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Parents of autistic children report barriers to engaging in physical activity, which may be exacerbated during subsequent pregnancies. We aimed to describe physical activity of parents caring for an autistic child, before and during a subsequent pregnancy, and to explore whether physical activity was associated with the autistic child's Social Responsiveness Scale score, a measure of autism-related traits. We used data from the Early Autism Risk Longitudinal Investigation, in which families with an autistic child were followed through a subsequent pregnancy. Mothers (n = 245) self-reported physical activity in the 3 months before conception and during pregnancy; fathers (n = 130) reported on the 6 months prior to enrollment. Approximately 40% of nonpregnant mothers and fathers and 9.3% of pregnant mothers met Physical Activity Guidelines for Americans recommendations. Most (83.5%) pregnant mothers reported no vigorous activity; after adjustment for covariates, this was more common among mothers of children with Social Responsiveness Scale T-scores >75 compared with mothers of children with lower T-scores (adjusted odds ratio (95% confidence interval) = 2.94 (1.11, 7.78)). Among parents caring for an autistic child before and during a subsequent pregnancy, physical activity was lower than recommended. Family-based interventions may be necessary to help support physical activity levels.

BACKGROUND: School physical education is an important population-level health intervention for improving youth fitness. This study estimated the impact of New York Citys PE Works program - which included providing PE teachers, training for classroom teachers, and administrative/ teacher support for PE - on student cardiorespiratory fitness as measured by the FitnessGrams 15-meter PACER test for aerobic capacity. METHODS: This longitudinal study (2014/15-2018/19) includes 581 elementary schools (n = 315,999 4th /5th -grade students; 84% non-white; 74% who qualify for free or reduced-price meals, a proxy for socioeconomic status). We apply the parametric g-formula to address schools time-varying exposure to intervention components and time-varying confounding. RESULTS: After four years of staggered PE Works implementation, 49.7% of students/school (95% CI: 42.6%, 54.2%) met age/sex-specific Healthy Fitness Zone (HFZ) aerobic capacity standards set by the FitnessGram. Had PE Works not been implemented, we estimate 45.7% (95% CI: 36.9%, 52.1%) would have met aerobic capacity HFZ standards. Had PE Works been fully implemented in all schools from the programs inception, we estimate 57.4% (95% CI: 49.1%, 63.3%) would have met aerobic capacity HFZ standards. Adding a PE teacher, alone, had the largest impact (6.4% (95% CI: 1.0, 12.0) increase). CONCLUSION: PE Works positively impacted student cardiorespiratory fitness. Mandating and funding multicomponent PE programs is an important public health intervention to increase childrens cardiorespiratory fitness.

BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.

BACKGROUND: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. OBJECTIVE: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits. METHODS: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively). RESULTS: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (β: -1.69; 95% CI: -3.3, -0.08). Estimates were similar across categories of fish consumption from any or less than once per week to more than twice per week. For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (β: 1.98; 95% CI: 0.33, 3.64). CONCLUSIONS: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals.

