Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. OBJECTIVES: To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. RESULTS: In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. DISCUSSION: PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.

Incidence rates of childhood asthma with recurrent exacerbations in the US Environmental influences on Child Health Outcomes (ECHO) program.

BACKGROUND: Descriptive epidemiological data on incidence rates (IRs) of asthma with recurrent exacerbations (ARE) are sparse. OBJECTIVES: This study hypothesized that IRs for ARE would vary by time, geography, age, and race and ethnicity, irrespective of parental asthma history. METHODS: The investigators leveraged data from 17,246 children born after 1990 enrolled in 59 US with 1 Puerto Rican cohort in the Environmental Influences on Child Health Outcomes (ECHO) consortium to estimate IRs for ARE. RESULTS: The overall crude IR for ARE was 6.07 per 1000 person-years (95% CI: 5.63-6.51) and was highest for children aged 2-4 years, for Hispanic Black and non-Hispanic Black children, and for those with a parental history of asthma. ARE IRs were higher for 2- to 4-year-olds in each race and ethnicity category and for both sexes. Multivariable analysis confirmed higher adjusted ARE IRs (aIRRs) for children born 2000-2009 compared with those born 1990-1999 and 2010-2017, 2-4 versus 10-19 years old (aIRR = 15.36; 95% CI: 12.09-19.52), and for males versus females (aIRR = 1.34; 95% CI 1.16-1.55). Black children (non-Hispanic and Hispanic) had higher rates than non-Hispanic White children (aIRR = 2.51; 95% CI 2.10-2.99; and aIRR = 2.04; 95% CI: 1.22-3.39, respectively). Children born in the Midwest, Northeast and South had higher rates than those born in the West (P < .01 for each comparison). Children with a parental history of asthma had rates nearly 3 times higher than those without such history (aIRR = 2.90; 95% CI: 2.43-3.46). CONCLUSIONS: Factors associated with time, geography, age, race and ethnicity, sex, and parental history appear to influence the inception of ARE among children and adolescents.

Ambient Air Pollutant Exposures and COVID-19 Severity and Mortality in a Cohort of Patients with COVID-19 in Southern California.

Rationale: Ecological studies have shown air pollution associations with coronavirus disease (COVID-19) outcomes. However, few cohort studies have been conducted. Objectives: To conduct a cohort study investigating the association between air pollution and COVID-19 severity using individual-level data from the electronic medical record. Methods: This cohort included all individuals who received diagnoses of COVID-19 from Kaiser Permanente Southern California between March 1 and August 31, 2020. One-year and 1-month averaged ambient air pollutant (particulate matter ⩽2.5 µm in aerodynamic diameter [PM2.5], NO2, and O3) exposures before COVID-19 diagnosis were estimated on the basis of residential address history. Outcomes included COVID-19-related hospitalizations, intensive respiratory support (IRS), and ICU admissions within 30 days and mortality within 60 days after COVID-19 diagnosis. Covariates included socioeconomic characteristics and comorbidities. Measurements and Main Results: Among 74,915 individuals (mean age, 42.5 years; 54% women; 66% Hispanic), rates of hospitalization, IRS, ICU admission, and mortality were 6.3%, 2.4%, 1.5%, and 1.5%, respectively. Using multipollutant models adjusted for covariates, 1-year PM2.5 and 1-month NO2 average exposures were associated with COVID-19 severity. The odds ratios associated with a 1-SD increase in 1-year PM2.5 (SD, 1.5 µg/m3) were 1.24 (95% confidence interval [CI], 1.16-1.32) for COVID-19-related hospitalization, 1.33 (95% CI, 1.20-1.47) for IRS, and 1.32 (95% CI, 1.16-1.51) for ICU admission; the corresponding odds ratios associated with 1-month NO2 (SD, 3.3 ppb) were 1.12 (95% CI, 1.06-1.17) for hospitalization, 1.18 (95% CI, 1.10-1.27) for IRS, and 1.21 (95% CI, 1.11-1.33) for ICU admission. The hazard ratios for mortality were 1.14 (95% CI, 1.02-1.27) for 1-year PM2.5 and 1.07 (95% CI, 0.98-1.16) for 1-month NO2. No significant interactions with age, sex or ethnicity were observed. Conclusions: Ambient PM2.5 and NO2 exposures may affect COVID-19 severity and mortality.

Asthma clustering methods: a literature-informed application to the children's health study data.

