Associations between prenatal and early-life air pollution exposure and lung function in young children: Exploring influential windows of exposure on lung development.

BACKGROUND: Evidence in the literature suggests that air pollution exposures experienced prenatally and early in life can be detrimental to normal lung development, however the specific timing of critical windows during development is not fully understood. OBJECTIVES: We evaluated air pollution exposures during the prenatal and early-life period in association with lung function at ages 6-9, in an effort to identify potentially influential windows of exposure for lung development. METHODS: Our study population consisted of 222 children aged 6-9 from the Fresno-Clovis metro area in California with spirometry data collected between May 2015 and May 2017. We used distributed-lag non-linear models to flexibly model the exposure-lag-response for monthly average exposure to fine particulate matter (PM2.5) and ozone (O3) during the prenatal months and first three years of life in association with forced vital capacity (FVC), and forced expiratory volume in the first second (FEV1), adjusted for covariates. RESULTS: PM2.5 exposure during the prenatal period and the first 3-years of life was associated with lower FVC and FEV1 assessed at ages 6-9. Specifically, an increase from the 5th percentile of the observed monthly average exposure (7.55 µg/m3) to the median observed exposure (12.69 µg/m3) for the duration of the window was associated with 0.42 L lower FVC (95% confidence interval (CI): -0.82, -0.03) and 0.38 L lower FEV1 (95% CI: -0.75, -0.02). The shape of the lag-response indicated that the second half of pregnancy may be a particularly influential window of exposure. Associations for ozone were not as strong and typically CIs included the null. CONCLUSIONS: Our findings indicate that prenatal and early-life exposures to PM2.5 are associated with decreased lung function later in childhood. Exposures during the latter months of pregnancy may be especially influential.

Traffic-related air pollution is associated with glucose dysregulation, blood pressure, and oxidative stress in children.

BACKGROUND: Metabolic syndrome increases the risk of cardiovascular disease in adults. Antecedents likely begin in childhood and whether childhood exposure to air pollution plays a contributory role is not well understood. OBJECTIVES: To assess whether children's exposure to air pollution is associated with markers of risk for metabolic syndrome and oxidative stress, a hypothesized mediator of air pollution-related health effects. METHODS: We studied 299 children (ages 6-8) living in the Fresno, CA area. At a study center visit, questionnaire and biomarker data were collected. Outcomes included hemoglobin A1c (HbA1c), urinary 8-isoprostane, systolic blood pressure (SBP), and BMI. Individual-level exposure estimates for a set of four pollutants that are constituents of traffic-related air pollution (TRAP) - the sum of 4-, 5-, and 6-ring polycyclic aromatic hydrocarbon compounds (PAH456), NO2, elemental carbon, and fine particulate matter (PM2.5) - were modeled at the primary residential location for 1-day lag, and 1-week, 1-month, 3-month, 6-month, and 1-year averages prior to each participant's visit date. Generalized additive models were used to estimate associations between each air pollutant exposure and outcome. RESULTS: The study population was 53% male, 80% Latinx, 11% Black and largely low-income (6% were White and 3% were Asian/Pacific Islander). HbA1c percentage was associated with longer-term increases in TRAP; for example a 4.42 ng/m3 increase in 6-month average PAH456 was associated with a 0.07% increase (95% CI: 0.01, 0.14) and a 3.62 µg/m3 increase in 6-month average PM2.5 was associated with a 0.06% increase (95% CI: 0.01, 0.10). The influence of air pollutants on blood pressure was strongest at 3 months; for example, a 6.2 ppb increase in 3-month average NO2 was associated with a 9.4 mmHg increase in SBP (95% CI: 2.8, 15.9). TRAP concentrations were not significantly associated with anthropometric or adipokine measures. Short-term TRAP exposure averages were significantly associated with creatinine-adjusted urinary 8-isoprostane. DISCUSSION: Our results suggest that both short- and longer-term estimated individual-level outdoor residential exposures to several traffic-related air pollutants, including ambient PAHs, are associated with biomarkers of risk for metabolic syndrome and oxidative stress in children.

