Reliability of a short diet and vitamin supplement questionnaire for retrospective collection of maternal nutrient intake.

Background: Gestational nutrition can protect against adverse neurodevelopmental outcomes. Objectives: We developed a short tool for collecting maternal nutritional intake during pregnancy to facilitate research in this area and compared its retrospective use to prospectively-collected food frequency questionnaires (FFQ). Methods: Maternal nutritional intake was retrospectively assessed using three versions (full interview, full self-administered online, and shortened interview) of the Early Life Exposure Assessment Tool (ELEAT) among participants of the MARBLES pregnancy cohort study of younger siblings of autistic children. Retrospective responses were compared with responses to supplement questions and the validated 2005 Block FFQ prospectively collected in MARBLES during pregnancies 2-7 years prior. ELEAT nutrient values were calculated using reported food intake frequencies and nutrient values from the USDA nutrient database. Correlations between retrospectively- and prospectively-reported intake were evaluated using Kappa coefficients, Youden's J, and Spearman Rank Correlation Coefficients (rs). Results: MARBLES FFQ dietary intakes were compared among 54 women who completed the ELEAT full form including 12 online, and among 23 who completed the ELEAT short form. Correlations across most foods were fair to moderate. Most ELEAT quantified nutrient values were moderately correlated (rs = 0.3-0.6) with those on the Block FFQ. Supplement questions in both MARBLES and the ELEAT were completed by 114 women. Kappas were moderate for whether or not supplements were taken, but modest for timing. Correlations varied by version and child diagnosis or concerns, and were higher when mothers completed the ELEAT when their child was 4 years old or younger. Conclusions: With recall up to several years, ELEAT dietary and supplement module responses were modestly to moderately reliable and produced nutrient values moderately correlated with prospectively-collected measures. The ELEAT dietary and vitamin supplements modules can be used to rank participants in terms of intake of several nutrients relevant for neurodevelopment.

Familial Recurrence of Autism: Updates From the Baby Siblings Research Consortium.

OBJECTIVES: Autism spectrum disorder (ASD) is estimated to be ∼10 times higher in children with versus without an autistic sibling in population-based studies. Prospective studies of infant siblings have revealed even higher familial recurrence rates. In the current prospective longitudinal study, we provide updated estimates of familial ASD recurrence using a multinational database of infants with older autistic siblings. METHODS: Data were collated across 18 sites of the Baby Siblings Research Consortium, an international network studying the earliest manifestations of ASD. A total of 1605 infants with an older autistic sibling were followed from early in life to 3 years, when they were classified as ASD or non-ASD. Hierarchical generalized linear modeling, with site as a random effect, was used to examine predictors of recurrence in families and calculate likelihood ratios. RESULTS: A total of 20.2% of siblings developed ASD, which is not significantly higher than the previously reported rate of 18.7%. Male infant sex and >1 older affected sibling were significant predictors of familial recurrence. Proband sex also influenced recurrence rates, with siblings of female probands significantly more likely to develop ASD than siblings of male probands. Race and maternal education were also associated with recurrence in families. CONCLUSIONS: The familial recurrence rate of ASD, as measured in infant sibling studies, has not changed appreciably since previous estimates were made in 2011. Younger siblings of autistic children, particularly those who are male, have an affected female sibling, multiple affected siblings, or are impacted by social inequities, should be closely monitored and promptly referred for diagnostic evaluation.

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Association of Maternal Fish Consumption and Omega-3 Supplement Use During Pregnancy With Child Autism-Related Outcomes: Results from a Cohort Consortium Analysis.

BACKGROUND: Prenatal fish intake is a key source of omega-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: To examine associations of prenatal fish intake and omega-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 (ECHO) 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 omega-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 n=3609 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 (OR=0.84, 95% CI 0.77 to 0.92), and a modest reduction in raw total SRS scores (b=-1.69, 95% CI -3.3 to -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 omega-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (ß=1.98, 95% CI 0.33-3.64). CONCLUSIONS: These results extend prior work by suggesting that prenatal fish intake, but not omega-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low fish intake in the U.S. 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.

Examining the association between prenatal cannabis exposure and child autism traits: A multi-cohort investigation in the environmental influences on child health outcome program.

This study examined the association between prenatal cannabis exposure and autism spectrum disorder (ASD) diagnoses and traits. A total sample of 11,570 children (ages 1-18; 53% male; 25% Hispanic; 60% White) from 34 cohorts of the National Institutes of Health-funded environmental influences on child health outcomes consortium were included in analyses. Results from generalized linear mixed models replicated previous studies showing that associations between prenatal cannabis exposure and ASD traits in children are not significant when controlling for relevant covariates, particularly tobacco exposure. Child biological sex did not moderate the association between prenatal cannabis exposure and ASD. In a large sample and measuring ASD traits continuously, there was no evidence that prenatal cannabis exposure increases the risk for ASD. This work helps to clarify previous mixed findings by addressing concerns about statistical power and ASD measurement.

