age 12 years, we collected serum for PFAS measurements and used dual-energy x-ray absorptiometry to measure BMC. We calculated dietary calcium intake and Health Eating Index (HEI) scores from repeated 24-h dietary recalls, physical activity scores using the Physical Activity Questionnaire for Older Children (PAQ-C), and average moderate to vigorous physical activity (MVPA) based on accelerometry. We estimated covariate-adjusted differences in BMC z-scores per interquartile range (IQR) increase of individual PFAS concentrations using linear regression and per simultaneous IQR increase in all four PFAS using g-computation. We evaluated effect measure modification (EMM) using interaction terms between each modifier and PFAS., Results: Higher serum perfluorooctanoic acid, perfluorooctanesulfonic acid, and perfluorononanoic acid concentrations and the PFAS mixture were associated with lower BMC z-scores. An IQR increase in all PFAS was associated with a 0.27 (-0.54, 0.01) lower distal radius BMC z-score. Associations with lower BMC were generally stronger among adolescents classified as < median for calcium intake, HEI scores, or MVPA compared to those ≥ median. The difference in distal radius BMC z-score per IQR increase in all PFAS was -0.38 (-0.72, -0.04) for those with

Background: Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals used as flame retardants in commercial and consumer products. Gestational PBDE concentrations are associated with adverse behaviors in children; however, the persistence of these associations into adolescence remains understudied., Objective: We estimated the association of gestational PBDE serum concentrations with early adolescent self- and caregiver-reported behaviors at age 12 years and determined the consistency with previously observed associations in childhood with caregiver-reported behaviors in a prospective pregnancy and birth cohort., Methods: We measured maternal serum concentrations of five individual PBDE congeners and created a summary exposure variable (∑ 5 BDE: 28, -47, -99, -100 and -153) during pregnancy. At age 12 years, we assessed behaviors for 237 adolescents using self- and caregiver-reports with the Behavioral Assessment System for Children-3 (BASC3). We used multivariable linear regression models to estimate covariate-adjusted associations of lipid standardized, log 10 -transformed gestational PBDE concentrations with BASC3 scores. We obtained estimates and 95% confidence intervals through a bootstrapping approach. We evaluated potential effect measure modification (EMM) of adolescent sex by examining sex-stratified regression models and estimating the EMM p-values., Results: Gestational PBDE concentrations were positively associated with adolescent-reported BASC3 composite indices for inattention & hyperactivity (BDE-28, -47, -99, -100, ∑ 5 BDE), internalizing problems (BDE-28, -47, -99), functional impairment (BDE-28, ∑ 5 BDE), and emotional symptoms (BDE-28). Gestational PBDE concentrations were positively associated with caregiver-reported BASC3 composite indices for externalizing problems (BDE-28, -47, -99, -100, -153, ∑ 5 BDE) and behavioral symptoms (BDE-99). For caregiver reported behaviors, we observed stronger associations with gestational BDE concentrations among males, especially for executive functioning (BDE-28, -47, -99, -100, ∑ 5 BDE)., Discussion: Gestational PBDE serum concentrations were associated with self-reported internalizing and externalizing behavior problems in early adolescence. Caregiver-reported externalizing behaviors recognized during childhood remain associated with gestational PBDE concentrations and persist into early adolescence. Internalizing behaviors were less recognized by caregivers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph M Braun reports a relationship that included paid expert testimony related to PFAS-contaminated drinking water. All other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Few methods have been used to characterize repeatedly measured biomarkers of chemical mixtures. We applied latent profile analysis (LPA) to serum concentrations of 4 perfluoroalkyl and polyfluoroalkyl substances (PFAS) measured at 4 time points from gestation to age 12 years. We evaluated the relationships between profiles and z scores of height, body mass index, fat mass index, and lean body mass index at age 12 years (n = 218). We compared LPA findings with an alternative approach for cumulative PFAS mixtures using g-computation to estimate the effect of simultaneously increasing the area under the receiver operating characteristic curve (AUC) for all PFAS. We identified 2 profiles: a higher PFAS profile (35% of sample) and a lower PFAS profile (relative to each other), based on their average PFAS concentrations at all time points. The higher PFAS profile had generally lower z scores for all outcomes, with somewhat larger effects for males, though all 95% CIs crossed the null. For example, the higher PFAS profile was associated with a 0.50-unit lower (β = -0.50; 95% CI, -1.07 to 0.08) BMI z score among males but not among females (β = 0.04; 95% CI, -0.45 to 0.54). We observed similar patterns with AUCs. We found that a higher childhood PFAS profile and higher cumulative PFAS mixtures may be associated with altered growth in early adolescence. This article is part of a Special Collection on Environmental Epidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Manganese (Mn) plays a significant role in both human health and global industries. Epidemiological studies of exposed populations demonstrate a dose-dependent association between Mn and neuromotor effects ranging from subclinical effects to a clinically defined syndrome. However, little is known about the relationship between early life Mn biomarkers and adolescent postural balance., Objectives: This study investigated the associations between childhood and adolescent Mn biomarkers and adolescent postural balance in participants from the longitudinal Marietta Communities Actively Researching Exposures Study (CARES) cohort., Methods: Participants were recruited into CARES when they were 7-9 y old, and reenrolled at 13-18 years of age. At both time points, participants provided samples of blood, hair, and toenails that were analyzed for blood Mn and lead (Pb), serum cotinine, hair Mn, and toenail Mn. In adolescence, participants completed a postural balance assessment. Greater sway indicates postural instability (harmful effect), whereas lesser sway indicates postural stability (beneficial effect). Multivariable linear regression models were conducted to investigate the associations between childhood and adolescent Mn biomarkers and adolescent postural balance adjusted for age, sex, height-weight ratio, parent/caregiver intelligence quotient, socioeconomic status, blood Pb, and serum cotinine., Results: CARES participants who completed the adolescent postural balance assessment ( n = 123 ) were 98% White and 54% female and had a mean age of 16 y (range: 13-18 y). In both childhood and adolescence, higher Mn biomarker concentrations were significantly associated with greater adolescent sway measures. Supplemental analyses revealed sex-specific associations; higher childhood Mn biomarker concentrations were significantly associated with greater sway in females compared with males., Discussion: This study found childhood and adolescent Mn biomarkers were associated with subclinical neuromotor effects in adolescence. This study demonstrates postural balance as a sensitive measure to assess the association between Mn biomarkers and neuromotor function. https://doi.org/10.1289/EHP13381.