Lung function in woodsmoke-exposed Guatemalan children following a chimney stove intervention.

RATIONALE: Household air pollution (HAP) from solid fuel combustion is a major contributor to the global burden of disease, with considerable impact from respiratory infections in children. The impact of HAP on lung function is unknown. OBJECTIVES: The Childhood Exposure to Respirable Particulate Matter (CRECER) prospective cohort study followed Guatemalan children who participated in the Randomised Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) trial of a chimney stove intervention to determine the effect of early childhood HAP exposure on growth of lung function. METHODS: RESPIRE households with pregnant women or infant children were randomised to receive a chimney stove at the beginning or at the end of the 18-month trial. During CRECER, a subset of these children, as well as children from households with newly installed stoves, were followed with spirometry beginning at age 5. Biomass smoke exposure was measured using personal carbon monoxide tubes. Two-stage regression models were employed to analyse associations with lung function growth. MEASUREMENTS AND MAIN RESULTS: Longitudinal peak expiratory flow (PEF) and FEV1 data were available for 443 and 437 children, respectively, aged 5-8 (mean follow-up 1.3 years). Decreases in PEF growth of 173 mL/min/year (95% CI -341 to -7) and FEV1 of 44 mL/year (95% CI -91 to 4) were observed with stove installation at 18 months compared with stove installation at birth in analyses adjusted for multiple covariates. No statistically significant associations were observed between personal HAP exposure and lung function. CONCLUSIONS: A significant decrease in PEF growth and a large non-significant decrease in FEV1 growth were observed with later stove installation. Additional studies including longer follow-up and cleaner stoves or fuels are needed.

Differential respiratory health effects from the 2008 northern California wildfires: A spatiotemporal approach.

We investigated health effects associated with fine particulate matter during a long-lived, large wildfire complex in northern California in the summer of 2008. We estimated exposure to PM2.5 for each day using an exposure prediction model created through data-adaptive machine learning methods from a large set of spatiotemporal data sets. We then used Poisson generalized estimating equations to calculate the effect of exposure to 24-hour average PM2.5 on cardiovascular and respiratory hospitalizations and ED visits. We further assessed effect modification by sex, age, and area-level socioeconomic status (SES). We observed a linear increase in risk for asthma hospitalizations (RR=1.07, 95% CI=(1.05, 1.10) per 5µg/m(3) increase) and asthma ED visits (RR=1.06, 95% CI=(1.05, 1.07) per 5µg/m(3) increase) with increasing PM2.5 during the wildfires. ED visits for chronic obstructive pulmonary disease (COPD) were associated with PM2.5 during the fires (RR=1.02 (95% CI=(1.01, 1.04) per 5µg/m(3) increase) and this effect was significantly different from that found before the fires but not after. We did not find consistent effects of wildfire smoke on other health outcomes. The effect of PM2.5 during the wildfire period was more pronounced in women compared to men and in adults, ages 20-64, compared to children and adults 65 or older. We also found some effect modification by area-level median income for respiratory ED visits during the wildfires, with the highest effects observed in the ZIP codes with the lowest median income. Using a novel spatiotemporal exposure model, we found some evidence of differential susceptibility to exposure to wildfire smoke.

Diurnal temperature range and short-term mortality in large US communities.

Research has shown that diurnal temperature range (DTR) is significantly associated with mortality and morbidity in regions of Asia; however, few studies have been conducted in other regions such as North America. Thus, we examined DTR effects on mortality in the USA. We used mortality and environmental data from the National Morbidity Mortality Air Pollution Study (NMMAPS). The data are daily mortality, air pollution, and temperature statistics from 95 large US communities collected between 1987 and 2000. To assess community-specific DTR effects on mortality, we used Poisson generalized linear models allowing for over-dispersion. After assessing community-specific DTR effects on mortality, we estimated region- and age-specific effects of DTR using two-level normal independent sampling estimation. We found a significant increase of 0.27 % [95 % confidence intervals (CI), 0.24-0.30 %] in nonaccidental mortality across 95 communities in the USA associated with a 1 °C increase in DTR, controlling for apparent temperature, day of the week, and time trend. This overall effect was driven mainly by effects of DTR on cardiovascular and respiratory mortality in the elderly: Mortality in the above 65 age group increased by 0.39 % (95 % CI, 0.33-0.44 %) and 0.33 % (95 % CI, 0.22-0.44 %), respectively. We found some evidence of regional differences in the effects of DTR on nonaccidental mortality with the highest effects in Southern California [0.31 % (95 % CI, 0.21-0.42 %)] and smallest effects in the Northwest and Upper Midwest regions [0.22 % (95 % CI, 0.11-0.33 %) and 0.22 % (95 % CI, 0.07-0.37 %), respectively]. These results indicate a statistically significant association between DTR and mortality on average for 95 large US communities. The findings indicate that DTR impacts on nonaccidental and cardiovascular-related mortality in most US regions and the elderly population was most vulnerable to the effects of DTR.