BackgroundEndocrine disrupting chemicals (EDCs) are widely used compounds with the potential to affect child neurodevelopmental outcomes including autism spectrum disorders (ASD). We aimed to examine the urinary concentrations of biomarkers of EDCs, including phthalates, phenols, and parabens, and investigate whether exposure during early infancy was associated with increased risk of later ASD or other non-typical development (Non-TD) or adverse cognitive development.MethodsThis analysis included infants from the Markers of Autism Risks in Babies-Learning Early Signs (MARBLES) study, a high-risk ASD cohort (n = 148; corresponding to 188 urine samples). Thirty-two EDC biomarkers were quantified in urine among infants 3 and/or 6 months of age. Trends in EDC biomarker concentrations were calculated using least square geometric means. At 36 months of age, children were clinically classified as having ASD (n = 36), nontypical development (Non-TD; n = 18), or typical development (TD; n = 81) through a clinical evaluation. Trinomial logistic regression analysis was used to test the associations between biomarkers with ASD, or Non-TD, as compared to children with TD. In single analyte analysis, generalized estimating equations were used to investigate the association between each EDC biomarkers and longitudinal changes in cognitive development using the Mullen Scales of Early Learning (MSEL) over the four assessment time points (6, 12, 24, and 36 months of age). Additionally, quantile g-computation was used to test for a mixture effect.ResultsEDC biomarker concentrations generally decreased over the study period, except for mono-2-ethyl-5-carboxypentyl terephthalate. Overall, EDC biomarkers at 3 and/or 6 months of age were not associated with an increased risk of ASD or Non-TD, and a few showed significant inverse associations. However, when assessing longitudinal changes in MSEL scores over the four assessment time points, elevated monoethyl phthalate (MEP) was significantly associated with reduced scores in the composite score (β = -0.16, 95% CI: 0.31, -0.02) and subscales of fine motor skills (β = -0.09, 95%CI: 0.17, 0.00), and visual reception (β = -0.11, 95% CI: 0.23, 0.01). Additionally, the sum of metabolites of di (2-ethylhexyl) terephthalate (ƩDEHTP) was associated with poorer visual reception (β = -0.09, 95% CI: 0.16, -0.02), and decreased composite scores (β = -0.11, 95% CI: 0.21, -0.01). Mixtures analyses using quantile g-computation analysis did not show a significant association between mixtures of EDC biomarkers and MSEL subscales or composite scores.ConclusionThese findings highlight the potential importance of infant exposures on cognitive development. Future research can help further investigate whether early infant exposures are associated with longer-term deficits and place special attention on EDCs with increasing temporal trends and whether they may adversely affect neurodevelopment.

BackgroundEarly-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited.MethodsThis study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2-5 years. Parents reported on children's ADHD symptoms at ages 8-18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated.ResultsAmong 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (β per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (β = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (β = 0.07, 95% CI: -0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females.ConclusionExposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations.

BACKGROUND: Wildfires in the Western United States are a growing and significant source of air pollution that is eroding decades of progress in air pollution reduction. The effects on preterm birth during critical periods of pregnancy are unknown. METHODS: We assessed associations between prenatal exposure to wildland fire smoke and risk of preterm birth (gestational age

Marine microalgae offer significant potential as sustainably cultivable microorganisms for the biorefining of a diverse array of functional metabolites. In this study, three species of marine microalgae, Tetraselmis chuii Butcher CCAP 66/21B (Chlorophyte), Phaeodactylum tricornutum Bohlin CCAP 1052/1 (Diatom) and Amphidinium carterae Hulburt CCAP 1102/8 (Dinoflagellate), were batch cultivated and their biomass retrieved for analysis in terms of pigment and fatty acid composition as well as bioactivity potential. Sequential solvent maceration of the biomass returned extracts was used to determine antioxidant capacity and assess their growth inhibition potential against A549 (a human lung carcinoma) and MCF-7 (a breast carcinoma) cell lines. The extracts of A. carterae showed higher antioxidant capacity (≤ 33.5 μmol Trolox Equivalent mg Recovered Dried Material‒1) compared to the other extracts. No major cytotoxic activity nor production of reactive oxygen species was observed using the extracts of T. chuii and P. tricornutum. However, the methanolic extraction of A. carterae inhibited the growth of both A549 and MCF-7 cells (< 4%) at 25, 50 and 100 µg ml−1 concentrations, as determined using the MTS assay and AO/PI cell staining. Microalgal metabolites have the potential for practical applications in a variety of industrial sectors. The absence of toxicity and substantial antioxidant potential of extracts of T. chuii and P. tricornutum confirm their suitability for incorporation into animal feeds or human nutrition supplements. A. carterae also appears to be a promising source of bioactives that can be further valorized via multi-compound biorefinery pipelines.

