Multi-omic integration reveals alterations in nasal mucosal biology that mediate air pollutant effects on allergic rhinitis.

BACKGROUND: Allergic rhinitis is a common inflammatory condition of the nasal mucosa that imposes a considerable health burden. Air pollution has been observed to increase the risk of developing allergic rhinitis. We addressed the hypotheses that early life exposure to air toxics is associated with developing allergic rhinitis, and that these effects are mediated by DNA methylation and gene expression in the nasal mucosa. METHODS: In a case-control cohort of 505 participants, we geocoded participants' early life exposure to air toxics using data from the US Environmental Protection Agency, assessed physician diagnosis of allergic rhinitis by questionnaire, and collected nasal brushings for whole-genome DNA methylation and transcriptome profiling. We then performed a series of analyses including differential expression, Mendelian randomization, and causal mediation analyses to characterize relationships between early life air toxics, nasal DNA methylation, nasal gene expression, and allergic rhinitis. RESULTS: Among the 505 participants, 275 had allergic rhinitis. The mean age of the participants was 16.4 years (standard deviation = 9.5 years). Early life exposure to air toxics such as acrylic acid, phosphine, antimony compounds, and benzyl chloride was associated with developing allergic rhinitis. These air toxics exerted their effects by altering the nasal DNA methylation and nasal gene expression levels of genes involved in respiratory ciliary function, mast cell activation, pro-inflammatory TGF-ß1 signaling, and the regulation of myeloid immune cell function. CONCLUSIONS: Our results expand the range of air pollutants implicated in allergic rhinitis and shed light on their underlying biological mechanisms in nasal mucosa.

Prenatal ambient air pollutant mixture exposure and neurodevelopment in urban children in the Northeastern United States.

BACKGROUND: Studies of prenatal air pollution (AP) exposure on child neurodevelopment have mostly focused on a single pollutant. We leveraged daily exposure data and implemented novel data-driven statistical approaches to assess effects of prenatal exposure to a mixture of seven air pollutants on cognitive functioning in school-age children from an urban pregnancy cohort. METHODS: Analyses included 236 children born at ≥37 weeks gestation. Maternal prenatal daily exposure levels for nitrogen dioxide (NO2), ozone (O3), and constituents of fine particles [elemental carbon (EC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), ammonium (NH4+)] were estimated based on residential addresses using validated satellite-based hybrid models or global 3-D chemical-transport models. Children completed Wide Range Assessment of Memory and Learning (WRAML-2) and Conners' Continuous Performance Test (CPT-II) at 6.5 ± 0.9 years of age. Time-weighted levels for mixture pollutants were estimated using Bayesian Kernel Machine Regression Distributed Lag Models (BKMR-DLMs), with which we also explored the interactions in the exposure-response functions among pollutants. Resulting time-weighted exposure levels were used in Weighted Quantile Sum (WQS) regressions to examine AP mixture effects on outcomes, adjusted for maternal age, education, child sex, and prenatal temperature. RESULTS: Mothers were primarily ethnic minorities (81% Hispanic and/or black) reporting ≤12 years of education (68%). Prenatal AP mixture (per unit increase in WQS estimated AP index) was associated with decreased WRAML-2 general memory (GM; ß = -0.64, 95%CI = -1.40, 0.00) and memory-related attention/concentration (AC; ß = -1.03, 95%CI = -1.78, -0.27) indices, indicating poorer memory functioning, as well as increased CPT-II omission errors (OE; ß = 1.55, 95%CI = 0.34, 2.77), indicating increased attention problems. When stratified by sex, association with AC index was significant among girls, while association with OE was significant among boys. Traffic-related pollutants (NO2, OC, EC) and SO42- were major contributors to these associations. There was no significant evidence of interactions among mixture components. CONCLUSIONS: Prenatal exposure to an AP mixture was associated with child neurocognitive outcomes in a sex- and domain-specific manner.

NICU-based stress response and preterm infant neurobehavior: exploring the critical windows for exposure.