Developing small-area predictions for smoking and obesity prevalence in the United States for use in Environmental Public Health Tracking.

BACKGROUND: Globally and in the United States, smoking and obesity are leading causes of death and disability. Reliable estimates of prevalence for these risk factors are often missing variables in public health surveillance programs. This may limit the capacity of public health surveillance to target interventions or to assess associations between other environmental risk factors (e.g., air pollution) and health because smoking and obesity are often important confounders. OBJECTIVES: To generate prevalence estimates of smoking and obesity rates over small areas for the United States (i.e., at the ZIP code and census tract levels). METHODS: We predicted smoking and obesity prevalence using a combined approach first using a lasso-based variable selection procedure followed by a two-level random effects regression with a Poisson link clustered on state and county. We used data from the Behavioral Risk Factor Surveillance System (BRFSS) from 1991 to 2010 to estimate the model. We used 10-fold cross-validated mean squared errors and the variance of the residuals to test our model. To downscale the estimates we combined the prediction equations with 1990 and 2000 U.S. Census data for each of the four five-year time periods in this time range at the ZIP code and census tract levels. Several sensitivity analyses were conducted using models that included only basic terms, that accounted for spatial autocorrelation, and used Generalized Linear Models that did not include random effects. RESULTS: The two-level random effects model produced improved estimates compared to the fixed effects-only models. Estimates were particularly improved for the two-thirds of the conterminous U.S. where BRFSS data were available to estimate the county level random effects. We downscaled the smoking and obesity rate predictions to derive ZIP code and census tract estimates. CONCLUSIONS: To our knowledge these smoking and obesity predictions are the first to be developed for the entire conterminous U.S. for census tracts and ZIP codes. Our estimates could have significant utility for public health surveillance.

Traffic-related air pollution, biomarkers of metabolic dysfunction, oxidative stress, and CC16 in children.

BACKGROUND: Previous research has revealed links between air pollution exposure and metabolic syndrome in adults; however, these associations are less explored in children. OBJECTIVE: This study aims to investigate the association between traffic-related air pollutants (TRAP) and biomarkers of metabolic dysregulation, oxidative stress, and lung epithelial damage in children. METHODS: We conducted cross-sectional analyses in a sample of predominantly Latinx, low-income children (n = 218) to examine associations between air pollutants (nitrogen dioxide (NO2), nitrogen oxides (NOx), elemental carbon, polycyclic aromatic hydrocarbons, carbon monoxide (CO), fine particulates (PM2.5)) and biomarkers of metabolic function (high-density lipoprotein (HDL), hemoglobin A1c (HbA1c), oxidative stress (8-isoprostane), and lung epithelial damage (club cell protein 16 (CC16)). RESULTS: HDL cholesterol showed an inverse association with NO2 and NOx, with the strongest relationship between HDL and 3-month exposure to NO2 (-15.4 mg/dL per IQR increase in 3-month NO2, 95% CI = -27.4, -3.4). 8-isoprostane showed a consistent pattern of increasing values with 1-day and 1-week exposure across all pollutants. Non-significant increases in % HbA1c were found during 1-month time frames and decreasing CC16 in 3-month exposure time frames. CONCLUSION: Our results suggest that TRAP is significantly associated with decreased HDL cholesterol in longer-term time frames and elevated 8-isoprostane in shorter-term time frames. TRAP could have the potential to influence lifelong metabolic patterns, through metabolic effects in childhood.