Young children may experience higher per- and polyfluoroalkyl substances (PFAS) exposure than adults due to breastfeeding, higher dust ingestion rates, and frequent hand-to-mouth activities. We explored temporal trends and determinants of child serum PFAS concentrations and their correlations with paired maternal PFAS concentrations. From 2009 to 2017, we collected one blood sample from each of 541 children aged 2-5 years participating in the Childhood Autism Risks from Genetics and Environment (CHARGE) study and quantified 14 PFAS in serum. For nine frequently detected PFAS (>65% of samples), we performed multiple regression adjusting for potential determinants to estimate mean percent concentration changes. For a subset of 327 children, we also quantified nine PFAS in their mother's serum collected at the same visit and computed Spearman correlation coefficients (rsp) between maternal and child PFAS concentrations. During 2009-2017, child serum concentrations of all nine PFAS decreased by 6-25% annually. Several PFAS concentrations were higher among non-Hispanic white children and those with highly educated parents. Most maternal and child PFAS concentrations were moderately correlated (rsp = 0.13-0.39), with a strong correlation for N-methyl perfluorooctane sulfonamido acetic acid (rsp = 0.68). Breastfeeding duration appeared to contribute to higher child and lower maternal PFAS concentrations, resulting in relatively weak correlations between maternal and child PFAS concentrations for samples collected in early childhood. Considering that more than half of our study children had neurodevelopmental concerns, the generalizability of our findings might be limited.

We examined relationships between prenatal dietary patterns and child autism-related outcomes, including parent-reported clinician diagnoses of autism spectrum disorder (ASD) and Social Responsiveness Scale (SRS-2) scores, in up to 6084 participants (with analytic samples ranging from 1671 to 4128 participants) from 14 cohorts in the Environmental Influences on Child Health Outcomes (ECHO) consortium. Associations between quartiles of the Healthy Eating Index (HEI-2015), the Alternative Healthy Eating Index modified for Pregnancy (AHEI-P), and the Empirical Dietary Inflammatory Pattern (EDIP), calculated based on reported prenatal diet, and outcomes were examined using crude and multivariable regression (quantile for SRS scores and logistic for diagnosis). In adjusted models, the higher quartile of prenatal HEI score was associated with lower SRS scores (Q4 vs. Q1 β for median quantile = -3.41 95% CI = -5.15, -1.26). A similar association was observed for the AHEI-P score when adjusting for total calories (Q4 vs. Q1 β = -2.52 95% -4.59, -0.45). There were no significant associations of prenatal diet with ASD diagnosis. Findings from this large U.S.-based study do not suggest strong associations between prenatal dietary patterns and ASD-related outcomes, although subtle associations with broader traits suggest the need to further consider how prenatal diet may relate to ASD-related phenotypes.

Exposure to air pollutants has been associated with adverse health outcomes in adults and children who were prenatally exposed. In addition to reducing exposure to air pollutants, it is important to identify their biologic targets in order to mitigate the health consequences of exposure. One molecular change associated with prenatal exposure to air pollutants is DNA methylation (DNAm), which has been associated with changes in placenta and cord blood tissues at birth. However, little is known about how air pollution exposure impacts the sperm epigenome, which could provide important insights into the mechanism of transmission to offspring. In the present study, we explored whether exposure to particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, nitrogen dioxide (NO2), or ozone (O3) was associated with DNAm in sperm contributed by participants in the Early Autism Risk Longitudinal Investigation prospective pregnancy cohort. Air pollution exposure measurements were calculated as the average exposure for each pollutant measured within 4 weeks prior to the date of sample collection. Using array-based genome-scale methylation analyses, we identified 80, 96, 35, and 67 differentially methylated regions (DMRs) significantly associated with particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, NO2, and O3, respectively. While no DMRs were associated with exposure to all four pollutants, we found that genes overlapping exposure-related DMRs had a shared enrichment for gene ontology biological processes related to neurodevelopment. Together, these data provide compelling support for the hypothesis that paternal exposure to air pollution impacts DNAm in sperm, particularly in regions implicated in neurodevelopment.