OBJECTIVE: The heterogeneity of asthma has inspired widespread application of statistical clustering algorithms to a variety of datasets for identification of potentially clinically meaningful phenotypes. There has not been a standardized data analysis approach for asthma clustering, which can affect reproducibility and clinical translation of results. Our objective was to identify common and effective data analysis practices in the asthma clustering literature and apply them to data from a Southern California population-based cohort of schoolchildren with asthma. METHODS: As of January 1, 2020, we reviewed key statistical elements of 77 asthma clustering studies. Guided by the literature, we used 12 input variables and three clustering methods (hierarchical clustering, k-medoids, and latent class analysis) to identify clusters in 598 schoolchildren with asthma from the Southern California Children's Health Study (CHS). RESULTS: Clusters of children identified by latent class analysis were characterized by exhaled nitric oxide, FEV1/FVC, FEV1 percent predicted, asthma control and allergy score; and were predictive of control at two year follow up. Clusters from the other two methods were less clinically remarkable, primarily differentiated by sex and race/ethnicity and less predictive of asthma control over time. CONCLUSION: Upon review of the asthma phenotyping literature, common approaches of data clustering emerged. When applying these elements to the Children's Health Study data, latent class analysis clusters-represented by exhaled nitric oxide and spirometry measures-had clinical relevance over time.

Ambient air pollution and COVID-19 incidence during four 2020-2021 case surges.

BACKGROUND: Air pollution exposure may make people more vulnerable to COVID-19 infection. However, previous studies in this area mostly focused on infection before May 2020 and long-term exposure. OBJECTIVE: To assess both long-term and short-term exposure to air pollution and COVID-19 incidence across four case surges from 03/1/2020 to 02/28/2021. METHODS: The cohort included 4.6 million members from a large integrated health care system in southern California with comprehensive electronic medical records (EMR). COVID-19 cases were identified from EMR. Incidence of COVID-19 was computed at the census tract-level among members. Prior 1-month and 1-year averaged air pollutant levels (PM2.5, NO2, and O3) at the census tract-level were estimated based on hourly and daily air quality data. Data analyses were conducted by each wave: 3/1/2020-5/31/2020, 6/1/202-9/30/2020, 10/1/2020-12/31/2020, and 1/1/2021-2/28/2021 and pooled across waves using meta-analysis. Generalized linear mixed effects models with Poisson distribution and spatial autocorrelation were used with adjustment for meteorological factors and census tract-level social and health characteristics. Results were expressed as relative risk (RR) per 1 standard deviation. RESULTS: The cohort included 446,440 COVID-19 cases covering 4609 census tracts. The pooled RRs (95% CI) of COVID-19 incidence associated with 1-year exposures to PM2.5, NO2, and O3 were 1.11 (1.04, 1.18) per 2.3 µg/m3,1.09 (1.02, 1.17) per 3.2 ppb, and 1.06 (1.00, 1.12) per 5.5 ppb respectively. The corresponding RRs (95% CI) associated with prior 1-month exposures were 1.11 (1.03, 1.20) per 5.2 µg/m3 for PM2.5, 1.09 (1.01, 1.17) per 6.0 ppb for NO2 and 0.96 (0.85, 1.08) per 12.0 ppb for O3. CONCLUSION: Long-term PM2.5 and NO2 exposures were associated with increased risk of COVID-19 incidence across all case surges before February 2021. Short-term PM2.5 and NO2 exposures were also associated. Our findings suggest that air pollution may play a role in increasing the risk of COVID-19 infection.

Plasma concentrations of lipophilic persistent organic pollutants and glucose homeostasis in youth populations.