BACKGROUND: Exposure to maternal stress in utero negatively impacts cognitive and behavioral outcomes of children born at term. The neonatal intensive care unit (NICU) can be stressful for preterm infants during a developmental period corresponding to the third trimester of gestation. It is unknown whether stress in the NICU contributes to adverse neurodevelopment among NICU graduates. The aim was to examine the association between salivary cortisol and early neurodevelopment in preterm infants. METHODS: We examined the association between cortisol levels during the NICU hospitalization and subsequent performance on the NICU Network Neurobehavioral Scales (NNNS), estimating time-specific associations and considering sex differences. RESULTS: Eight hundred and forty salivary cortisol levels were measured from 139 infants. Average cortisol levels were inversely associated with NNNS Regulation scores for both male and female infants (ß = -0.19; 95% CI: -0.44, -0.02). Critical developmental windows based on postmenstrual age were identified, with cortisol measured <30 weeks PMA positively associated with Habituation and Lethargy scores (ß = 0.63-1.04). Critical developmental windows based on chronological age were identified, with cortisol measured in the first week of life inversely associated with Attention score (ß = -1.01 for females; -0.93 for males). CONCLUSIONS: Stress in the NICU at specific developmental time points may impact early preterm infant neurodevelopment. IMPACT: Stress in the neonatal intensive care unit can impact the neurodevelopmental trajectory of premature infants. The impact of stress is different at different points in development. The impact of stress is sexually dimorphic.

Prenatal Ambient Ultrafine Particle Exposure and Childhood Asthma in the Northeastern United States.

Rationale: Ambient ultrafine particles (UFPs; with an aerodynamic diameter < 0.1 µm) may exert greater toxicity than other pollution components because of their enhanced oxidative capacity and ability to translocate systemically. Studies examining associations between prenatal UFP exposure and childhood asthma remain sparse. Objectives: We used daily UFP exposure estimates to identify windows of susceptibility of prenatal UFP exposure related to asthma in children, accounting for sex-specific effects. Methods: Analyses included 376 mother-child dyads followed since pregnancy. Daily UFP exposure during pregnancy was estimated by using a spatiotemporally resolved particle number concentration prediction model. Bayesian distributed lag interaction models were used to identify windows of susceptibility for UFP exposure and examine whether effect estimates varied by sex. Incident asthma was determined at the first report of asthma (3.6 ± 3.2 yr). Covariates included maternal age, education, race, and obesity; child sex; nitrogen dioxide (NO2) and temperature averaged over gestation; and postnatal UFP exposure. Measurements and Main Results: Women were 37.8% Black and 43.9% Hispanic, with 52.9% reporting having an education at the high school level or lower; 18.4% of children developed asthma. The cumulative odds ratio (95% confidence interval) for incident asthma per doubling of the UFP exposure concentration across pregnancy was 4.28 (1.41-15.7), impacting males and females similarly. Bayesian distributed lag interaction models indicated sex differences in the windows of susceptibility, with the highest risk of asthma seen in females exposed to higher UFP concentrations during late pregnancy. Conclusions: Prenatal UFP exposure was associated with asthma development in children, independent of correlated ambient NO2 and temperature. Findings will benefit future research and policy-makers who are considering appropriate regulations to reduce the adverse effects of UFPs on child respiratory health.

Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex.

INTRODUCTION: In utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences. METHODS: Women who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n = 423 for analyses). Mothers' prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models. RESULTS: In models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4-9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14-19 and 34-36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys. CONCLUSIONS: Increased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.

Bayesian distributed lag interaction models to identify perinatal windows of vulnerability in children's health.

Epidemiological research supports an association between maternal exposure to air pollution during pregnancy and adverse children's health outcomes. Advances in exposure assessment and statistics allow for estimation of both critical windows of vulnerability and exposure effect heterogeneity. Simultaneous estimation of windows of vulnerability and effect heterogeneity can be accomplished by fitting a distributed lag model (DLM) stratified by subgroup. However, this can provide an incomplete picture of how effects vary across subgroups because it does not allow for subgroups to have the same window but different within-window effects or to have different windows but the same within-window effect. Because the timing of some developmental processes are common across subpopulations of infants while for others the timing differs across subgroups, both scenarios are important to consider when evaluating health risks of prenatal exposures. We propose a new approach that partitions the DLM into a constrained functional predictor that estimates windows of vulnerability and a scalar effect representing the within-window effect directly. The proposed method allows for heterogeneity in only the window, only the within-window effect, or both. In a simulation study we show that a model assuming a shared component across groups results in lower bias and mean squared error for the estimated windows and effects when that component is in fact constant across groups. We apply the proposed method to estimate windows of vulnerability in the association between prenatal exposures to fine particulate matter and each of birth weight and asthma incidence, and estimate how these associations vary by sex and maternal obesity status in a Boston-area prospective pre-birth cohort study.