Altered pulmonary function in children with asthma associated with highway traffic near residence.

Cross-sectional analyses were conducted to evaluate the effects of exposure to highway traffic on pulmonary function in Fresno, California. Traffic and spirometry data were available for 214 children (enrollment ages six to 11 years). Multiple linear regression was used to evaluate the relations between pulmonary function and traffic parameters. Heavy-duty vehicle count was used as a surrogate measure for diesel-related exposures. Pulmonary function was non-significantly associated with longer distance-to-road and non-significantly associated with higher traffic intensity. Evaluation of effect modification by FEF(25-75)/FVC (a measure of intrinsic airway size) showed that all pulmonary function measures of flow were significantly inversely related to a traffic metric that incorporates traffic intensity and roadway proximity. The results indicate that residence proximity to highway traffic is associated with lower pulmonary function among children with asthma, and smaller airway size is an important modifier of the effect of traffic exposure on pulmonary function and a marker of increased susceptibility.

Hin-mediated DNA knotting and recombining promote replicon dysfunction and mutation.

BACKGROUND: The genetic code imposes a dilemma for cells. The DNA must be long enough to encode for the complexity of an organism, yet thin and flexible enough to fit within the cell. The combination of these properties greatly favors DNA collisions, which can knot and drive recombination of the DNA. Despite the well-accepted propensity of cellular DNA to collide and react with itself, it has not been established what the physiological consequences are. RESULTS: Here we analyze the effects of recombined and knotted plasmids in E. coli using the Hin site-specific recombination system. We show that Hin-mediated DNA knotting and recombination (i) promote replicon loss by blocking DNA replication; (ii) block gene transcription; and (iii) cause genetic rearrangements at a rate three to four orders of magnitude higher than the rate for an unknotted, unrecombined plasmid. CONCLUSION: These results show that DNA reactivity leading to recombined and knotted DNA is potentially toxic and may help drive genetic evolution.

Topological information embodied in local juxtaposition geometry provides a statistical mechanical basis for unknotting by type-2 DNA topoisomerases.

Topoisomerases may unknot by recognizing specific DNA juxtapositions. The physical basis of this hypothesis is investigated by considering single-loop conformations in a coarse-grained polymer model. We determine the statistical relationship between the local geometry of a juxtaposition of two chain segments and whether the loop is knotted globally, and ascertain how the knot/unknot topology is altered by a topoisomerase-like segment passage at the juxtaposition. Segment passages at a "free" juxtaposition tend to increase knot probability. In contrast, segment passages at a "hooked" juxtaposition cause more transitions from knot to unknot than vice versa, resulting in a steady-state knot probability far lower than that at topological equilibrium. The reduction in knot population by passing chain segments through a hooked juxtaposition is more prominent for loops of smaller sizes, n, but remains significant even for larger loops: steady-state knot probability is only approximately 2%, and approximately 5% of equilibrium, respectively, for n=100 and 500 in the model. An exhaustive analysis of approximately 6000 different juxtaposition geometries indicates that the ability of a segment passage to unknot correlates strongly with the juxtaposition's "hookedness". Remarkably, and consistent with experiments on type-2 topoisomerases from different organisms, the unknotting potential of a juxtaposition geometry in our polymer model correlates almost perfectly with its corresponding decatenation potential. These quantitative findings suggest that it is possible for topoisomerases to disentangle by acting selectively on juxtapositions with "hooked" geometries.

Air pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia.