BACKGROUND: Exposure to lipophilic persistent organic pollutants (POPs) is ubiquitous. POPs are metabolic disrupting chemicals and are potentially diabetogenic. METHODS: Using a multi-cohort study including overweight adolescents from the Study of Latino Adolescents at Risk (SOLAR, N = 301, 2001-2012) and young adults from the Southern California Children's Health Study (CHS, N = 135, 2014-2018), we examined associations of POPs and risk factors for type 2 diabetes. SOLAR participants underwent annual visits for a median of 2.2 years and CHS participants performed a single visit, during which a 2-h oral glucose tolerance test was performed. Linear mixed models were used to examine associations between plasma concentrations of POPs [4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE), hexachlorobenzene (HCB), PCBs-153, 138, 118, 180 and PBDEs-154, 153, 100, 85, 47] and changes in glucose homeostasis across age and pubertal stage. RESULTS: In SOLAR, exposure to HCB, PCB-118, and PBDE-153 was associated with dysregulated glucose metabolism. For example, each two-fold increase in HCB was associated with approximately 2 mg/dL higher glucose concentrations at 30 min (p = 0.001), 45 min (p = 0.0006), and 60 min (p = 0.03) post glucose challenge. Compared to individuals with low levels of PCB-118, individuals with high levels exhibited a 4.7 mg/dL (p = 0.02) higher glucose concentration at 15 min and a 3.6 mg/dL (p = 0.01) higher glucose concentration at 30 min. The effects observed with exposure to organochlorine compounds were independent of pubertal stages. PBDE-153 was associated with the development of dysregulated glucose metabolism beginning in late puberty. At Tanner stage 4, exposure to PBDE-153 was associated with a 12.7 mg/dL higher 60-min glucose concentration (p = 0.009) and a 16.1 mg*dl-1*hr-1 higher glucose AUC (p = 0.01). These associations persisted at Tanner 5. In CHS, PBDE-153 and total PBDE were associated with similar increases in glucose concentrations. CONCLUSION: Our results suggest that childhood exposure to lipophilic POPs is associated with dysregulated glucose metabolism.

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity.

Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10-6) and 19 (p = 5.6x10-7). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10-6). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans.

W-TSS: A Wavelet-Based Algorithm for Discovering Time Series Shapelets.

Many approaches to time series classification rely on machine learning methods. However, there is growing interest in going beyond black box prediction models to understand discriminatory features of the time series and their associations with outcomes. One promising method is time-series shapelets (TSS), which identifies maximally discriminative subsequences of time series. For example, in environmental health applications TSS could be used to identify short-term patterns in exposure time series (shapelets) associated with adverse health outcomes. Identification of candidate shapelets in TSS is computationally intensive. The original TSS algorithm used exhaustive search. Subsequent algorithms introduced efficiencies by trimming/aggregating the set of candidates or training candidates from initialized values, but these approaches have limitations. In this paper, we introduce Wavelet-TSS (W-TSS) a novel intelligent method for identifying candidate shapelets in TSS using wavelet transformation discovery. We tested W-TSS on two datasets: (1) a synthetic example used in previous TSS studies and (2) a panel study relating exposures from residential air pollution sensors to symptoms in participants with asthma. Compared to previous TSS algorithms, W-TSS was more computationally efficient, more accurate, and was able to discover more discriminative shapelets. W-TSS does not require pre-specification of shapelet length.

The Dynamic Relationship Between Asthma and Obesity in Schoolchildren.

Asthma and obesity are among the most prevalent chronic health conditions in children. Although there has been compelling evidence of co-occurrence of asthma and obesity, it is uncertain whether asthma contributes to the development of obesity or obesity contributes to the onset of asthma or both. In this study, we used a joint transition modeling approach with cross-lagged structure to understand how asthma and obesity influence each other dynamically over time. Subjects for this study included 5,193 kindergarten and first-grade students enrolled from 13 communities in 2002-2003 in the Southern California Children's Health Study, with up to 10 years of follow-up. We found that nonobese children with diagnosed asthma at a study visit were at 37% higher odds of becoming obese by the next annual visit compared with children without asthma (odds ratio = 1.38; 95% credible interval: 1.12, 1.71). However, the presence of obesity at the current visit was not statistically significantly associated with asthma onset in the next visit (odds ratio = 1.25; 95% credible interval: 0.94, 1.62). In conclusion, childhood asthma appears to drive an increase in the onset of obesity among schoolchildren, while the onset of obesity does not necessarily imply the future onset of asthma, at least in the short term.

Patterns and determinants of exhaled nitric oxide trajectories in schoolchildren over a 7-year period.