Maternal Lifetime Trauma and Birthweight: Effect Modification by In Utero Cortisol and Child Sex.

OBJECTIVES: To evaluate associations between maternal lifetime traumatic stress and offspring birthweight and examine modifying effects of third trimester cortisol and fetal sex. STUDY DESIGN: Analyses included 314 mother-infant dyads from an ethnically mixed pregnancy cohort. Maternal lifetime trauma was reported via the Life Stressor Checklist-Revised. Fenton birthweight for gestational age z-scores (BWGA-z) were calculated. A 3-cm scalp-nearest maternal hair segment collected at birth was assayed to reflect cumulative third trimester cortisol secretion. Multivariable regression was used to investigate associations between maternal lifetime trauma and BWGA-z and examine 2- and 3-way interactions with cortisol and fetal sex. Because subjects with low or high cortisol levels could represent susceptible populations, varying coefficient models that relax the linearity assumption on cortisol level were used to assess the modification of maternal lifetime trauma associations with BWGA-z as a function of cortisol. RESULTS: Women were primarily minorities (41% Hispanic, 26% black) with ≤12 years education (63%); 63% reported ≥1 traumatic event. Prenatal cortisol modified the association between maternal lifetime trauma and birthweight. Women with higher lifetime trauma and increased cortisol had significantly lower birthweight infants in males; among males exposed to the 90th percentile of cortisol, a 1-unit increase in trauma score was associated with a 0.19-unit decrease in BWGA-z (95% CI, -0.34 to -0.04). Associations among females were nonsignificant, regardless of cortisol level. CONCLUSIONS: These findings underscore the need to consider complex interactions among maternal trauma, disrupted in utero cortisol production, and fetal sex to fully elucidate intergenerational effects of maternal lifetime trauma.

Prenatal fine particulate exposure associated with reduced childhood lung function and nasal epithelia GSTP1 hypermethylation: Sex-specific effects.

BACKGROUND: In utero exposure to particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) has been linked to child lung function. Overlapping evidence suggests that child sex and exposure timing may modify effects and associations may be mediated through glutathione S-transferase P1 (GSTP1) methylation. METHODS: We prospectively examined associations among prenatal PM2.5 exposure and child lung function and GSTP1 methylation in an urban pregnancy cohort study. We employed a validated satellite-based spatiotemporally resolved prediction model to estimate daily prenatal PM2.5 exposure over gestation. We used Baysian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM2.5 exposure on child lung function and nasal epithelia GSTP1 methylation at age 7 years, and to examine effect modification by child sex. RESULTS: BDLIMs identified a sensitive window for prenatal PM2.5 exposure at 35-40 weeks gestation [cumulative effect estimate (CEE) = - 0.10, 95%CI = - 0.19 to - 0.01, per µg/m3 increase in PM2.5] and at 36-40 weeks (CEE = - 0.12, 95%CI = - 0.20 to - 0.01) on FEV1 and FVC, respectively, in boys. BDLIMs also identified a sensitive window of exposure at 37-40 weeks gestation between higher prenatal PM2.5 exposure and increased GSTP1 percent methylation. The association between higher GSTP1 percent methylation and decreased FEV1 was borderline significant in the sample as a whole (ß = - 0.37, SE = 0.20, p = 0.06) and in boys in stratified analyses (ß = - 0.56, SE = 0.29, p = 0.05). CONCLUSIONS: Prenatal PM2.5 exposure in late pregnancy was associated with impaired early childhood lung function and hypermethylation of GSTPI in DNA isolated from nasal epithelial cells. There was a trend towards higher GSTP1 percent methylation being associated with reduced FEV1. All findings were most evident among boys.

Prenatal Nitrate Exposure and Childhood Asthma. Influence of Maternal Prenatal Stress and Fetal Sex.