Very preterm (VPT) infants (born at less than 32 weeks gestational age) are at high risk for various adverse neurodevelopmental deficits. Unfortunately, most of these deficits cannot be accurately diagnosed until the age of 2-5 years old. Given the benefits of early interventions, accurate diagnosis and prediction soon after birth are urgently needed for VPT infants. Previous studies have applied deep learning models to learn the brain structural connectome (SC) to predict neurodevelopmental deficits in the preterm population. However, none of these models are specifically designed for graph-structured data, and thus may potentially miss certain topological information conveyed in the brain SC. In this study, we aim to develop deep learning models to learn the SC acquired at term-equivalent age for early prediction of neurodevelopmental deficits at 2 years corrected age in VPT infants. We directly treated the brain SC as a graph, and applied graph convolutional network (GCN) models to capture complex topological information of the SC. In addition, we applied the supervised contrastive learning (SCL) technique to mitigate the effects of the data scarcity problem, and enable robust training of GCN models. We hypothesize that SCL will enhance GCN models for early prediction of neurodevelopmental deficits in VPT infants using the SC. We used a regional prospective cohort of ∼280 VPT infants who underwent MRI examinations at term-equivalent age from the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS). These VPT infants completed neurodevelopmental assessment at 2 years corrected age to evaluate cognition, language, and motor skills. Using the SCL technique, the GCN model achieved mean areas under the receiver operating characteristic curve (AUCs) in the range of 0.72∼0.75 for predicting three neurodevelopmental deficits, outperforming several competing models. Our results support our hypothesis that the SCL technique is able to enhance the GCN model in our prediction tasks., Competing Interests: Declaration of competing interest None of the authors has any conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Executive functioning (EF) abilities develop through childhood, but this development can be impacted by various psychosocial environmental influences. Using longitudinal data from the Health Outcome and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort study, we examined if psychosocial environmental factors were significant predictors of EF development. Study participants comprised 271 children and their primary caregivers (98.5% mothers) followed from birth to age 12. We identified four distinct EF developmental trajectory groups comprising a consistently impaired group (13.3%), a descending impairment group (27.7%), an ascending impairment group (9.95%), and a consistently not impaired group (49.1%). Higher levels of maternal ADHD and relational frustration appear to be risk factors for increased EF difficulty over time, while higher family income may serve as a protective factor delaying predisposed EF impairment. Important intervention targets might include teaching positive and effective parenting strategies to mothers whose children are at risk for EF dysfunction.

Background: Prenatal or early childhood secondhand tobacco smoke (SHS) exposure increases obesity risk. However, the potential mechanisms underlying this association are unclear, but obesogenic eating behaviors are one pathway that components of SHS could perturb. Our aim was to assess associations of prenatal and early childhood SHS exposure with adolescent eating behaviors., Methods: Data came from a prospective pregnancy and birth cohort (N = 207, Cincinnati, OH). With multiple informant models, we estimated associations of prenatal (mean of 16 and 26 weeks of gestation maternal serum cotinine concentrations) and early childhood cotinine (average concentration across ages 12, 24, 36, and 48 months) with eating behaviors at age 12 years (Child Eating Behaviors Questionnaire). We tested whether associations differed by exposure periods and adolescent's sex. Models adjusted for maternal and child covariates., Results: We found no statistically significant associations between cotinine measures and adolescent's eating behaviors. Yet, in females, prenatal cotinine was associated with greater food responsiveness (β: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (β: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: β: -0.25; 95% CI: -0.04, -0.06; postnatal: β: -0.36; 95% CI: -0.06, -0.11). No significant effect modification by sex or exposure window was found for other eating behaviors., Conclusion: Prenatal and early childhood SHS exposures were not related to adolescent's eating behavior in this cohort; however, biological sex may modify these associations., (© 2024. The Author(s).)

Background: Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage., Methods: We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003-2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]-dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males-testosterone; females-estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche., Results: For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (-29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: -18%, -2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1-3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months., Conclusion: Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Study Objectives: This study examines the impact of sleep duration, bedtime, and sleep disturbance during early childhood on the risk of cardiometabolic disorder (CMD) in early adolescence., Methods: Within the Health Outcomes and Measures of Environment Study, we examined sleep patterns of 330 children from ages 2 to 8 years and the relationship of these sleep patterns with cardiometabolic risk measures at age 12 (N = 220). We used a group-based semi-parametric mixture model to identify distinct trajectories in sleep duration, bedtime timing, and sleep disturbance for the entire sample. We then examined the associations between sleep trajectories and CMD risk measures using general linear models using both an unadjusted model (no covariates) and an adjusted model (adjusting for child pubertal stage, child sex, duration of breastfeeding, household income, maternal education, and maternal serum cotinine)., Results: In the unadjusted and adjusted models, we found significant differences in CMD risk scores by trajectories of sleep disturbance. Children in the "high" disturbance trajectory had higher CMD risk scores than those in the 'low' disturbance trajectory (p's = 0.002 and 0.039, respectively). No significant differences in CMD risk were observed for bedtime timing or total sleep time trajectories in the unadjusted or adjusted models., Conclusions: In this cohort, caregiver-reported sleep disturbance in early childhood was associated with more adverse cardiometabolic profiles in early adolescence. Our findings suggest that trials to reduce CMD risk via sleep interventions-which have been conducted in adolescents and adults-may be implemented too late., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Organophosphate esters (OPEs) have replaced flame retardant polybrominated diphenyl ethers as flame retardants in consumer products, but few longitudinal studies have characterized childhood OPE exposure., Objective: We aimed to examine the exposure pattern of urinary OPE metabolites in children., Methods: We quantified three urinary OPE metabolites five times in children (1, 2, 3, 5, 8 years) from 312 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA. We examined the associations of average maternal OPE metabolite concentrations with OPE metabolite concentrations in childhood, characterized childhood OPE trajectories with latent class growth analysis (LCGA), and examined factors related to trajectory membership., Results: Bis(2-chloroethyl) phosphate (BCEP) had the lowest median concentrations over time (0.66-0.97 mg/L) while the median concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) increased with age (1.44-3.80 mg/L). The median concentrations of diphenyl phosphate (DPHP) fluctuated between 1.96 and 2.69 mg/L. Intraclass correlation coefficients for urinary metabolites measured at five time points indicated high