Fractional exhaled nitric oxide (F ENO50 ), a marker of allergic airway inflammation, is used in respiratory research and asthma clinical care; however, its trajectory with increasing age during childhood has not been well characterised. We examined F ENO50 longitudinally during a period of important somatic growth to describe trajectories across childhood and adolescence in healthy participants and evaluate clinical factors as potential determinants of trajectories.F ENO50 was collected at six visits over 8 years in a population-based cohort of 1791 schoolchildren without asthma (median age at entry 8.4 years). Smooth sex-specific F ENO50 trajectories were estimated using generalised additive mixed models, with participant-level random effects. We evaluated whether sex-specific trajectories were influenced by race/ethnicity, body mass index (BMI) percentile, allergic rhinitis or puberty.Different F ENO50 patterns were observed by sex in later childhood and several factors were associated with either F ENO50 level or change in F ENO50 as participants aged. F ENO50 -age trajectories were similar by sex until age ∼11.5 years, after which males had greater F ENO50 change than females. This divergence in F ENO50 -age trajectories coincides with puberty. Males with higher starting BMI percentile had attenuated F ENO50 -age slopes. Among males, F ENO50 levels were lower in non-Hispanic white subjects. Among both sexes, participants with rhinitis had higher F ENO50 F ENO50 levels within individuals tracked over time; however, there was considerable variation in F ENO50 patterns across participants.F ENO50 trajectories from longitudinal data provide evidence of sex differences coinciding with puberty, suggesting potential hormone link. Improved understanding of determinants of F ENO50 trajectories is needed to realise the potential for using individualised predicted F ENO50 trajectories.

Understanding the importance of key risk factors in predicting chronic bronchitic symptoms using a machine learning approach.

BACKGROUND: Chronic respiratory symptoms involving bronchitis, cough and phlegm in children are underappreciated but pose a significant public health burden. Efforts for prevention and management could be supported by an understanding of the relative importance of determinants, including environmental exposures. Thus, we aim to develop a prediction model for bronchitic symptoms. METHODS: Schoolchildren from the population-based southern California Children's Health Study were visited annually from 2003 to 2012. Bronchitic symptoms over the prior 12 months were assessed by questionnaire. A gradient boosting model was fit using groups of risk factors (including traffic/air pollution exposures) for all children and by asthma status. Training data consisted of one observation per participant in a random study year (for 50% of participants). Validation data consisted of: (1) a random (later) year in the same participants (within-participant); (2) a random year in participants excluded from the training data (across-participant). RESULTS: At baseline, 13.2% of children had asthma and 18.1% reported bronchitic symptoms. Models performed similarly within- and across-participant. Previous year symptoms/medication use provided much of the predictive ability (across-participant area under the receiver operating characteristic curve (AUC): 0.76 vs 0.78 for all risk factors, in all participants). Traffic/air pollution exposures added modestly to prediction as did body mass index percentile, age and parent stress. CONCLUSIONS: Regardless of asthma status, previous symptoms were the most important predictors of current symptoms. Traffic/air pollution variables contribute modest predictive information, but impact large populations. Methods proposed here could be generalized to personalized exacerbation predictions in future longitudinal studies to support targeted prevention efforts.

Gene Promoter Hypermethylation Detected in Sputum Predicts FEV1 Decline and All-Cause Mortality in Smokers.

RATIONALE: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV1 is a major driver for development of airway obstruction. OBJECTIVES: To assess the effects of methylation of 12 genes on FEV1 decline and of FEV1 decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study]). METHODS: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV1 decline. MEASUREMENTS AND MAIN RESULTS: A dose-dependent relationship between number of genes methylated and FEV1 decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV1 decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P < 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P < 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV1 (by 5.2 ml, P = 0.038) than smoker control subjects. CONCLUSIONS: Gene methylation detected in sputum predicted FEV1 decline, LC incidence, and all-cause mortality in smokers. Rapid FEV1 decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC.

Within-subject effects of environmental and social stressors on pre- and post-partum obesity-related biobehavioral responses in low-income Hispanic women: protocol of an intensive longitudinal study.