RATIONALE: Impact of ambient pollution upon children's asthma may differ by sex, and exposure dose and timing. Psychosocial stress can also modify pollutant effects. These associations have not been examined for in utero ambient nitrate exposure. OBJECTIVES: We implemented Bayesian-distributed lag interaction models to identify sensitive prenatal windows for the influence of nitrate (NO3-) on child asthma, accounting for effect modification by sex and stress. METHODS: Analyses included 752 mother-child dyads. Daily ambient NO3- exposure during pregnancy was derived using a hybrid chemical transport (Geos-Chem)/land-use regression model and natural log transformed. Prenatal maternal stress was indexed by a negative life events score (high [>2] vs. low [≤2]). The outcome was clinician-diagnosed asthma by age 6 years. MEASUREMENTS AND MAIN RESULTS: Most mothers were Hispanic (54%) or black (29%), had a high school education or less (66%), never smoked (80%), and reported low prenatal stress (58%); 15% of children developed asthma. BDILMs adjusted for maternal age, race, education, prepregnancy obesity, atopy, and smoking status identified two sensitive windows (7-19 and 33-40 wk gestation), during which increased NO3- was associated with greater odds of asthma, specifically among boys born to mothers reporting high prenatal stress. Cumulative effects of NO3- across pregnancy were also significant in this subgroup (odds ratio = 2.64, 95% confidence interval = 1.27-5.39; per interquartile range increase in ln NO3-). CONCLUSIONS: Prenatal NO3- exposure during distinct sensitive windows was associated with incident asthma in boys concurrently exposed to high prenatal stress.

Potential for Bias When Estimating Critical Windows for Air Pollution in Children's Health.

Evidence supports an association between maternal exposure to air pollution during pregnancy and children's health outcomes. Recent interest has focused on identifying critical windows of vulnerability. An analysis based on a distributed lag model (DLM) can yield estimates of a critical window that are different from those from an analysis that regresses the outcome on each of the 3 trimester-average exposures (TAEs). Using a simulation study, we assessed bias in estimates of critical windows obtained using 3 regression approaches: 1) 3 separate models to estimate the association with each of the 3 TAEs; 2) a single model to jointly estimate the association between the outcome and all 3 TAEs; and 3) a DLM. We used weekly fine-particulate-matter exposure data for 238 births in a birth cohort in and around Boston, Massachusetts, and a simulated outcome and time-varying exposure effect. Estimates using separate models for each TAE were biased and identified incorrect windows. This bias arose from seasonal trends in particulate matter that induced correlation between TAEs. Including all TAEs in a single model reduced bias. DLM produced unbiased estimates and added flexibility to identify windows. Analysis of body mass index z score and fat mass in the same cohort highlighted inconsistent estimates from the 3 methods.

Prenatal particulate matter exposure and wheeze in Mexican children: Effect modification by prenatal psychosocial stress.

BACKGROUND: Air pollution exposure in childhood is associated with greater incidence and exacerbation of asthma, particularly in children whose parents report high levels of psychological stress. However, this interaction has not been completely elucidated in pregnancy. OBJECTIVE: To examine whether the association between prenatal exposure to particulate matter no larger than 2.5 µm in diameter (PM2.5) and wheeze in children is modified by prenatal stress. METHODS: Mexican women were recruited during pregnancy (N = 552). Residential prenatal daily exposure to PM2.5 was estimated using a satellite-based spatiotemporally resolved prediction model and averaged over trimesters. Maternal stress was indexed by maternal negative life events (NLE) score (range 0-11) ascertained during mid to late pregnancy. NLE scores were dichotomized at the median as low (NLE score ≤ 3) and high (NLE score > 3) stress. Reports of ever wheeze and wheeze in the past 12 months (current wheeze) for children were obtained using the International Study of Asthma and Allergies in Childhood survey at 48 months. The association between prenatal PM2.5 and wheeze was analyzed using a modified Poisson regression and stratified by low vs high stress. RESULTS: Greater PM2.5 exposure during the first trimester was associated with increased risk of current wheeze among children with mothers reporting high prenatal stress (relative risk 1.35, 95% confidence interval 1.00-1.83, per interquartile range increase 3.8 µg/m3) but not among those reporting low stress (relative risk 0.84, 95% confidence interval 0.61-1.16, per interquartile range increase 3.8 µg/m3; P for interaction = .04). CONCLUSION: Increased prenatal stress enhanced the association between PM2.5 exposure in early pregnancy, and child wheeze at 48 months of age. It is important to consider chemical and nonchemical stressors together to more comprehensively characterize children's environmental risk.

Prenatal particulate air pollution exposure and body composition in urban preschool children: Examining sensitive windows and sex-specific associations.

