Sex- and Trimester-Specific Associations of Prenatal Co-Exposure to Organophosphate Esters and Phthalates with Preschoolers' Trajectories of Co-Occurring ADHD and ASD Symptoms: Cord Blood Metabolomic Study in the Ma'anshan Birth Cohort.
Jul 2026· Environmental Science and Technology· Vol 60 31, pp.
21465-21479
· 2 citations· 66 references
Medicine
TL;DR
Cord blood metabolomics identified pyrimidine, biotin, lysine, cysteine, and methionine metabolism as key mediators of OPE-induced cotrajectories, and purine metabolism mediated PAEs' effects (p < 0.05), which highlights OPE/PAE neurotoxicity and reveals novel cord metabolomic insights.
Abstract
Although neurotoxic, prenatal exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) and their effects on preschoolers' autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) cotrajectories and underlying metabolic mechanisms remain unclear, we aimed to elucidate these links. Maternal urinary OPEs/PAEs were measured in 3040 dyads from the Ma'anshan Birth Cohort across three trimesters. Child ADHD/ASD symptom scale scores were assessed at ages 3, 5, and 6, and cotrajectories were identified using group-based multitrajectory modeling. Single-pollutant models revealed that bis(2-ethylhexyl) phosphate (BEHP) across pregnancy was positively associated with high-score trajectories (HST) (OR = 1.20, 95% CI: 1.06, 1.37), whereas bis(2-butoxyethyl) phosphate (BBOEP) exhibited U-shaped associations. Second-trimester diphenyl phosphate (DPHP) (OR = 1.13, 95% CI: 1.01, 1.26), BEHP (OR = 1.14, 95% CI: 1.04, 1.24), and monobutyl phthalate (OR = 1.15, 95% CI: 1.00, 1.32) were positively associated with HST. First-trimester DPHP exhibited a positive correlation with moderate-score trajectories and HST in girls, while bis(1-chloro-2-propyl) phosphate across pregnancy was inversely associated with HST in boys (psex-int < 0.05). No mixed effects were detected. BBOEP across pregnancy was negatively associated with ADHD symptoms, whereas BEHP was positively associated. BEHP, monomethyl phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate were positively associated with ASD symptoms, whereas dibutyl phosphate and monoethyl phthalate were negatively associated (p < 0.05). Cord blood metabolomics identified pyrimidine, biotin, lysine, cysteine, and methionine metabolism as key mediators of OPE-induced cotrajectories, and purine metabolism mediated PAEs' effects (p < 0.05). This study highlights OPE/PAE neurotoxicity and reveals novel cord metabolomic insights.
INTRODUCTION
Few studies have examined prenatal co-exposure to organophosphate esters (OPEs) and phthalic acid esters (PAEs) in relation to childhood autism spectrum disorder (ASD) symptoms, and whether vitamin D modifies these associations.
METHODS
Included 2400 mother-child dyads from the Ma'anshan Birth Cohort and examined levels of maternal OPEs, PAEs, and vitamin D across the three trimesters. Used the Clancy Autism Behavior Scale to assess preschoolers' ASD symptoms at ages 3, 5, and 6, then used group-based trajectory modeling to fit ASD symptom trajectories.
RESULTS
ASD symptom scores fit 3 trajectories: low, moderate, and high. Average-MEOHP, average-ΣHMWP, first-trimester-ΣHMWP, third-trimester-DPHP, and third-trimester-BCIPP were associated with increased risk in the moderate group (p < 0.05). Average-MMP, average-ΣHMWP, second-trimester-BEHP, and third-trimester-ΣHMWP were associated with increased risk in the high-score group (p < 0.05). By contrast, first-trimester-BCIPP was negatively correlated with the moderate group. DPHP, DBP, and Σdi-OPEs showed sex-specific effects (psex-int < 0.05). Maternal vitamin D levels modified these associations, with women with vitamin D deficiency showing significantly higher risks. OPEs and PAEs showed mixed effects.
CONCLUSION
Prenatal exposure to OPEs/PAEs exhibited heterogeneous associations with preschoolers' ASD symptom trajectories, and maternal vitamin D deficiency exacerbates the effects of OPEs/PAEs individual exposure on symptom trajectories.
Xing Wang, J. Tong, Ling Luo et al.· Environment International· 0 citations
OBJECTIVE
To examine the association between prenatal exposure to a mixture of EDCs and attention-deficit/hyperactivity disorder (ADHD) symptoms in children.
METHODS
Participating were mother-child pairs from the Environmental influences on Child Health Outcomes (ECHO) Cohort (n = 3,962, 18 Sites, 2001-2021). Maternal spot urine samples collected during pregnancy were sent to the Wadsworth Center Human Health Exposure Analysis Resource laboratory and analyzed using a single assay workflow. From those samples, 24 urinary metabolites of EDCs with detection frequency > 70%, were grouped as molar sum of high- and low-molecular-weight phthalates, polycyclic aromatic hydrocarbons, bisphenol S, organophosphate esters, and organophosphate and pyrethroid pesticides. Child ADHD symptoms were assessed using raw scores from the Child Behavior Checklist for preschool-aged (CBCL/1½-5) and school-aged (CBCL/6-18) Attention-Deficit/Hyperactivity Problems subscale. Scores ≥ the 85th and 95th percentiles were respectively classified as borderline and clinical thresholds. Quantile g-computation estimated the expected change in ADHD outcome associated with a one-quartile increase in all prenatal EDC mixture concentrations, using negative binomial models for raw scores and binomial models for percentile thresholds.