variability within individuals (0.13-0.24). Average maternal urinary BCEP and BDCIPP were associated with concentrations in early childhood. Maternal education, the birth year of the child, and having a carpet in the main activity room were associated with BCEP and BDCIPP trajectory while none of the factors were associated with DPHP trajectory., Significance: The trajectory analysis showed different patterns of urinary OPE metabolite concentrations, suggesting the need to collect multiple samples to adequately reflect OPE exposure., Impact Statement: In this well-established cohort, we evaluated the patterns of urinary OPE metabolites in children ages 1-8 years. The number of repeated measures over childhood has not been achieved in prior studies. Our results suggested the high variability of urinary OPE metabolites within individuals. Maternal metabolite concentrations during pregnancy were related to child concentrations at ages 1-3 years. BCEP, BDCIPP, and DPHP demonstrated different trajectories in children, which suggests that multiple samples may be required to capture OPE exposure patterns in childhood., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Exposure to per- and polyfluoroalkyl substances (PFAS) throughout gestation and childhood may impact cardiometabolic risk., Methods: In 179 HOME Study participants (Cincinnati, OH; recruited 2003-2006), we used latent profile analysis to identify two distinct patterns of PFAS exposure from serum concentrations of four PFAS measured at birth and ages 3, 8, and 12 years. We assessed the homeostatic model of insulin resistance, triglycerides-to-high-density lipoprotein cholesterol ratio, leptin-to-adiponectin ratio, systolic blood pressure, visceral fat, and hemoglobin A1c levels at age 12 years. We used multivariable linear regression to assess the association of membership in the longitudinal PFAS mixture exposure group with a summary measure of overall cardiometabolic risk and individual components., Results: One PFAS exposure profile (n = 66, 39%) had higher geometric means of all PFAS across all visits than the other. Although adjusted associations were null in the full sample, child sex modified the association of longitudinal PFAS mixture exposure group with overall cardiometabolic risk, leptin-to-adiponectin ratio, systolic blood pressure, and visceral fat (interaction term P values: 0.02-0.08). Females in the higher exposure group had higher cardiometabolic risk scores (ß = 0.43; 95% CI = -0.08, 0.94), systolic blood pressures (ß = 0.6; 95% CI = 0.1, 1.1), and visceral fat (ß = 0.44; 95% CI = -0.13, 1.01); males had lower cardiometabolic risk scores (ß = -0.52; 95% CI = -1.06, -0.06), leptin-to-adiponectin ratios (ß = -0.7; 95% CI = -1.29, -0.1), systolic blood pressures (ß = -0.14; 95% CI = -0.7, 0.41), and visceral fat (ß = -0.52; 95% CI = -0.84, -0.19)., Conclusions: Exposure to this PFAS mixture throughout childhood may have sex-specific effects on adolescent cardiometabolic risk., Competing Interests: J.B. and C.E. were financially compensated for their services as expert witnesses for plaintiffs in litigation related to PFAS-contaminated drinking water. Other authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent chemicals associated with multiple adverse health outcomes; however, the biological pathways affected by these chemicals are unknown. To address this knowledge gap, we used data from 264 mother-infant dyads in the Health Outcomes and Measures of the Environment (HOME) Study and employed quantile-based g-computation to estimate covariate-adjusted associations between a prenatal (∼16 weeks' gestation) serum PFAS mixture [perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] and 14,402 features measured in cord serum. The PFAS mixture was associated with four features: PFOS, PFHxS, a putatively identified metabolite (3-monoiodo-l-thyronine 4- O -sulfate), and an unidentified feature (590.0020 m / z and 441.4 s retention time; false discovery rate <0.20). Using pathway enrichment analysis coupled with quantile-based g-computation, the PFAS mixture was associated with 49 metabolic pathways, most notably amino acid, carbohydrate, lipid and cofactor and vitamin metabolism, as well as glycan biosynthesis and metabolism (P(Gamma) <0.05). Future studies should assess if these pathways mediate associations of prenatal PFAS exposure with infant or child health outcomes, such as birthweight or vaccine response.

Background: Prenatal and childhood exposure to per- and polyfluoroalkyl substances (PFAS) may be associated with lower reproductive hormones and later puberty, but epidemiological studies evaluating these associations are scarce., Objectives: We examined associations of PFAS concentrations assessed from pregnancy to adolescence with pubertal development and reproductive hormones at age 12 years., Methods: We studied 200 mother-child pairs from the HOME Study in Cincinnati, OH (enrolled: 2003-2006). We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in pregnant women and their children at age 3, 8 and 12 years. At age 12 years, children self-assessed pubertal development using Tanner staging of pubic hair growth (males and females) and breast growth (females), and age at menarche. We quantified serum concentrations of dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone in both sexes; estradiol in females; testosterone in males. We estimated associations of PFAS with pubertal outcomes and reproductive hormones using a combination of ordinal regression, Cox proportional-hazard regression, and linear regression. Quantile-based g-computation was used for PFAS mixture., Results: In females, adolescent PFAS concentrations and their mixture were associated with later pubic hair growth, breast maturation, and age at menarche, but there was no pattern for prenatal or other postnatal concentrations. For instance, in females, each doubling in adolescent PFAS concentrations was associated with 79 % (PFOA), 63 % (PFOS), 56 % (PFNA), and 47 % (PFHxS) lower odds of attaining a higher stage for breast growth. In addition, adolescent PFAS concentrations were consistently associated with lower estradiol concentrations in females. No pattern was observed for associations of PFAS concentrations with pubic hair growth or reproductive hormones in males., Conclusions: We observed associations between PFAS concentrations in adolescence and later pubertal development in females, but this could be due to reverse causation induced by excretion of PFAS through menstrual fluid., Competing Interests: Declaration of competing interest Joseph M. Braun's was financially compensated for his services as an expert witness for plaintiffs in litigation related to PFAS-contaminated drinking water. The other authors declare they have no actual or potential competing financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Diet is the primary exposure pathway for per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations. Few studies have examined associations of dietary quality and macronutrient intake with PFAS exposure among US adolescents., Objective: To assess relationships of self-reported dietary quality and macronutrient intake with serum PFAS concentrations in adolescents., Methods: We used cross-sectional data from 193 Cincinnati, Ohio area adolescents (median age 12.3 years) collected from 2016 to 2019. Using 24-h food recalls completed by adolescents on three separate days, we derived Healthy Eating Index (HEI) scores, HEI components, and macronutrient intake. We measured perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations in fasting serum samples. Using linear regression, we estimated covariate-adjusted associations between dietary variables and serum PFAS concentrations., Results: The median HEI score was 44 and median serum PFOA, PFOS, PFHxS, and PFNA concentrations were 1.3, 2.4, 0.7, and 0.3 ng/mL respectively. In adjusted models, higher total HEI scores, whole fruit and total fruit HEI component scores, and total dietary fiber intake were associated with lower concentrations of all four PFAS. For example, serum PFOA concentrations were 7% lower (95% CI: -15, 2) per standard deviation increase in total HEI score and 9% lower (95% CI: -18, 1) per standard deviation increase in dietary fiber., Significance: Given adverse health effects associated with PFAS exposure, it