BackgroundPrenatal exposure to metals is hypothesized to be associated with child autism. We aim to investigate the joint and individual effects of prenatal exposure to urine metals including lead (Pb), mercury (Hg), manganese (Mn), and selenium (Se) on child Social Responsiveness Scale (SRS) scores.MethodsWe used data from 2 cohorts enriched for likelihood of autism spectrum disorder (ASD): Early Autism Risk Longitudinal Investigation (EARLI) and the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) studies. Metal concentrations were measured in urine collected during pregnancy. We used Bayesian Kernel Machine Regression and linear regression models to investigate both joint and independent associations of metals with SRS Z-scores in each cohort. We adjusted for maternal age at delivery, interpregnancy interval, maternal education, child race/ethnicity, child sex, and/or study site.ResultsThe final analytic sample consisted of 251 mother-child pairs. When Pb, Hg, Se, and Mn were at their 75th percentiles, there was a 0.03 increase (95% credible interval [CI]: -0.11, 0.17) in EARLI and 0.07 decrease (95% CI: -0.29, 0.15) in MARBLES in childhood SRS Z-scores, compared to when all 4 metals were at their 50th percentiles. In both cohorts, increasing concentrations of Pb were associated with increasing values of SRS Z-scores, fixing the other metals to their 50th percentiles. However, all the 95% credible intervals contained the null.ConclusionsThere were no clear monotonic associations between the overall prenatal metal mixture in pregnancy and childhood SRS Z-scores at 36 months. There were also no clear associations between individual metals within this mixture and childhood SRS Z-scores at 36 months. The overall effects of the metal mixture and the individual effects of each metal within this mixture on offspring SRS Z-scores might be heterogeneous across child sex and cohort. Further studies with larger sample sizes are warranted.

BackgroundWidespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results.ObjectivesWe conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex.MethodsWe included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as log2-transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex.ResultsThree OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in >85% of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling=1.07; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect=1.25; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age z-scores (β for detect vs. nondetect=0.04-0.07); other chemicals showed null associations.DiscussionIn the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.

ObjectiveThis cohort study assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized that several would be associated with emotional, cognitive, and behavioral dysregulation in youth.MethodThe Environmental influences on Child Health Outcomes (ECHO) is a research consortium of 69 pediatric longitudinal cohorts. A subset of 18 cohorts that had both Child Behavior Checklist (CBCL) data on children (6-18 years) and information on perinatal exposures including maternal prenatal infections was used. Children were classified as having the CBCL-Dysregulation Profile (CBCL-DP) if the sum of their T scores for 3 CBCL subscales (attention, anxious/depressed, and aggression) was ≥180. Primary exposures were perinatal factors associated with maternal and/or neonatal inflammation, and associations between these and outcome were assessed.ResultsApproximately 13.4% of 4,595 youth met criteria for CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with CBCL-DP (35%) were born to mothers with prenatal infections compared with 28% of youth without CBCL-DP. Adjusted odds ratios indicated the following were significantly associated with dysregulation: having a first-degree relative with a psychiatric disorder; being born to a mother with lower educational attainment, who was obese, had any prenatal infection, and/or who smoked tobacco during pregnancy.ConclusionIn this large study, a few modifiable maternal risk factors with established roles in inflammation (maternal lower education, obesity, prenatal infections, and smoking) were strongly associated with CBCL-DP and could be targets for interventions to improve behavioral outcomes of offspring.Diversity & inclusion statementWe worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

BackgroundPhthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth.ObjectivesWe investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity.MethodsWe pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth.ResultsIn comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants.ConclusionsPhthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Children on the autism spectrum have been shown to have immune dysregulation that often correlates with behavioral deficits. The role of the post-natal environment in this dysregulation is an area of active investigation. We examined the association between plasma levels of polybrominated diphenyl ether (PBDE) and immune cell function in age-matched autistic children and non-autistic controls. Plasma from children on the autism spectrum (n = 38) and typically developing controls (TD; n = 60) were analyzed for 14 major PBDE congeners. Cytokine/chemokine production was measured in peripheral blood mononuclear cell (PBMC) supernatants with and without ex vivo BDE-49 exposure. Total plasma concentration (∑PBDE14) and individual congener levels were also correlated with T cell function. ∑PBDE14 did not differ between diagnostic groups but correlated with reduced immune function in children on the autism spectrum. In autistic children, IL-2 and IFN-γ production was reduced in association with several individual BDE congeners, especially BDE-49 (p = 0.001). Furthermore, when PBMCs were exposed ex vivo to BDE-49, cells from autistic children produced elevated levels of IL-6, TNF-α, IL-1β, MIP-1α and MCP-1 (p

Abstract Background Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. Methods We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. Results Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. Limitations. The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. Conclusions We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.