BACKGROUND: Evolving animal studies and limited epidemiological data show that prenatal air pollution exposure is associated with childhood obesity. Timing of exposure and child sex may play an important role in these associations. We applied an innovative method to examine sex-specific sensitive prenatal windows of exposure to PM2.5 on anthropometric measures in preschool-aged children. METHODS: Analyses included 239 children born ≥ 37 weeks gestation in an ethnically-mixed lower-income urban birth cohort. Prenatal daily PM2.5 exposure was estimated using a validated satellite-based spatio-temporal model. Body mass index z-score (BMI-z), fat mass, % body fat, subscapular and triceps skinfold thickness, waist and hip circumferences and waist-to-hip ratio (WHR) were assessed at age 4.0 ± 0.7 years. Using Bayesian distributed lag interaction models (BDLIMs), we examined sex differences in sensitive windows of weekly averaged PM2.5 levels on these measures, adjusting for child age, maternal age, education, race/ethnicity, and pre-pregnancy BMI. RESULTS: Mothers were primarily Hispanic (55%) or Black (26%), had ≤ 12 years of education (66%) and never smoked (80%). Increased PM2.5 exposure 8-17 and 15-22 weeks gestation was significantly associated with increased BMI z-scores and fat mass in boys, but not in girls. Higher PM2.5 exposure 10-29 weeks gestation was significantly associated with increased WHR in girls, but not in boys. Prenatal PM2.5 was not significantly associated with other measures of body composition. Estimated cumulative effects across pregnancy, accounting for sensitive windows and within-window effects, were 0.21 (95%CI = 0.01-0.37) for BMI-z and 0.36 (95%CI = 0.12-0.68) for fat mass (kg) in boys, and 0.02 (95%CI = 0.01-0.03) for WHR in girls, all per µg/m3 increase in PM2.5. CONCLUSIONS: Increased prenatal PM2.5 exposure was more strongly associated with indices of increased whole body size in boys and with an indicator of body shape in girls. Methods to better characterize vulnerable windows may provide insight into underlying mechanisms contributing to sex-specific associations.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents.

INTRODUCTION: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school-age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. METHODS: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right-handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11-14 years old. We examined the relationships of tooth Mn (ln-transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. RESULTS: We found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn × sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye-hand coordination in boys compared to girls in sex-stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right-hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). CONCLUSIONS: This study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex-specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex-specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period.

Subconstructs of the Edinburgh Postnatal Depression Scale in a multi-ethnic inner-city population in the U.S.

The ten-item Edinburgh Postnatal Depression Scale (EPDS) is one of the most widely used self-report measures of postpartum depression. Although originally described as a one-dimensional measure, the recognition that depressive symptoms may be differentially experienced across cultural and racial/ethnic groups has led to studies examining structural equivalence of the EPDS in different populations. Variation of the factor structure remains understudied across racial/ethnic groups of US women. We examined the factor structure of the EPDS assessed 6 months postpartum in 515 women (29% black, 53% Hispanic, 18% white) enrolled in an urban Boston longitudinal birth cohort. Exploratory factor analysis (EFA) identified that a three-factor model, including depression, anxiety, and anhedonia subscales, was the most optimal fit in our sample as a whole and across race/ethnicity. Confirmatory factor analysis (CFA) was used to examine the fit of both the two- and three-factor models reported in prior research. CFA confirmed the best fit for a three-factor model, with minimal differences across race/ethnicity. "Things get on top of me" loaded on the anxiety factor among Hispanics, but loaded on the depression factor in whites and African Americans. These findings suggest that EPDS factor structure may need to be adjusted for diverse samples and warrants further study.

Prenatal Particulate Air Pollution and Asthma Onset in Urban Children. Identifying Sensitive Windows and Sex Differences.

RATIONALE: The influence of particulate air pollution on respiratory health starts in utero. Fetal lung growth and structural development occurs in stages; thus, effects on postnatal respiratory disorders may differ based on timing of exposure. OBJECTIVES: We implemented an innovative method to identify sensitive windows for effects of prenatal exposure to particulate matter with a diameter less than or equal to 2.5 µm (PM2.5) on children's asthma development in an urban pregnancy cohort. METHODS: Analyses included 736 full-term (≥37 wk) children. Each mother's daily PM2.5 exposure was estimated over gestation using a validated satellite-based spatiotemporal resolved model. Using distributed lag models, we examined associations between weekly averaged PM2.5 levels over pregnancy and physician-diagnosed asthma in children by age 6 years. Effect modification by sex was also examined. MEASUREMENTS AND MAIN RESULTS: Most mothers were ethnic minorities (54% Hispanic, 30% black), had 12 or fewer years of education (66%), and did not smoke in pregnancy (80%). In the sample as a whole, distributed lag models adjusting for child age, sex, and maternal factors (education, race and ethnicity, smoking, stress, atopy, prepregnancy obesity) showed that increased PM2.5 exposure levels at 16-25 weeks gestation were significantly associated with early childhood asthma development. An interaction between PM2.5 and sex was significant (P = 0.01) with sex-stratified analyses showing that the association exists only for boys. CONCLUSIONS: Higher prenatal PM2.5 exposure at midgestation was associated with asthma development by age 6 years in boys. Methods to better characterize vulnerable windows may provide insight into underlying mechanisms.