is crucial to understand modifiable exposure pathways. Findings from this study may inform future policy decisions aiming to limit human exposure to PFAS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Braun reports financial support was provided by National Institute of Environmental Health Sciences. Joseph Braun reports a relationship with Morgan and Morgan that includes: paid expert testimony., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The hypergraph structure has been utilized to characterize the brain functional connectome (FC) by capturing the high order relationships among multiple brain regions of interest (ROIs) compared with a simple graph. Accordingly, hypergraph neural network (HGNN) models have emerged and provided efficient tools for hypergraph embedding learning. However, most existing HGNN models can only be applied to pre-constructed hypergraphs with a static structure during model training, which might not be a sufficient representation of the complex brain networks. In this study, we propose a dynamic weighted hypergraph convolutional network (dwHGCN) framework to consider a dynamic hypergraph with learnable hyperedge weights. Specifically, we generate hyperedges based on sparse representation and calculate the hyper similarity as node features. The hypergraph and node features are fed into a neural network model, where the hyperedge weights are updated adaptively during training. The dwHGCN facilitates the learning of brain FC features by assigning larger weights to hyperedges with higher discriminative power. The weighting strategy also improves the interpretability of the model by identifying the highly active interactions among ROIs shared by a common hyperedge. We validate the performance of the proposed model on two classification tasks with three paradigms functional magnetic resonance imaging (fMRI) data from Philadelphia Neurodevelopmental Cohort. Experimental results demonstrate the superiority of our proposed method over existing hypergraph neural networks. We believe our model can be applied to other applications in neuroimaging for its strength in representation learning and interpretation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Autism Spectrum Disorder (ASD) affects about 1 in 44 children and environmental exposures may contribute to disease onset. Air pollution has been associated with adverse neurobehavioral outcomes, yet little research has examined its association with autistic-like behaviors. Therefore, our objective was to examine the association between exposure to air pollution, including NO 2 and PM 2.5 , during pregnancy and the first year of life to ASD-like behaviors during childhood. Participants (n = 435) enrolled in the Cincinnati Childhood Allergy and Air Pollution Study and the Health Outcomes and Measures of the Environment Study were included in the analysis. Daily exposures to NO 2 and PM 2.5 at the residential addresses of participants were estimated using validated spatiotemporal models and averaged to obtain prenatal and first year exposure estimates. ASD-like behaviors were assessed via the Social Responsiveness Scale (SRS) questionnaire at age 12. Linear regression models adjusting for confounders were applied to estimate the association between pollutants and SRS scores. After adjusting for covariates, the association between NO 2 and PM 2.5 and SRS scores remained positive but were no longer statistically significant. Prenatal and first year exposure to NO 2 were associated with total SRS T-scores with an estimated 0.4 point increase (95% CI: -0.7, 1.6) per 5.2 ppb increase in NO 2 exposure and 0.7 point (95% CI: -0.3, 1.6) per 4.2 ppb increase in NO 2 exposure, respectively. For PM 2.5 , a 2.6 μg/m 3 increase in prenatal exposure was associated with a 0.1 point increase (95% CI: -1.1, 1.4) in SRS Total T-scores and a 1.3 μg/m 3 increase first year of life was associated with a 1 point increase (95% CI: -0.2, 2.3). In summary, exposure to NO 2 and PM 2.5 during pregnancy and the first year of life were not significantly associated with higher autistic-like behaviors measured with SRS scores after adjustment of covariates. Additional research is warranted given prior studies suggesting air pollution contributes to ASD., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: To identify periods of heightened susceptibility to the association of secondhand tobacco smoke (SHS) exposure with cardiometabolic (CM) risk at age 12 years., Methods: We used data from 212 adolescents from the HOME Study, a prospective pregnancy and birth cohort in Cincinnati, OH. Using multiple informant models, we estimated associations of maternal serum cotinine (mean of concentrations at 16 and 26 weeks of pregnancy) and children's serum cotinine concentrations (mean of concentrations at ages 1, 2, 3, and 4 years) with a CM risk summary score constructed of five risk components measured at age 12 years. We determined if these associations differed for pre- and postnatal exposure periods, and adolescent's sex., Results: We found some evidence that the cotinine-outcome associations differed by exposure period and sex. Postnatal, but not prenatal, cotinine was associated with higher CM risk scores and individual CM risk component values (interaction p-values = 0.04 to 0.35). Each 10-fold increase in postnatal cotinine was associated with 0.57 (95% CI: 0.32, 1.45), 0.09 (95% CI: 0.13, 0.31), 0.14 (-0.08, 0.35), 0.07 (95% CI: 0.34, 0.48), and 0.11 (95% CI: 0.04, 0.27) higher CM risk, HOMA-IR, TG to HDL-C ratio, leptin to adiponectin ratio, and visceral fat area. Postnatal cotinine was associated with higher visceral fat area among females but not males (sex × period × cotinine interaction p-value = 0.01)., Conclusions: Serum cotinine concentrations during the postnatal period had greater influence on adolescent's CM risk compared to the prenatal period, and these associations may be sex-specific. This study reinforces the need for ongoing public health interventions to minimize children's exposure to SHS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Organophosphate esters (OPEs), widely used as flame retardants and plasticizers for commercial and residential purposes, are suspected of being neurotoxic. We aimed to assess exposure to an OPE mixture in early life and its relationship to parent-reported child behavior. We measured urinary concentrations of three OPE metabolites, bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP), at pregnancy (16 and 26 weeks of gestation and delivery) and postnatal time points (ages 1, 2, 3, and 5 years) in the Health Outcomes and Measures of the Environment Study, a longitudinal pregnancy and birth cohort in Cincinnati, Ohio, USA (enrolled 2003-2006, n = 219). We used latent variable analysis in structural equations models and quantile g-computation to investigate associations of a mixture of the three OPE metabolites with parent-reported child behaviors at 3 and 8 years, measured using the Behavioral Assessment System for Children, Second Edition. Higher log-transformed urinary OPE latent variable values at 16 weeks were associated with fewer externalizing problem behaviors (ß = -5.74; 95% CI = -11.24, -0.24) and fewer overall behavioral problems at age 3 years (ß = -5.26; 95% CI = -10.33, -0.19), whereas having higher OPEs at delivery was associated with poorer overall behavioral problems at age 3 years (ß = 2.87; 95% CI = 0.13, 5.61). OPE latent variable values at 16 weeks, 26 weeks, and delivery were not associated with child behavior at 8 years. However, higher OPE latent variable values at 3 years were associated with fewer externalizing behaviors at 8 years (ß = -2.62; 95% CI = -5.13, -0.12). The quantile g-computation estimates had directions largely consistent with the latent variable analysis results. Pregnancy and postnatal urinary OPE metabolite mixtures were associated with child internalizing, externalizing, and overall negative behaviors at 3 and 8 years, but we did not identify a consistent pattern in terms of the direction of the effects or a particularly sensitive time point., Competing Interests: Declaration of competing interest Dr. Braun was financially compensated for serving as an expert witness in litigation related to perfluorooctanonic acid contamination in drinking water., (Copyright © 2023. Published by Elsevier GmbH.)