BACKGROUND: Disproportionately high rates of maternal overweight and obesity among the Hispanic population before, during, and after pregnancy pose serious health concerns for both mothers (e.g., preeclampsia, gestational diabetes, weight retention) and children (e.g., elevated lifelong obesity risk). A growing body of evidence implicates environmental exposures (e.g., air pollution, metals) and social stressors (e.g., poverty, violence) in contributing to obesity-related biobehavioral processes, such as physical activity, dietary intake, perceived stress, and cortisol regulation. However, current understanding of the role of environmental exposures and social stressors on obesity-related biobehavioral processes is limited by infrequent, inter-individual measurement, and lack of personal exposure monitoring. METHODS: The "Maternal and Developmental Risks from Environmental and Social Stressors" (MADRES) real-time and personal sampling study examines the within-subject day-level effects of environmental and social stressors on maternal pre- and post-partum obesity-related biobehavioral responses. Among a cohort of 65 low-income, Hispanic women in urban Los Angeles, this study uses innovative personal, real-time data capture strategies (e.g., ecological momentary assessment [EMA], personal exposure monitoring, geolocation monitoring, accelerometry) to repeatedly assess obesity-related processes during the 1st and 3rd trimester, and at 4-6 months postpartum. Day-level effects of environmental exposures and social stressors on women's physical activity, diet, perceived stress and salivary cortisol measured across repeated days will be tested using multilevel modeling. DISCUSSION: Hispanic women of childbearing age bear a disproportionately high burden of obesity, and this population is also unduly exposed to numerous obesogenic settings. By using innovative real-time data capture strategies, the current study will uncover the daily impacts of environmental and social stressor exposures on women's obesity-related biobehavioral responses, which over time can lead to excessive gestational weight gain, postpartum weight retention and can pose serious consequences for both mother and child. Findings from the real-time and personal sampling study will identify key mechanistic targets for policy, clinical, and programmatic interventions, with the potential for broad-reaching public health impacts.

Association of Changes in Air Quality With Incident Asthma in Children in California, 1993-2014.

Importance: Exposure to air pollutants is a well-established cause of asthma exacerbation in children; whether air pollutants play a role in the development of childhood asthma, however, remains uncertain. Objective: To examine whether decreasing regional air pollutants were associated with reduced incidence of childhood asthma. Design, Setting, and Participants: A multilevel longitudinal cohort drawn from 3 waves of the Southern California Children's Health Study over a period of air pollution decline. Each cohort was followed up from 4th to 12th grade (8 years): 1993-2001, 1996-2004, and 2006-2014. Final follow-up for these data was June 2014. Population-based recruitment was from public elementary schools. A total of 4140 children with no history of asthma and residing in 1 of 9 Children's Health Study communities at baseline were included. Exposures: Annual mean community-level ozone, nitrogen dioxide, and particulate matter less than 10 µm (PM10) and less than 2.5 µm (PM2.5) in the baseline year for each of 3 cohorts. Main Outcomes and Measures: Prospectively identified incident asthma, collected via questionnaires during follow-up. Results: Among the 4140 children included in this study (mean [SD] age at baseline, 9.5 [0.6] years; 52.6% female [n = 2 179]; 58.6% white [n = 2273]; and 42.2% Hispanic [n = 1686]), 525 incident asthma cases were identified. For nitrogen dioxide, the incidence rate ratio (IRR) for asthma was 0.80 (95% CI, 0.71-0.90) for a median reduction of 4.3 parts per billion, with an absolute incidence rate decrease of 0.83 cases per 100 person-years. For PM2.5, the IRR was 0.81 (95% CI, 0.67-0.98) for a median reduction of 8.1 µg/m3, with an absolute incidence rate decrease of 1.53 cases per 100 person-years. For ozone, the IRR for asthma was 0.85 (95% CI, 0.71-1.02) for a median reduction of 8.9 parts per billion, with an absolute incidence rate decrease of 0.78 cases per 100 person-years. For PM10, the IRR was 0.93 (95% CI, 0.82-1.07) for a median reduction of 4.0 µg/m3, with an absolute incidence rate decrease of 0.46 cases per 100 person-years. Conclusions and Relevance: Among children in Southern California, decreases in ambient nitrogen dioxide and PM2.5 between 1993 and 2014 were significantly associated with lower asthma incidence. There were no statistically significant associations for ozone or PM10.

Exposure to traffic-related air pollution and the composition of the gut microbiota in overweight and obese adolescents.