Sensitive development windows of prenatal air pollution and cognitive functioning in preschool age Mexican children.

Introduction: Neurotoxicity resulting from air pollution is of increasing concern. Considering exposure timing effects on neurodevelopmental impairments may be as important as the exposure dose. We used distributed lag regression to determine the sensitive windows of prenatal exposure to fine particulate matter (PM2.5) on children's cognition in a birth cohort in Mexico. Methods: Analysis included 553 full-term (≥37 weeks gestation) children. Prenatal daily PM2.5 exposure was estimated using a validated satellite-based spatiotemporal model. McCarthy Scales of Children's Abilities (MSCA) were used to assess children's cognitive function at 4-5 years old (lower scores indicate poorer performance). To identify susceptibility windows, we used Bayesian distributed lag interaction models to examine associations between prenatal PM2.5 levels and MSCA. This allowed us to estimate vulnerable windows while testing for effect modification. Results: After adjusting for maternal age, socioeconomic status, child age, and sex, Bayesian distributed lag interaction models showed significant associations between increased PM2.5 levels and decreased general cognitive index scores at 31-35 gestation weeks, decreased quantitative scale scores at 30-36 weeks, decreased motor scale scores at 30-36 weeks, and decreased verbal scale scores at 37-38 weeks. Estimated cumulative effects (CE) of PM2.5 across pregnancy showed significant associations with general cognitive index (CE^ = -0.35, 95% confidence interval [CI] = -0.68, -0.01), quantitative scale (CE^ = -0.27, 95% CI = -0.74, -0.02), motor scale (CE^ = -0.25, 95% CI = -0.44, -0.05), and verbal scale (CE^ = -0.2, 95% CI = -0.43, -0.02). No significant sex interactions were observed. Conclusions: Prenatal exposure to PM2.5, particularly late pregnancy, was inversely associated with subscales of MSCA. Using data-driven methods to identify sensitive window may provide insight into the mechanisms of neurodevelopmental impairment due to pollution.

Prenatal Ambient Air Pollutant Mixture Exposure and Early School-age Lung Function.

Research linking prenatal ambient air pollution with childhood lung function has largely considered one pollutant at a time. Real-life exposure is to mixtures of pollutants and their chemical components; not considering joint effects/effect modification by co-exposures contributes to misleading results. Methods: Analyses included 198 mother-child dyads recruited from two hospitals and affiliated community health centers in Boston, Massachusetts, USA. Daily prenatal pollutant exposures were estimated using satellite-based hybrid chemical-transport models, including nitrogen dioxide(NO2), ozone(O3), and fine particle constituents (elemental carbon [EC], organic carbon [OC], nitrate [NO3 -], sulfate [SO4 2-], and ammonium [NH4 +]). Spirometry was performed at age 6.99 ± 0.89 years; forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and forced mid-expiratory flow (FEF25-75) z-scores accounted for age, sex, height, and race/ethnicity. We examined associations between weekly-averaged prenatal pollution mixture levels and outcomes using Bayesian Kernel Machine Regression-Distributed Lag Models (BKMR-DLMs) to identify susceptibility windows for each component and estimate a potentially complex mixture exposure-response relationship including nonlinear effects and interactions among exposures. We also performed linear regression models using time-weighted-mixture component levels derived by BKMR-DLMs adjusting for maternal age, education, perinatal smoking, and temperature. Results: Most mothers were Hispanic (63%) or Black (21%) with ≤12 years of education (67%). BKMR-DLMs identified a significant effect for O3 exposure at 18-22 weeks gestation predicting lower FEV1/FVC. Linear regression identified significant associations for O3, NH4 +, and OC with decreased FEV1/FVC, FEV1, and FEF25-75, respectively. There was no evidence of interactions among pollutants. Conclusions: In this multi-pollutant model, prenatal O3, OC, and NH4 + were most strongly associated with reduced early childhood lung function.