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Early-life phthalate exposures may disrupt metabolic processes; however few prospective studies have assessed whether these associations extend to cardiometabolic outcomes during adolescence., Methods: Among 183 mother-adolescent pairs in a prospective cohort study that enrolled pregnant women in Cincinnati, OH (2003-2006), we quantified nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children. At age 12 years, we assessed triglycerides, high-density (HDL) and low-density (LDL) lipoprotein cholesterol, insulin, and glucose from fasting serum samples and calculated homeostatic model assessment of insulin resistance (HOMA-IR). Using multiple informant models, we estimated covariate-adjusted associations between urinary phthalate concentrations at each time period and cardiometabolic biomarkers at age 12 years, including modification by child sex., Results: Although most associations were weak or null, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and monobenzyl phthalate (MBzP) concentrations were generally associated with lower LDL at age 12 years. A 10-fold increase in 4- and 12-year MEP was associated with -15.3 mg/dL (95% CI: 27.5, -3.13 mg/dL) and -11.8 mg/dL (-22.0, -1.51 mg/dL) lower LDL, respectively. Discrepant associations were observed in females versus males: a 10-fold increase in 3-year MEP concentrations was associated with 12.0 mg/dL (95% CI: 7.11, 31.1 mg/dL) higher LDL levels in males and -30.4 mg/dL (95% CI: 50.9, -9.8 mg/dL) lower LDL levels in females. Some urinary phthalate concentrations were cross-sectionally associated with HOMA-IR., Conclusions: Early-life phthalate biomarker concentrations may be inversely associated with LDL during early adolescence in an exposure-period and sex-dependent manner., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Early life environmental exposures may affect bone mass accrual in childhood, but only one study has assessed the role of environmental phenols on child bone health., Methods: We used data from 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, OH; 2003-2006). We quantified benzophenone-3, bisphenol A (BPA), 2,5-dichlorophenol, and triclosan in maternal urine collected at 16- and 26-weeks gestation and calculated the average of creatinine-adjusted concentrations. We performed dual x-ray absorptiometry at age 12 years and calculated Z-scores for whole body (less head), total hip, femoral neck, and 1/3rd distal radius bone mineral content (BMC) and areal bone mineral density (aBMD) as well as ultra-distal radius aBMD and spine BMC and bone mineral apparent density (BMAD). We estimated covariate-adjusted associations per doubling of maternal urinary environmental phenol concentrations in linear regression models. We also examined effect measure modification by child's sex and estimated associations of the environmental phenol mixture with BMC and aBMD using quantile g-computation., Results: We observed generally null associations for all analytes and bone measures. Yet, in adjusted models, higher urinary 2,5-dichlorophenol concentrations were associated with higher 1/3rd distal radius BMC (β: 0.09; 95% CI: 0.02, 0.17) and aBMD (β: 0.09; 95% CI: 0.02, 0.17) Z-scores in the overall sample. In sex-stratified analyses, the magnitude of the BMC association was positive for females (β: 0.16; 95% CI: 0.06, 0.26) and null for males (β: 0.02; 95% CI: 0.08, 0.13). The environmental phenol mixture was associated with greater 1/3rd distal radius BMC and aBMD Z-scores in both sexes, which was mostly driven by benzophenone-3 in males and 2,5-dichlorophenol in females., Conclusion: In this prospective cohort study, we observed generally null associations for environmental phenols with BMC and aBMD at age 12 years. While there was a positive association of 2,5-dichlorophenol concentrations during fetal development with distal radius BMC and aBMD at age 12 years, future studies utilizing methods capable of differentiating cortical and trabecular bone are needed to elucidate potential mechanisms and implications for bone strength and microarchitecture., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Eating behaviours are associated with childhood obesity, but their associations with cardiometabolic risk are less clear., Objectives: We evaluated cross-sectional associations between eating behaviours and cardiometabolic risk among 185 adolescents (age 12.4 ± 0.7 years; 53% female; body mass index (BMI)-z 0.72 ± 1.37) from Cincinnati, Ohio (HOME Study; enrolled 2003-2006)., Methods: Caregivers assessed adolescents' eating behaviours with the Child Eating Behaviour Questionnaire. We computed adolescents' cardiometabolic risk scores based on HOMA-IR, triglycerides to high-density lipoprotein cholesterol ratio, adiponectin to leptin ratio, systolic blood pressure, and cross-sectional area of fat inside the abdominal cavity. Using multivariable linear regression models, we estimated associations of eating behaviour subscales with cardiometabolic risk scores or individual risk components., Results: Emotional overeating (ß = 1.34, 95% CI: 0.67, 2.01), food responsiveness (ß = 0.99, 95% CI: 0.41, 1.57), and emotional undereating (ß = 0.64, 95% CI: 0.08, 1.21) were associated with higher cardiometabolic risk scores. Satiety responsiveness (ß = -0.79, 95% CI: -1.59, 0.00) was associated with lower cardiometabolic risk scores. Adjusting for adolescent BMI-z at age 12 attenuated these associations, suggesting that adiposity may mediate these associations., Conclusion: Hedonistic eating behaviours were associated with higher cardiometabolic risk in these adolescents., (© 2022 World Obesity Federation.)