Newborn Dried Blood Spot Folate in Relation to Maternal Self-reported Folic Acid Intake, Autism Spectrum Disorder, and Developmental Delay.

BACKGROUND: Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined. METHODS: We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes. RESULTS: Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08). CONCLUSION: Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.

Development and Validation of a Novel Placental DNA Methylation Biomarker of Maternal Smoking during Pregnancy in the ECHO Program.

BACKGROUND: Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established. OBJECTIVE: Our aim was to develop biomarkers of MSDP using DNAm measured in placentas (N=96), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost. METHODS: We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, N=426; and the Rhode Island Children's Health Study, N=237. RESULTS: Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only (n=72) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array (R2=0.98). DISCUSSION: To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

Reproducibility between preschool and school-age Social Responsiveness Scale forms in the Environmental influences on Child Health Outcomes program.

Evidence suggests core autism trait consistency in older children, but development of these traits is variable in early childhood. The Social Responsiveness Scale (SRS) measures autism-related traits and broader autism phenotype, with two age-dependent forms in childhood (preschool, 2.5-4.5 years; school age, 4-18 years). Score consistency has been observed within forms, though reliability across forms has not been evaluated. Using data from the Environmental Influences on Child Health Outcomes (ECHO) program (n = 853), preschool, and school-age SRS scores were collected via maternal report when children were an average of 3.0 and 5.8 years, respectively. We compared reproducibility of SRS total scores (T-scores) and agreement above a clinically meaningful cutoff (T-scores ≥ 60) and examined predictors of discordance in cutoff scores across forms. Participant scores across forms were similar (mean difference: 3.3 points; standard deviation: 7), though preschool scores were on average lower than school-age scores. Most children (88%) were classified below the cutoff on both forms, and overall concordance was high (92%). However, discordance was higher in cohorts following younger siblings of autistic children (16%). Proportions of children with an autism diagnoses were also higher among those with discordant scores (27%) than among those with concordant scores (4%). Our findings indicate SRS scores are broadly reproducible across preschool and school-age forms, particularly for capturing broader, nonclinical traits, but also suggest that greater variability of autism-related traits in preschool-age children may reduce reliability with later school-age scores for those in the clinical range.

Neurodevelopment and Metabolism in the Maternal-Placental-Fetal Unit.

Importance: Disturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied. Objective: To investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD). Design, Setting, and Participants: This cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024. Exposures: Quantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery. Main Outcomes and Measures: Using the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD). Results: This analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P < .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group. Conclusions and Relevance: In this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD.

Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Early childhood exposures to phthalates in association with attention-deficit/hyperactivity disorder behaviors in middle childhood and adolescence in the ReCHARGE study.

BACKGROUND: Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. METHODS: This 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. RESULTS: Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (ß per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (ß = 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 (ß = 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. CONCLUSION: Exposure 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.

Food, nutrition, and autism: from soil to fork.

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.

Pre-pregnancy ozone and ultrafine particulate matter exposure during second year of life associated with decreased cognitive and adaptive functioning at aged 2-5 years.

BACKGROUND: This study sought to investigate the association of prenatal and early life exposure to a mixture of air pollutants on cognitive and adaptive outcomes separately in children with or without autism spectrum disorder (ASD). METHODS: Utilizing data from the CHARGE case-control study (birth years: 2000-2016), we predicted daily air concentrations of NO2, O3, and particulate matter <0.1 µm (PM0.1), between 0.1 and 2.5 µm (PM0.1-2.5), and between 2.5 and 10 µm (PM2.5-10) using chemical transport models with ground-based monitor adjustments. Exposures were evaluated for pre-pregnancy, each trimester, and the first two years of life. Individual and combined effects of pollutants were assessed with Vineland Adaptive Behavior Scales (VABS) and Mullen Scales of Early Learning (MSEL), separately for children with ASD (n = 660) and children without ASD (typically developing (TD) and developmentally delayed (DD) combined; n = 753) using hierarchical Bayesian Kernel Machine Regression (BKMR) models with three groups: PM size fractions (PM0.1, PM0.1-2.5, PM2.5-10), NO2, and O3. RESULTS: Pre-pregnancy Ozone was strongly negatively associated with all scores in the non-ASD group (group posterior inclusion probability (gPIP) = 0.83-1.00). The PM group during year 2 was also strongly negatively associated with all scores in the non-ASD group (gPIP = 0.59-0.93), with PM0.1 driving the group association (conditional PIP (cPIP) = 0.73-0.96). Weaker and less consistent associations were observed between PM0.1-2.5 during pre-pregnancy and ozone during year 1 and VABS scores in the ASD group. CONCLUSIONS: These findings prompt further investigation into ozone and ultrafine PM as potential environmental risk factors for neurodevelopment.

Association of Breastfeeding Duration with Neurodevelopmental Outcomes in an Enriched Familial Likelihood Cohort for Autism Spectrum Disorder.