Abstract The application of extracellular vesicles (EVs) as therapeutics or nanocarriers in cell‐free therapies necessitates meticulous evaluations of different features, including their identity, bioactivity, batch‐to‐batch reproducibility, and stability. Given the inherent heterogeneity in EV preparations, this assessment demands sensitive functional assays to provide key quality control metrics, complementing established methods to ensure that EV preparations meet the required functionality and quality standards. Here, we introduce the detectEV assay, an enzymatic‐based approach for assessing EV luminal cargo bioactivity and membrane integrity. This method is fast, cost‐effective, and quantifiable through enzymatic units. Utilizing microalgae‐derived EVs, known as nanoalgosomes, as model systems, we optimised the assay parameters and validated its sensitivity and specificity in quantifying the enzymatic activity of esterases within the EV lumen while also evaluating EV membrane integrity. Compared to conventional methods that assess physicochemical features of EVs, our single‐step analysis efficiently detects batch‐to‐batch variations by evaluating changes in luminal cargo bioactivity and integrity across various EV samples, including differences under distinct storage conditions and following diverse isolation and exogenous loading methods, all using small sample sizes. The detectEV assay's application to various human‐derived EV types demonstrated its versatility and potential universality. Additionally, the assay effectively predicted EV functionality, such as the antioxidant activity of different nanoalgosome batches. Our findings underscore the detectEV assay's utility in comprehensive characterization of EV functionality and integrity, enhancing batch‐to‐batch reproducibility and facilitating their therapeutic applications.

Abstract Due to their intercellular communication properties and involvement in a wide range of biological processes, extracellular vesicles (EVs) are increasingly being studied and exploited for different applications. Nevertheless, their complex nature and heterogeneity, as well as the challenges related to their purification and characterization procedures, require a cautious assessment of the qualitative and quantitative parameters that need to be monitored. This translates into a multitude of choices and putative solutions that any EV researcher must confront in both research and translational environments. In this respect, decision‐making tools may help assess various options, weigh pros and cons, and ultimately arrive at a thought‐out decision that considers both the best fit‐to‐source and fit‐to‐scope EV application(s). Here, we present a multi‐criteria EV decision‐making grid (EV‐DMG) as a novel, efficient, customizable, and easy‐to‐use tool to support EV research and innovation. By identifying and weighing key assessment criteria for comparing distinct EV‐based preparations and related processes, our EV‐DMG may assist any EV community member in making informed, traceable, and reproducible decisions regarding the management of EV sources or samples. Ultimately, this EV‐DMG may guide the adoption of the most suitable EV production and analytical pipelines for targeting a defined aim or application.

Summary: Patients with focal temporal lobe seizures often experience loss of consciousness associated with cortical slow waves, like those in deep sleep. Previous work in rat models suggests that decreased subcortical arousal causes depressed cortical function during focal seizures. However, these studies were performed under light anesthesia, making it impossible to correlate conscious behavior with physiology. We show in an awake mouse model that electrically induced focal seizures in the hippocampus cause impaired behavioral responses to auditory stimuli, cortical slow waves, and reduced mean cortical high-frequency activity. Behavioral responses are related to cortical cholinergic release at two different timescales. Slow state-related decreases in acetylcholine correlate with overall impaired behavior during seizures. Fast phasic acetylcholine release is related to variable spared or impaired behavioral responses with each auditory stimulus. These findings establish a strong relationship between decreased cortical arousal and impaired consciousness in focal seizures, which may help guide future treatment.