Background: Few studies have examined whether gestational exposure to organophosphate esters (OPEs), widely used chemicals with potential endocrine-disrupting potency and developmental toxicity, is associated with impaired infant growth., Methods: We analyzed data from 329 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006, Cincinnati, Ohio, USA). We quantified concentrations of four OPE metabolites in maternal urine collected at 16 and 26 weeks of gestation, and at delivery. We calculated z-scores using 2006 World Health Organization (WHO) child growth standards for the 4-week anthropometric measures (weight, length, and head circumference), the ponderal index, and weekly growth rates. We used multiple informant models to examine window-specific associations between individual OPE metabolites and anthropometric outcomes. We further modeled OPEs as a mixture for window-specific associations with 4-week anthropometric outcomes using mean field variational Bayesian inference procedure for lagged kernel machine regression (MFVB-LKMR). We stratified the models by infant sex., Results: Diphenyl phosphate (DPHP) in mothers at 16 weeks, and bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at delivery were positively associated with z-scores of weight, length, and head circumference in all infants at 4 weeks of age. After stratifying by infant sex, positive associations were only observed in males for DPHP at 16 weeks and BCEP at delivery and in females for BDCIPP at delivery. Negative associations not present in all infants were observed in males for di-n-butyl phosphate (DNBP) at 26 weeks of gestation with weight z-score and DPHP at delivery with head circumference z-score. Results were generally similar using MFVB-LKMR models with more conservative 95 % credible intervals. We did not identify consistent associations of gestational OPE metabolite concentrations with the ponderal index and weekly growth rates., Conclusion: In this cohort, exposure to OPEs during gestation was associated with altered infant anthropometry at 4 weeks after birth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Organophosphate esters (OPEs) are developmental toxicants in experimental studies of animals, but limited evidence is available in humans. We included 340 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio, USA) for the analysis. We evaluated gestational exposure to OPEs with gestation age at birth and newborn anthropometric measures. We quantified four OPE urinary metabolites at 16 weeks and 26 weeks of gestation. We extracted gestational age at birth, newborn weight, length, and head circumference from the chart review. We calculated z-scores for these anthropometric measures and the ponderal index. We used multiple informant models to examine the associations between repeated OPE measurements and the outcomes. We used modified Poisson regression to estimate the association of gestational exposure to OPEs with preterm birth. We also explored effect modification by infant sex and the potential mediation effect by the highest maternal blood pressure and glucose levels. We found that bis(2-chloroethyl) phosphate (BCEP) at 16 weeks and diphenyl phosphate at 26 weeks of pregnancy were positively associated with gestational age and inversely associated with preterm birth. In female newborns, BCEP at 16 weeks was inversely related to birth weight and length z-scores. In male newborns, we observed negative associations of 26-week di-n-butyl phosphate with the ponderal index at birth. No mediation by the highest maternal blood pressure or glucose levels during pregnancy was identified. In this cohort, gestational exposure to some OPEs was associated with gestational age, preterm birth, and neonatal anthropometric measures. Certain associations tended to be window- and infant sex-specific., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: No human studies have evaluated early life organophosphate ester (OPE) exposures with bone health outcomes, despite evidence of osteotoxicity., Objectives: We assessed associations of urinary OPE metabolites measured across early life with areal bone mineral density (aBMD) and bone mineral content (BMC) at age 12 years., Methods: Among 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, we quantified concentrations of bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in urine collected from mothers during pregnancy and children at ages 1, 2, 3, 5, and 8 years. At age 12 years, we performed dual energy x-ray absorptiometry and calculated aBMD and BMC z-scores at six skeletal sites. We estimated overall and sex-stratified BMD/BMC z-score differences per interquartile range (IQR) increase in OPE concentrations at multiple exposure timepoints: gestation (average) and 1-3 (average), 5, and 8 years., Results: In adjusted models, overall associations of BCEP and BDCIPP with total hip and 1/3rd distal radius aBMD and BMC varied significantly by exposure timepoint, as did BDCIPP with whole body aBMD. For example, differences (95 % CI) in total hip aBMD z-score per IQR increase in BDCIPP were 0.33 (0.01, 0.64), -0.10 (-0.34, 0.14), -0.18 (-0.40, 0.05), and 0.14 (-0.09, 0.38) for concentrations during gestation and at 1-3, 5, and 8 years, respectively. Overall DnBP and DPHP associations were generally null at all timepoints. We observed sex-specific associations for some timepoints and skeletal sites. For example, an IQR increase in 8-year DPHP was associated with a 0.21 (0.05, 0.38) greater total hip aBMD z-score among females but -0.19 (-0.43, 0.05) lower z-score among males., Discussion: Early life OPE exposures may be associated with sex- and exposure period-dependent alterations in early adolescent bone mineral accrual and strength., Competing Interests: Declaration of competing interest Dr. Braun's institution was financially compensated for his services as an expert witness for plaintiffs in litigation related to PFAS-contaminated drinking water; these funds were not paid to JMB directly. Dr. Lanphear served as an expert witness in cases related to childhood lead poisoning, but he was not personally compensated. The other authors declare they have no actual or potential competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans, especially children. Animal studies and some human studies have reported that OPEs may adversely impact brain development, but few human studies evaluated OPE exposure during early childhood and neurodevelopmental outcomes. We aimed to fill this knowledge gap with the present study on urinary OPE metabolite concentrations at ages 1-5 years and cognitive abilities at 8 years. We used data of 223 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio. The point estimates for bis-2-chloroethyl-phosphate (BCEP) and bis(1,3-dichloro-2-propyl)-phosphate (BDCIPP) in association with IQ tended to be small and positive, while the point estimates for diphenyl-phosphate (DPHP) were small and negative, with 95% CIs including the null. However, we did find that socioeconomic status (SES) variables modified associations between OPEs and child IQ, with adverse OPE-IQ associations being stronger in socioeconomically disadvantaged children than in others. We identified an additional 1- to 2-point decrease in Full Scale IQ for every log-unit increase in BDCIPP, BCEP, and DPHP among those with lower maternal education, non-white race, lower income, or living in more deprived neighborhoods. We observed similar results for the Perceptual Reasoning, Verbal Comprehension, and Working Memory Index Scores. We suspect that there is residual confounding related to socioeconomic disadvantage, which was not captured with the available SES variables typically used in epidemiologic studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Anxiety disorders emerge during childhood and adolescence and are frequently preceded by subsyndromal anxiety symptoms. Environmental toxicants, including gestational polybrominated diphenyl ether (PBDE) exposure, are associated with neuropsychiatric sequelae; however, the role of PBDEs as risk factors for anxiety in adolescence is unclear., Methods: Using data from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort enrolled from 2003 to 2006, we investigated the relationship between gestational serum PBDE concentrations