Longitudinal assessment of maternal depression and early childhood asthma and wheeze: Effect modification by child sex.

BACKGROUND: Studies report associations between maternal mental health and adverse respiratory outcomes in children; however, the impact of timing and duration of maternal distress remains understudied. We sought to longitudinally examine associations between maternal depression and childhood asthma and wheeze, and explore sex differences. METHODS: Maternal depression (n = 601) was assessed using the Edinburgh Depression Scale questionnaire, dichotomized at a clinically relevant cutoff (>12) (a) during pregnancy, (b) postpartum, and (c) postpartum and subsequent time points postnatally (recurrent depression). Report of wheeze in the past 12 months (current wheeze) and asthma were obtained using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire at 48 and 72 months. Associations were analyzed using a modified Poisson regression adjusted for covariates, and in interaction models. RESULTS: Both postpartum and recurrent depression were associated with higher risk of current wheeze (relative risk [RR]: 1.87, 95% confidence interval [CI]: 1.21, 2.90; RR: 2.41, 95% CI: 1.53, 3.79) and asthma at 48 months (RR: 2.42, 95% CI: 1.01, 5.84; RR: 2.45, 95% CI: 1.02, 5.84). In interaction analyses, associations were stronger in females. Recurrent depression was associated with a higher risk of current wheeze at 48 months in females (RR: 4.34, 95% CI: 2.02, 9.32) when compared to males (RR: 1.89, 95% CI: 1.05, 3.39). CONCLUSIONS: Postpartum and recurrent depression were associated with a higher risk of wheeze and asthma in children. Understanding the temporal- and sex-specific effects of maternal depression may better inform prevention strategies.

KERNEL MACHINE AND DISTRIBUTED LAG MODELS FOR ASSESSING WINDOWS OF SUSCEPTIBILITY TO ENVIRONMENTAL MIXTURES IN CHILDREN'S HEALTH STUDIES.

Exposures to environmental chemicals during gestation can alter health status later in life. Most studies of maternal exposure to chemicals during pregnancy have focused on a single chemical exposure observed at high temporal resolution. Recent research has turned to focus on exposure to mixtures of multiple chemicals, generally observed at a single time point. We consider statistical methods for analyzing data on chemical mixtures that are observed at a high temporal resolution. As motivation, we analyze the association between exposure to four ambient air pollutants observed weekly throughout gestation and birth weight in a Boston-area prospective birth cohort. To explore patterns in the data, we first apply methods for analyzing data on (1) a single chemical observed at high temporal resolution, and (2) a mixture measured at a single point in time. We highlight the shortcomings of these approaches for temporally-resolved data on exposure to chemical mixtures. Second, we propose a novel method, a Bayesian kernel machine regression distributed lag model (BKMR-DLM), that simultaneously accounts for nonlinear associations and interactions among time-varying measures of exposure to mixtures. BKMR-DLM uses a functional weight for each exposure that parameterizes the window of susceptibility corresponding to that exposure within a kernel machine framework that captures non-linear and interaction effects of the multivariate exposure on the outcome. In a simulation study, we show that the proposed method can better estimate the exposure-response function and, in high signal settings, can identify critical windows in time during which exposure has an increased association with the outcome. Applying the proposed method to the Boston birth cohort data, we find evidence of a negative association between organic carbon and birth weight and that nitrate modifies the organic carbon, elemental carbon, and sulfate exposure-response functions.

Prenatal particulate matter exposure and mitochondrial mutational load at the maternal-fetal interface: Effect modification by genetic ancestry.

Prenatal ambient particulate matter (PM2.5) exposure impacts infant development and alters placental mitochondrial DNA abundance. We investigated whether the timing of PM2.5 exposure predicts placental mitochondrial mutational load using NextGen sequencing in 283 multi-ethnic mother-infant dyads. We observed increased PM2.5exposure, particularly during mid- to late-pregnancy and among genes coding for NADH dehydrogenase and subunits of ATP synthase, was associated with a greater amount of nonsynonymous mutations. The strongest associations were observed for participants of African ancestry. Further work is needed to tease out the role of mitochondrial genetics and its impact on offspring development and emerging disease disparities.