RESULTS
Prenatal exposure to the EDC mixture was not associated with child ADHD symptoms in preschool-aged or school-aged children in adjusted models for either continuous raw scores or percentile thresholds.
CONCLUSION
Overall our findings on prenatal EDC mixture exposure and ADHD symptoms were not robust to full adjustment. Future research that can delineate factors such as windows of vulnerability and trajectories of ADHD-related symptoms may help clarify mixed findings in the literature.
Teresa Herrera, Sara Hyman, Roger Newman et al.· Environment International· 0 citations
Prenatal exposure to OPFRs and OPPs was associated with smaller left ventricular structural measures in early childhood, mainly reflected by lower left ventricular volume and mass, with OPFRs emerging as main contributors and stronger associations among girls.
Meng Wang, Xi Zhang, Hualin Wang et al.· Environmental Pollution· 0 citations
Prenatal exposure to environmental chemicals has been implicated in impaired fetal and early childhood growth. However, most previous studies have focused on single exposure domains, limiting understanding of the combined effects of co-occurring chemical mixtures. We investigated the joint effects of a prenatal multi-domain chemical mixture comprising endocrine-disrupting chemicals (EDCs), heavy metals, and ambient air pollutants on infant growth from birth to 36 months using data from the Korean Children's Environmental Health Study (Ko-CHENS), a nationwide prospective birth cohort of 5,056 mother-child pairs. We applied weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) to estimate mixture effects and identify key contributing exposures, WQS and BKMR were fitted separately at each of five assessment ages, and a latent class mixed model (LCMM) was used to characterize prenatal exposure trajectory subgroups, whose association with repeated growth measures was then evaluated in a linear mixed model. Ten mixture-outcome tests (two outcomes x five ages) were pre-specified as primary and were corrected for multiplicity using the Benjamini-Hochberg false discovery rate (FDR) procedure. WQS regression identified a significant inverse association between the prenatal chemical mixture and infant length-for-age z-scores at birth and 6 months, with late-pregnancy BPF and BPS consistently emerging as the top-weighted contributors; both associations remained below a 5% FDR threshold. Overall mixture effects estimated by BKMR were null at every assessment age, although BKMR suggested nonlinear and exposure-specific dose-response relationships involving bisphenol analogues and ambient air pollutants across multiple assessment time points. No significant associations were observed between LCMM-derived exposure trajectory class and longitudinal growth outcomes through 36 months. Domain-specific patterns were observed across both analyses: bisphenol analogues showed more consistent associations with length outcomes, whereas ambient air pollutants were more frequently identified as key contributors in weight-related models. These exploratory findings suggest that prenatal exposure to bisphenol analogues and ambient air pollutants may be associated with early childhood growth and warrants further investigation. They support the use of mixture-based approaches in environmental health research but should not be interpreted as evidence of causal effects.
Sungryul Shim, Taemi Kim, Sungchul Seo et al.· Environmental Pollution· 0 citations
The findings add to a limited evidence base on prenatal PFAS exposure and parent-reported sleep-related behaviors in early childhood and warrant confirmation in future studies that incorporate harmonized trimester-specific exposure assessment, objective sleep measures, and mixture-based analytic approaches.
Cai Zhang, T. Etzel, S. Schantz et al.· Environmental Research· 0 citations
Background Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by restricted and repetitive behaviours (ICD-11) and severe and persistent difficulties in social interaction and communication. A marked male predominance has consistently been reported, with ASD being three times more common among boys than girls, although the biological mechanisms underlying this sex difference remain unknown. Physical and chemical stressors occurring during critical windows of development may alter foetal and infant physiology and interfere with neurodevelopmental trajectories. Among these stressors, endocrine-disrupting chemicals (EDCs), including phthalates, have been proposed as potential environmental contributors to neurodevelopmental vulnerability. In this systematic review, we examined whether early-life exposure to phthalates may be associated with sex-specific vulnerability to ASD and autistic traits. Methods The systematic review was conducted in accordance with the PRISMA guidelines and followed a PECO framework. The target population included human children of both sexes, ranging from early childhood to adolescence. Exposures of interest included prenatal and/or early-life exposure to phthalates, assessed through biological matrices during prenatal and/or postnatal periods. Eligible outcomes included ASD and autistic-like traits assessed using validated diagnostic or screening tools. The review was registered in PROSPERO (CRD420261438630). Results A total of 18 studies were included. Phthalates exposure was assessed across a broad developmental window, ranging from the preconception period to 8 years of age. Urinary biomarkers represented the primary method for assessing chemical exposure, while a smaller proportion of studies also relied on blood samples. Sample size ranged from 77 to 3,220, and the age at assessment of autistic traits or ASD-related outcomes ranged from 18 months to 15 years. The Social Responsiveness Scale (SRS) was the most frequently used instrument for assessing autistic traits, followed by the Autism Diagnostic Observation Schedule (ADOS). Conclusion Prenatal exposure to phthalates, especially during early and mid-gestation, appears to be associated with subtle increases in autistic traits, with some evidence suggesting greater susceptibility among boys, particularly in relation to MBP, MEP, and DEHP-related metabolites. However, evidence remains limited and heterogeneous, and current findings require further confirmation. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/home, PROSPERO CRD420261438630.
Ivana Bucaro, P. Palanza, Davide Ponzi· Frontiers in child and adole...· 0 citations
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