and anxiety symptoms in adolescents (N = 236). We measured five PBDE congeners (PBDE-28, -47, -99, -100, and -153) at 16 ± 3 weeks of gestation and calculated their sum (∑PBDE). We assessed self-reported anxiety symptoms using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and depressive symptoms using the Children's Depression Inventory (CDI-2) at age 12 years. We estimated the associations of maternal PBDE concentrations with child anxiety and depressive symptoms using multivariable linear regression and modified Poisson regression. Covariates included child sex, maternal race, maternal age at delivery, maternal marital status, maternal education, and household income at the 12-year study visit as well as maternal depressive and anxiety symptoms. Sensitivity analyses were performed to control for maternal lead and mercury at delivery., Results: After adjusting for predetermined covariates, each doubling in maternal PBDE concentrations was associated with increased SCARED scores (e.g., for ∑PBDE, SCARED total score, β = 1.6 95% confidence interval [CI]: 0.3-2.9, p = .019) and a nonsignificant increase in depressive symptoms (e.g., for CDI total score, β = .8, 95% CI: -0.2-1.8, p = .11)., Conclusions: Gestational serum PBDE concentrations just before mid-pregnancy and during a period of active cortical and limbic neurogenesis, synaptogenesis and myelogenesis may be a risk factor for developing anxiety symptoms in early adolescence., (© 2022 The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

Objective: To identify clinical and central features that differentiate ADHD youth with and without familial risk for bipolar I disorder (BD). Methods: Psychostimulant-free ADHD youth (10-18 years) with and without a first-degree relative with BD and healthy controls were enrolled. Bilateral ventrolateral prefrontal cortex (VLPFC) proton magnetic resonance spectroscopy ( 1 H MRS) scans and a range of symptom ratings were performed. Results: A total of n  = 145 youth were enrolled. ADHD youth with a family history of BD exhibited greater manic and depressive symptom severity, ADHD hyperactivity/impulsive symptom severity, and higher parent-reported ratings of dysregulation compared with ADHD youth without a BD family history. Although VLPFC metabolite levels did not differ across groups, choline levels in the left VLPFC correlated with different symptom ratings. Conclusion: Symptom profiles including more severe mood and externalizing symptoms, but not VLPFC neurochemistry, differentiate psychostimulant-free ADHD youth with and without a family history of BD.

Objective: Exposure to per- and polyfluoroalkyl substances (PFAS) - endocrine disrupting chemicals - may increase cardiometabolic risk. We evaluated whether adolescent lifestyle factors modified associations between gestational PFAS exposure and cardiometabolic risk using a prospective cohort study., Methods: In 166 mother-child pairs (HOME Study), we measured concentrations of four PFAS in maternal serum collected during pregnancy. When children were age 12 years, we calculated cardiometabolic risk scores from visceral adiposity area, blood pressure, and fasting serum biomarkers. We assessed adolescent physical activity and Healthy Eating Index scores using the Physical Activity Questionnaire for Older Children (PAQ-C), actigraphy, and 24-h diet recalls. Using multivariable linear regression and weighted quantile sum regression, we examined whether physical activity or diet modified covariate-adjusted associations of PFAS and their mixture with cardiometabolic risk scores., Results: Physical activity modified associations between perfluorooctanoic acid (PFOA) and cardiometabolic risk scores. Each doubling of PFOA was associated with worse cardiometabolic risk scores among children with PAQ-C scores < median (β:1.4; 95% CI:0.5, 2.2, n = 82), but not among those with PAQ-C scores ≥ median (β: 0.2; 95% CI: 1.2, 0.7, n = 84) (interaction p-value = 0.01). Associations were most prominent for insulin resistance, leptin-adiponectin ratio, and visceral fat area. We observed results suggesting that physical activity modified the association of PFAS mixture with cardiometabolic risk scores, insulin resistance, and visceral fat area (interaction p-values = 0.17, 0.07, and 0.10, respectively); however, the 95% CIs of the interaction terms included the null value. We observed similar, but attenuated patterns for PFOA and actigraphy-based measures of physical activity. Diet did not modify any associations. Physical activity or diet did not modify associations for other PFAS., Conclusions: Childhood physical activity modified associations of prenatal serum PFOA concentrations with children's cardiometabolic risk in this cohort, indicating that lifestyle interventions may ameliorate the adverse effects of PFOA exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Braun reports financial support was provided by National Institute of Environmental Health Sciences. Kimberly Yolton, Kim Cecil, Clara G. Sears, Jessie P. Buckley, Nan Li, Karl T. Kelsey, Charles B. Eaton, George Papandonatos, Aimin Chen, Heidi Kalkwarf, reports financial support was provided by National Institute of Environmental Health Sciences. Joseph Braun reports a relationship with Morgan & Morgan Law Firm that includes: paid expert testimony. Charles B. Eaton reports a relationship with Morgan and Morgan Law Firm that includes: paid expert testimony. Karl T. Kelsey is a founder and scientific advisor for Cellintec, which had no role in this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Early life phthalate exposures may disrupt metabolism but results from human studies are inconsistent and few have examined body composition during adolescence. We investigated associations of gestational and childhood urinary phthalate biomarker concentrations with body composition at age 12 years., Methods: We used data from 206 mother-child pairs in a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003 to 2006. We measured nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children at 1, 2, 3, 4, 5, 8, and 12 years. At age 12 years, we assessed fat and lean mass of the whole body and android and gynoid subregions, and visceral fat area with dual x-ray absorptiometry, and calculated android to gynoid %fat ratio and age- and sex-standardized fat and lean mass index z-scores. Using a multiple informant model, we estimated covariate-adjusted associations between urinary phthalate biomarker concentrations at each time period and outcomes at age 12 years. We assessed effect measure modification by child sex using stratified models., Results: Generally, urinary mono-benzyl phthalate (MBzP) concentrations were modestly associated with lower fat and lean mass. Each 10-fold increase in urinary MBzP concentrations during gestation and at ages 5 and 8 years was associated with a -0.34 (95%CI: -0.72, 0.05), -0.44 (95% CI: -0.83, -0.05), and -0.35 (95% CI: -0.71, 0.00) z-score difference in lean body mass index, respectively. Urinary monoethyl phthalate, mono-(3-carboxypropyl) phthalate, and summed di(2-ethylhexyl) phthalate metabolites were associated with greater lean mass at some exposure periods. Slightly weaker but similar patterns of association were found with other body composition measures; associations did not differ by child sex., Conclusion: While most associations were weak, exposure to certain phthalates during gestation and childhood may be associated with adolescent body composition, particularly lean mass., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The study aimed to identify periods of heightened susceptibility to the effects of pre- and postnatal secondhand tobacco smoke (SHS) exposure on body composition at age 12 years., Methods: The study used data from 217 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective cohort in Cincinnati, Ohio. Using multiple informant models, the study estimated associations of maternal serum cotinine (16 and 26 weeks of pregnancy) and child serum cotinine concentrations (at age 12, 24, 36, and 48 months) with measures of body composition obtained with anthropometry and dual-energy x-ray absorptiometry at 12 years. We examined whether there were differences between these associations for pre- and postnatal exposure periods and potential