Background: Suicides, overdoses, and drug-related liver diseases (deaths of despair) are greatly elevated in the mining and extraction industries compared to other industries. To better understand the drivers of these deaths, we examined suicide or overdose mortality in relation to age at worker exit among a retrospective cohort of 11,009 male mine workers from the Diesel Exhaust in Miners Study II. Methods: We calculated age-adjusted mortality rates (1947–2015) and estimated hazard ratios (HRs) and 95% Confidence Intervals (CI) for suicide or overdose death in relation to age at worker exit (leaving work). The mining industry curtailed its workforce in the early 1980s due to economic downturn; therefore, separate models were fit for worker exit pre- and post-1980. Results: Suicide deaths peaked between 1980 and 1989 at 67.2 per 100,000, more than double the rate in the general population. The hazard rate for suicide or overdose was 2.56 times higher for inactive versus actively employed workers (95% CI: 1.88, 3.50). Based on 187 suicides or overdoses, associations between younger age at worker exit and suicide or overdose death were null or protective before 1980. However post-1980, those who exited between ages 30–39 years had an elevated risk of death HR = 1.33, 95% CI (0.70, 2.53) and those who exited before age 30 had a HR for suicide or overdose of 1.57 (0.83, 2.96) compared to those who exited work after age 55. Conclusion: Worker exit may contribute to the elevated mortality from suicide or overdose among male mine workers, particularly among younger age groups.

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

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

We examined associations between prenatal oxidative stress (OS) and child autism-related outcomes. Women with an autistic child were followed through a subsequent pregnancy and that younger siblings childhood. Associations between glutathione (GSH), glutathione disulfide (GSSG), 8-oxo-deoxyguanine (8-OHdG), and nitrotyrosine and younger sibling Social Responsiveness Scale (SRS) scores were examined using quantile regression. Increasing GSH:GSSG (suggesting decreasing OS) was associated with minor increases in SRS scores (50th percentile β: 1.78, 95% CI: 0.67, 3.06); no other associations were observed. Results from this cohort with increased risk for autism do not support a strong relationship between OS in late pregnancy and autism-related outcomes. Results may be specific to those with enriched autism risk; future work should consider other timepoints and biomarkers.

BackgroundPrior work has suggested relationships between prenatal intake of certain nutrients and autism.ObjectivesWe examined a broad set of prenatal nutrients and foods using a Bayesian modeling approach.MethodsParticipants were drawn from the Early Autism Risks Longitudinal Investigation (n = 127), a cohort following women with a child with autism through a subsequent pregnancy. Participants were also drawn from the Nurses' Health Study II (NHSII, n = 713), a cohort of United States female nurses, for comparison analyses. In both studies, information on prospectively reported prenatal diet was drawn from food frequency questionnaires, and child autism-related traits were measured by the Social Responsiveness Scale (SRS). Bayesian kernel machine regression was used to examine the combined effects of several nutrients with neurodevelopmental relevance, including polyunsaturated fatty acids (PUFAs), iron, zinc, vitamin D, folate, and other methyl donors, and separately, key food sources of these, in association with child SRS scores in crude and adjusted models.ResultsIn adjusted analyses, the overall mixture effects of nutrients in Early Autism Risks Longitudinal Investigation and foods in both cohorts on SRS scores were not observed, though there was some suggestion of decreasing SRS scores with increasing overall nutrient mixture in NHSII. No associations were observed with folate within the context of this mixture, but holding other nutrients fixed, n-6 PUFAs were associated with lower SRS scores in NHSII. In both cohorts, lower SRS scores were observed with higher intake of some groupings of vegetables, though for differing types of vegetables across cohorts, and some vegetable groups were associated with higher SRS scores in NHSII.ConclusionsOur work extends prior research and suggests the need to further consider prenatal dietary factors from a combined effects perspective. In addition, findings here point to potential differences in nutrient associations based on a family history of autism, which suggests the need to consider gene interactions in future work.

BackgroundLiterature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits.ObjectiveTo evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study.MethodsMaternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs.ResultsHigher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (β = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p'-DDE was associated with lower social deficits (β = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (β = 5.68, 95% CI: 0.18, 11.17; β = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p'-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores.ConclusionsWe observed independent effects of PCB180, PCB187, PBDE47, and p,p' DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.