We examined whether ischemic heart disease (IHD) hospital admissions were associated with air pollutants in those with and without secondary diagnoses of arrhythmia (ARR) or congestive heart failure (CHF). We assessed the occurrence of increased vulnerability among persons with these conditions to daily variations in ozone, carbon monoxide, nitrogen dioxide, or particulate matter less than or equal to 10 micro m in aerodynamic diameter (PM10). The study population consisted of members of a large health maintenance organization residing in the South Coast Air Basin of California from 1988 to 1995. After adjustment for day of week, study year, and smoothing splines for day of study, temperature, and relative humidity, CO and NO2 were both associated with admissions with the greatest effects for CO. A 1-ppm increase in 8-hr average CO was associated with a 3.60% [95% confidence interval (CI), 1.62-5.63%] increase in same-day IHD admissions in persons with a secondary diagnosis of CHF, a 2.99% (95% CI, 1.80-4.19%) increase in persons with a secondary diagnosis of ARR, and a 1.62% (95% CI, 0.65-2.59%) increase in IHD admissions in persons without either secondary diagnosis. Air pollution was most strongly associated with myocardial infarction hospital admissions. The vulnerability of the secondary CHF subgroup may be due to a greater prevalence of myocardial infarction primary diagnoses and not the modifying effect of CHF. This study suggests that people with IHD and accompanying CHF and/or ARR constitute a sensitive subgroup in relation to the effects of criteria ambient air pollutants associated with motor vehicle combustion.

Evaluation of a heat vulnerability index on abnormally hot days: an environmental public health tracking study.

BACKGROUND: Extreme hot weather conditions have been associated with increased morbidity and mortality, but risks are not evenly distributed throughout the population. Previously, a heat vulnerability index (HVI) was created to geographically locate populations with increased vulnerability to heat in metropolitan areas throughout the United States. OBJECTIVES: We sought to determine whether areas with higher heat vulnerability, as characterized by the HVI, experienced higher rates of morbidity and mortality on abnormally hot days. METHODS: We used Poisson regression to model the interaction of HVI and deviant days (days whose deviation of maximum temperature from the 30-year normal maximum temperature is at or above the 95th percentile) on hospitalization and mortality counts in five states participating in the Environmental Public Health Tracking Network for the years 2000 through 2007. RESULTS: The HVI was associated with higher hospitalization and mortality rates in all states on both normal days and deviant days. However, associations were significantly stronger (interaction p-value < 0.05) on deviant days for heat-related illness, acute renal failure, electrolyte imbalance, and nephritis in California, heat-related illness in Washington, all-cause mortality in New Mexico, and respiratory hospitalizations in Massachusetts. CONCLUSION: Our results suggest that the HVI may be a marker of health vulnerability in general, although it may indicate greater vulnerability to heat in some cases.

Short-term effects of air pollution on wheeze in asthmatic children in Fresno, California.

BACKGROUND: Although studies have demonstrated that air pollution is associated with exacerbation of asthma symptoms in children with asthma, little is known about the susceptibility of subgroups, particularly those with atopy. OBJECTIVE: This study was designed to evaluate our a priori hypothesis that identifiable subgroups of asthmatic children are more likely to wheeze with exposure to ambient air pollution. METHODS: A cohort of 315 children with asthma, 6-11 years of age, was recruited for longitudinal follow-up in Fresno, California (USA). During the baseline visit, children were administered a respiratory symptom questionnaire and allergen skin-prick test. Three times a year, participants completed 14-day panels during which they answered symptom questions twice daily. Ambient air quality data from a central monitoring station were used to assign exposures to the following pollutants: particulate matter ≤ 2.5 µm in aerodynamic diameter, particulate matter between 2.5 and 10 µm in aerodynamic diameter (PM10-2.5), elemental carbon, nitrogen dioxide (NO2), nitrate, and O3. RESULTS: For the group as a whole, wheeze was significantly associated with short-term exposures to NO2 [odds ratio (OR) = 1.10 for 8.7-ppb increase; 95% confidence interval (CI), 1.02-1.20] and PM10-2.5 (OR = 1.11 for 14.7-µg/m3 increase; 95% CI, 1.01-1.22). The association with wheeze was stronger for these two pollutants in children who were skin-test positive to cat or common fungi and in boys with mild intermittent asthma. CONCLUSION: A pollutant associated with traffic emissions, NO2, and a pollutant with bioactive constituents, PM10-2.5, were associated with increased risk of wheeze in asthmatic children living in Fresno, California. Children with atopy to cat or common fungi and boys with mild intermittent asthma were the subgroups for which we observed the largest associations.