effect measure modification by sex., Results: Postnatal cotinine concentrations were associated with higher weight, BMI, body fat and lean mass, waist circumference, and visceral, android, and gynoid fat. Each 10-fold increase in postnatal cotinine was associated with 76% increased risk of overweight or obesity (95% CI: 1.13-2.75). Associations between prenatal concentrations and measures of body composition at 12 years were generally null., Conclusions: Postnatal exposure to SHS may increase adolescent adiposity and lean mass. Future studies should determine whether early-life exposures to SHS are associated with other cardiometabolic risk markers., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Background: Endocrine-disrupting chemicals may alter glucose homeostasis, especially during pregnancy. Biomonitoring studies suggest ubiquitous human exposure to organophosphate esters (OPEs), chemicals with endocrine-disrupting capabilities. Few studies have examined the association between maternal exposure to OPEs and blood glucose during pregnancy., Methods: With data from 301 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA, we examined whether OPE concentrations were associated with changes in blood glucose. We quantified four OPE metabolites in maternal spot urine samples collected at 16- and 26-weeks pregnancy. We extracted results from the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) via medical chart review. Women with GCT ≥ 140 mg/dL or any abnormal values in OGTT (≥ 95 mg/dL fasting glucose, ≥ 180 mg/dL 1-h glucose, ≥ 155 mg/dL 2-h glucose, ≥ 140 mg/dL 3-h glucose) were defined as having elevated glucose levels. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate the associations of individual OPE metabolites and OPE mixtures with blood glucose levels during pregnancy. We used modified Poisson regression to estimate the associations of OPE metabolite concentrations with elevated glucose levels. We further examined effect measure modification by maternal characteristics (age, pre-pregnancy body mass index [BMI], and race/ethnicity)., Results: Diphenyl phosphate (DPHP) had the highest geometric mean concentration of the urinary OPE metabolites (1.83 μg/L at 16 weeks, 1.24 μg/L at 26 weeks). Thirty women (10.0%) had elevated glucose levels. Individual OPE metabolites or their mixtures were not significantly associated with continuous GCT results. We did not observe effect measure modification by maternal age, pre-pregnancy BMI categories, or race/ethnicity. Compared with women in the 1st tertile of average DPHP of 16- and 26 weeks of pregnancy, women in the 3rd tertile tended to have a reduced risk of elevated glucose levels (RR = 0.41, 95% CI = 0.16-1.06, p for trend = 0.06)., Conclusion: In this cohort, maternal urinary OPE metabolite concentrations were weakly associated with blood glucose levels during pregnancy., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Noninvasive advanced neuroimaging and neurochemical assessment can identify subtle abnormalities and predict neurodevelopmental impairments. Our objective was to quantify white matter metabolite levels and evaluate their relationship with neurodevelopmental outcomes at age 3 years., Methods: Our study evaluated a longitudinal prospective cohort of very premature infants (<32 weeks gestational age) with single-voxel proton magnetic resonance spectroscopy from the centrum semiovale performed at term-equivalent age and standardized cognitive, verbal, and motor assessments at 3 years corrected age. We separately examined metabolite ratios in the left and right centrum semiovale. We also conducted an exploratory interaction analysis for high/low socioeconomic status (SES) to evaluate the relationship between metabolites and neurodevelopmental outcomes, after adjusting for confounders., Results: We found significant relationships between choline/creatine levels in the left and right centrum semiovale and motor development scores. Exploratory interaction analyses revealed that, for infants with low SES, there was a negative association between choline/creatine in the left centrum semiovale and motor assessment scores at age 3 years., Conclusions: Brain metabolites from the centrum semiovale at term-equivalent age were associated with motor outcomes for very preterm infants at 3 years corrected age. This effect may be most pronounced for infants with low SES., Impact: Motor development at 3 years corrected age for very preterm infants is inversely associated with choline neurochemistry within the centrum semiovale on magnetic resonance spectroscopy at term-equivalent age, especially in infants with low socioeconomic status. No prior studies have studied metabolites in the centrum semiovale to predict neurodevelopmental outcomes at 3 years corrected age based on high/low socioeconomic status. For very preterm infants with lower socioeconomic status, higher choline-to-creatine ratio in central white matter is associated with worse neurodevelopmental outcomes., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Few studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy., Methods: We analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP., Results: ICCs of OPEs were 0.17-0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97-9.15). Other OPE metabolites were not significantly associated with HDP., Conclusion: Maternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments-selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Heavy metals, including lead and manganese, air pollution, pesticides, environmental tobacco smoke, and flame retardants are among the known and suspected environmental neurotoxicant exposures examined with magnetic resonance imaging (MRI)-based studies of pediatric populations. Many studies feature morphological changes associated with the exposures while others employ magnetic resonance spectroscopy, diffusion imaging, task-based, and resting state functional magnetic resonance imaging to reveal abnormal metabolic concentrations, white matter disorganization, and atypical patterns of activation. Some studies follow pregnant women and their offspring throughout the lifespan with collection of individual specimens as exposure biomarkers. Others innovatively make use of public databases to obtain relevant exposure biomarkers while taking advantage of these studies in their efforts to monitor developmental features in large, population-based, imaging cohorts. As exposures to neurotoxicants in the womb and throughout childhood have life-long impacts on health and well-being, the importance of these innovative neuroimaging investigations is ever increasing.

Background: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS., Objective: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS., Methods: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (M Age  = 10.59, SD Age  = 1.33) and 41 typically developing control subjects (M Age  = 10.26, SD Age  = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity., Results: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity., Conclusions: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation., Objectives: We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006; Cincinnati, Ohio)., Methods: We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood ( n = 266 ) and peripheral leukocytes at 12 years of age ( n = 160 ) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations between log 2 -transformed PFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002; Boston, Massachusetts) to replicate significant associations., Results: After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate, q < 0.05 ). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age., Discussion: In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health. https://doi.org/10.1289/EHP10118.

Aims: To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder., Methods: We conducted an 8-week open label clinical trial of NAC 2400 mg/days in 15-24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC)., Results: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p < .001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p = .007)., Conclusions: This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC., (© 2021 John Wiley & Sons Australia, Ltd.)