Maternal Exposure

BACKGROUND: Organophosphate ester flame retardants and plasticizers (OPEs) have myriad uses in industry and consumer products. Increasing human exposure to OPEs has raised concerns about their potential effects on child neurodevelopment during the pregnancy. Objective: We investigated whether OPE urinary concentrations during pregnancy were associated with child's autism-related outcomes. METHODS: We included 4159 mother-child pairs from 15 cohorts in the NIH Environmental influences on Child Health Outcomes (ECHO) Consortium, with children born from 2006-2020 (median age [interquartile range]: 6 [4,10] years). Nine OPE biomarkers were measured in urine samples collected mid- to late pregnancy. Dilution-adjusted biomarkers were modeled continuously, categorically (high [>median], moderate [≤median], nondetect), or as detect/nondetect depending on their detection frequency. We assessed child autism-related traits via a) parent report on the Social Responsiveness Scale (SRS) and b) clinical autism diagnosis. We examined associations of OPEs with child outcomes, including modification by child sex, using generalized estimating equations to account for clustering by ECHO cohort. RESULTS: Compared with nondetectable concentrations, high exposure to bis-(butoxyethyl) phosphate (BBOEP) was associated with higher autistic trait scores (adj-β 0.97, 95% confidence interval [CI]: 0.42, 1.52) and greater odds of autism diagnosis (adjusted odds ratio [adj-OR]: 1.27, 95% CI: 1.07, 1.50). Bis-(1-chloro-2-propyl) phosphate (BCPP) showed associations with autistic trait scores (BCPP adj-β for high exposure vs nondetect: 0.34, 95% CI: -0.46, 1.13; BCPP adj-β for moderate exposure vs nondetect: 0.72, 95% CI: 0.24, 1.20). High exposure to bis-(2-chloroethyl) phosphate (BCETP) was associated with lower odds of autism diagnosis (adj-OR: 0.76, 95% CI: 0.60, 0.95). Other OPEs showed no associations in adjusted models. Associations between BBOEP and higher autistic trait scores were stronger in males than females. DISCUSSION: Prenatal exposure to OPEs, specifically BCPP and BBOEP, may be associated with a higher risk of autism diagnosis and related traits in childhood.

BackgroundExposure to PM2·5 from wildfire smoke during pregnancy has been implicated as a risk factor for preterm birth. We investigated this association in the prospective nationwide US Environmental Influences on Child Health Outcomes (ECHO) Cohort, focusing on prenatal wildfire PM2·5 exposure intensity, duration, and timing.MethodsIn this cohort analysis, we included live singleton births recorded in the ECHO Cohort with available data on gestational age at birth and birthweight and dates of conception between Jan 1, 2006, and March 20, 2020. Census tract-level estimates of daily mean wildfire-derived PM2·5 for the years 2006-20 from a previous machine learning model were linked to residential address history. We calculated the mean concentration of daily wildfire PM2·5, days with wildfire PM2·5 (>0, ≥2·5, ≥5·0, and ≥10·0 μg/m3; termed smoke days) and consecutive smoke days (2, 3, or ≥4 days; termed smoke waves) above the prespecified concentration thresholds across pregnancy. Associations of cumlative pregnancy wildfire PM2·5 exposure with preterm birth (delivery before 37 weeks of gestation) were analysed by adjusted pooled logistic regression in the nationwide ECHO sample and in the US West census region. Associations between smoke days in gestational weeks 0-35 and preterm birth were evaluated by logistic regression in the national sample.FindingsWe included 20 034 births from 30 ECHO Cohort study sites, with residences during pregnancy in all 48 contiguous US states and the District of Columbia. 1687 (8·4%) of the 20 034 infants were preterm. The mean daily wildfire PM2·5 concentration during pregnancy was 0·36 μg/m3 (SD 0·46), with exposure to a mean of 22·2 smoke days (SD 16·6) of any wildfire PM2·5 concentration (>0 μg/m3). Estimates of association between wildfire PM2·5 exposure metrics and preterm birth included the null in nationwide analyses; whereas, in the US West sample (N=5807), we estimated increased odds of preterm birth associated with mean daily wildfire PM2·5 (odds ratio [OR] 1·139 per 1-μg/m3 increase [95% CI 1·001-1·296]), exposure to smoke days with a wildfire PM2·5 concentration of 5·0 μg/m3 or greater (OR 1·018 per additional smoke day [1·003-1·032]) and 10·0 μg/m3 or greater (OR 1·030 [1·006-1·054]), and exposure to ≥4-day smoke waves of 5·0 μg/m3 or greater (OR 1·185 per additional smoke wave [1·044-1·347]) and 10·0 μg/m3 or greater (OR 1·232 [1·029-1·475]). At the national level, by week of gestation, associations with preterm birth were observed in mid-pregnancy for smoke days with wildfire PM2·5 concentrations above 0 μg/m3, of 2·5 μg/m3 or greater, and of 5·0 μg/m3 or greater, and in late pregnancy for smoke days of 10·0 μg/m3 or greater.InterpretationIn a prospective cohort, we observed increased odds of preterm birth associated with wildfire PM2·5 exposure in the western USA, with findings suggesting an exposure-response relationship for increasing exposure intensity and duration. Preterm birth was also associated with exposure to smoke days in mid-to-late pregnancy at the national level. For practice and policy, these findings support the need for public health interventions aimed at reducing exposure to wildfire smoke during pregnancy.FundingECHO Program, US National Institutes of Health Office of the Director.

Currently regulated per- and polyfluoroalkyl substances (PFAS) have been associated with immune, endocrine, and neurotoxicity following gestational exposures. As a result, industries have effectively replaced them with next-generation PFAS, including perfluorohexanoic acid (PFHxA). PFHxA is increasingly found in the serum of pregnant women and in breast milk, and adult human post-mortem studies indicate that PFHxA is found in the brain, with the highest concentrations in the cerebellum and hypothalamus. Despite evidence of gestational, lactational, and nervous system exposure to PFHxA, developmental neurotoxicity (DNT) testing in mammals has not been conducted. For DNT evaluation, we exposed pregnant C57Bl/6J mice daily from gestational day 0 through postnatal day (P) 21 to two PFHxA exposure levels (a lower (0.32 mg/kg of body weight (bw), or higher (50 mg/kg of bw) dose of PFHxA)) or ddH2O using treat-based administration. Given the high PFHxA levels in the cerebellum in post-mortem studies and the cerebellum's protracted developmental window, we assessed acute transcriptional dysregulation and cellular morphology in this brain region on the last day of exposure at P21. Using bulk-RNA sequencing, we found that PFHxA exposure had subtle effects on transcripts related to neurons and glia, with females having a greater number of dysregulated transcripts than males. Using immunohistochemistry, we found that Purkinje cell linear frequency was increased in specific lobules in the higher-exposure group and that microglial morphology underwent subtle changes in specific cerebellar layers in the lower-exposure group in both sexes. Together these data suggest that PFHxA exposure may have lobule-specific impacts on the development of both neurons and glia in the cerebellum, highlighting the importance of studying the neurotoxicity of PFHxA in both sexes.