BACKGROUND: Traffic-related air pollution (TRAP) exposure has been linked to type 2 diabetes and metabolic dysfunction in humans. Animal studies suggest that air pollutants may alter the composition of the gut microbiota, which may negatively impact metabolic health through changes in the composition and/or function of the gut microbiome. OBJECTIVES: The primary aim of this study was to determine whether elevated TRAP exposure was correlated with gut bacterial taxa in overweight and obese adolescents from the Meta-AIR (Metabolic and Asthma Incidence Research) study. The secondary aim was to examine whether gut microbial taxa correlated with TRAP were also correlated with risk factors for type 2 diabetes (e.g., fasting glucose levels). We additionally explored whether correlations between TRAP and these metabolic risk factors could be explained by the relative abundance of these taxa. METHODS: Participants (17-19 years; n=43) were enrolled between 2014 and 2016 from Southern California. The CALINE4 line dispersion model was used to model prior year residential concentrations of nitrogen oxides (NOx) as a marker of traffic emissions. The relative abundance of fecal microbiota was characterized by 16S rRNA sequencing and spearman partial correlations were examined after adjusting for body fat percent. RESULTS: Freeway TRAP was correlated with decreased Bacteroidaceae (r=-0.48; p=0.001) and increased Coriobacteriaceae (r=0.48; p<0.001). These same taxa were correlated with fasting glucose levels, including Bacteroidaceae (r=-0.34; p=0.04) and Coriobacteriaceae (r=0.41; p<0.01). Further, freeway TRAP was positively correlated fasting glucose (r=0.45; p=0.004) and Bacteroidaceae and Coriobacteriaceae explained 24% and 29% of the correlation between TRAP and fasting glucose levels. CONCLUSIONS: Increased TRAP exposure was correlated with gut microbial taxa and fasting glucose levels. Gut microbial taxa that were correlated with TRAP partially explained the correlation between TRAP and fasting glucose levels. These results suggest that exposure to air pollutants may negatively impact metabolic health via alterations in the gut microbiota.

Longitudinal associations of in utero and early life near-roadway air pollution with trajectories of childhood body mass index.

BACKGROUND: Evidence suggests that childhood near-roadway air pollution (NRAP) exposures contribute to increased body mass index (BMI); however, effects of NRAP exposure during the vulnerable periods including in utero and first year of life have yet to be established. In this study, we examined whether exposure to elevated concentrations of NRAP during in utero and/or first year of life increase childhood BMI growth. METHODS: Participants in the Children's Health Study enrolled from 2002 to 2003 with annual visits over a four-year period and who changed residences before study entry were included (n = 2318). Annual height and weight were measured and lifetime residential NRAP exposures including in utero and first year of life periods were estimated by nitrogen oxides (NOx) using the California line-source dispersion model. Linear mixed effects models assessed in utero or first year near-road freeway and non-freeway NOx exposures and BMI growth after adjusting for age, sex, race/ethnicity, parental education, Spanish questionnaire, and later childhood near-road NOx exposure. RESULTS: A two-standard deviation difference in first year of life near-road freeway NOx exposure was associated with a 0.1 kg/m2 (95% confidence interval (CI): 0.03, 0.2) faster increase in BMI growth per year and a 0.5 kg/m2 (95% CI: 0.02, 0.9) higher attained BMI at age 10 years. CONCLUSIONS: Higher exposure to early life NRAP increased the rate of change of childhood BMI and resulted in a higher attained BMI at age 10 years that were independent of later childhood exposures. These findings suggest that elevated early life NRAP exposures contribute to increased obesity risk in children.

Effects of Childhood Asthma on the Development of Obesity among School-aged Children.

RATIONALE: Asthma and obesity often occur together in children. It is unknown whether asthma contributes to the childhood obesity epidemic. OBJECTIVES: We aimed to investigate the effects of asthma and asthma medication use on the development of childhood obesity. METHODS: The primary analysis was conducted among 2,171 nonobese children who were 5-8 years of age at study enrollment in the Southern California Children's Health Study (CHS) and were followed for up to 10 years. A replication analysis was performed in an independent sample of 2,684 CHS children followed from a mean age of 9.7 to 17.8 years. MEASUREMENTS AND MAIN RESULTS: Height and weight were measured annually to classify children into normal, overweight, and obese categories. Asthma status was ascertained by parent- or self-reported physician-diagnosed asthma. Cox proportional hazards models were fitted to assess associations of asthma history with obesity incidence during follow-up. We found that children with a diagnosis of asthma at cohort entry were at 51% increased risk of developing obesity during childhood and adolescence compared with children without asthma at baseline (hazard ratio, 1.51; 95% confidence interval, 1.08-2.10) after adjusting for confounders. Use of asthma rescue medications at cohort entry reduced the risk of developing obesity (hazard ratio, 0.57; 95% confidence interval, 0.33-0.96). In addition, the significant association between a history of asthma and an increased risk of developing obesity was replicated in an independent CHS sample. CONCLUSIONS: Children with asthma may be at higher risk of obesity. Asthma rescue medication use appeared to reduce obesity risk independent of physical activity.

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

RATIONALE: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. OBJECTIVES: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. METHODS: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). MEASUREMENTS AND MAIN RESULTS: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. CONCLUSIONS: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).