This study aimed to compare the breastfeeding (BF) duration of the younger siblings of children with ASD in an enriched-likelihood cohort for autism spectrum disorder (ASD), and to determine whether longer BF duration was associated with differences in neurodevelopmental outcomes in this cohort. Information on BF practices was collected via surveys in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. Developmental evaluations, including the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, were conducted by expert clinicians. Participants' neurodevelopmental outcome was classified by an algorithm into three groups: typical development, ASD, and non-typical development. The median duration of BF was 10.70 months (interquartile range of 12.07 months). There were no significant differences in the distribution of duration of BF among the three neurodevelopmental outcome categories. Children in this enriched-likelihood cohort who were breastfed for > 12 months had significantly higher scores on cognitive testing compared to those who were breastfed for 0-3 months. There was no significant difference in ASD symptomatology or ASD risk based on BF duration.

"Air That Once Was Breath" Part 1: Wildfire-Smoke-Induced Mechanisms of Airway Inflammation - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Wildfires are a global concern due to their wide-ranging environmental, economic, and public health impacts. Climate change contributes to an increase in the frequency and intensity of wildfires making smoke exposure a more significant and recurring health concern for individuals with airway diseases. Some of the most prominent effects of wildfire smoke exposure are asthma exacerbations and allergic airway sensitization. Likely due to the delayed recognition of its health impacts in comparison with cigarette smoke and industrial or traffic-related air pollution, research on the composition, the mechanisms of toxicity, and the cellular/molecular pathways involved is poor or non-existent. SUMMARY: This review discusses potential underlying pathological mechanisms of wildfire-smoke-related allergic airway disease and asthma. We focused on major gaps in understanding the role of wildfire smoke composition in the development of airway disease and the known and potential mechanisms involving cellular and molecular players of oxidative injury at the epithelial barrier in airway inflammation. We examine how PM2.5, VOCs, O3, endotoxin, microbes, and toxic gases may affect oxidative stress and inflammation in the respiratory mucosal barrier. We discuss the role of AhR in mediating smoke's effects in alarmin release and IL-17A production and how glucocorticoid responsiveness may be impaired by IL-17A-induced signaling and epigenetic changes leading to steroid-resistant severe airway inflammation. KEY MESSAGE: Effective mitigation of wildfire-smoke-related respiratory health effects would require comprehensive research efforts aimed at a better understanding of the immune regulatory effects of wildfire smoke in respiratory health and disease.

"Air That Once Was Breath" Part 2: Wildfire Smoke and Airway Disease - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Population growth and climate change have led to more frequent and larger wildfires, increasing the exposure of individuals to wildfire smoke. Notably, asthma exacerbations and allergic airway sensitization are prominent outcomes of such exposure. SUMMARY: Key research questions relate to determining the precise impact on individuals with asthma, including the severity, duration, and long-term consequences of exacerbations. Identifying specific risk factors contributing to vulnerability, such as age, genetics, comorbidities, or environmental factors, is crucial. Additionally, reliable biomarkers for predicting severe exacerbations need exploration. Understanding the long-term health effects of repeated wildfire smoke exposures in individuals with asthma and addressing healthcare disparities are important research areas. KEY MESSAGES: This review discusses the need for comprehensive research efforts to better grasp wildfire smoke-induced respiratory health, particularly in vulnerable populations such as farmworkers, firefighters, pregnant women, children, the elderly, and marginalized communities. Effective mitigation would require addressing the current limitations we face by supporting research aimed at a better understanding of wildfire smoke-induced airway disease.

Prediction of internalizing and externalizing symptoms in late childhood from attention-deficit/hyperactivity disorder symptoms in early childhood.

Limited analyses based on national samples have assessed whether early attention-deficit/hyperactivity disorder (ADHD) symptoms predict later internalizing and externalizing symptoms in youth and the influence of sex and pubertal timing on subsequent psychiatric symptoms. This study analyzed data (n = 2818) from the Environmental influences on Child Health Outcomes Program national cohort. Analyses used data from early childhood (mean age = 5.3 years) utilizing parent-reported ADHD symptoms to predict rates of internalizing and externalizing symptoms from late childhood/adolescence (mean age = 11.9 years). Within a subsample age at peak height velocity (APHV) acted as a proxy to assess pubertal timing from early childhood (mean age = 5.4 years) to adolescence (mean age = 12.3 years). Early-childhood ADHD symptoms predicted later psychiatric symptoms, including anxiety, depression, aggressive behavior, conduct problems, oppositional defiant disorder, and rule-breaking behavior. Earlier APHV was associated with increased Conduct Disorder symptoms from late childhood to adolescence for females only. A stronger relation between ADHD symptoms and later aggression was observed in females with earlier APHV, whereas this same pattern with aggression, conduct problems and depression was observed in males with later APHV. Clinicians should consider that both young girls and boys with elevated ADHD symptoms, particularly with off-set pubertal timing, may be at risk for later psychiatric symptoms.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.