Long-term exposure to PM2.5 species and all-cause mortality among Medicare patients using mixtures analyses.

BACKGROUND: The relationship between long-term exposure to PM2.5 and mortality is well-established; however, the role of individual species is less understood. OBJECTIVES: In this study, we assess the overall effect of long-term exposure to PM2.5 as a mixture of species and identify the most harmful of those species while controlling for the others. METHODS: We looked at changes in mortality among Medicare participants 65 years of age or older from 2000 to 2018 in response to changes in annual levels of 15 PM2.5 components, namely: organic carbon, elemental carbon, nickel, lead, zinc, sulfate, potassium, vanadium, nitrate, silicon, copper, iron, ammonium, calcium, and bromine. Data on exposure were derived from high-resolution, spatio-temporal models which were then aggregated to ZIP code. We used the rate of deaths in each ZIP code per year as the outcome of interest. Covariates included demographic, temperature, socioeconomic, and access-to-care variables. We used a mixtures approach, a weighted quantile sum, to analyze the joint effects of PM2.5 species on mortality. We further looked at the effects of the components when PM2.5 mass levels were at concentrations below 8 µg/m3, and effect modification by sex, race, Medicaid status, and Census division. RESULTS: We found that for each decile increase in the levels of the PM2.5 mixture, the rate of all-cause mortality increased by 1.4% (95% CI: 1.3%-1.4%), the rate of cardiovascular mortality increased by 2.1% (95% CI: 2.0%-2.2%), and the rate of respiratory mortality increased by 1.7% (95% CI: 1.5%-1.9%). These effects estimates remained significant and slightly higher when we restricted to lower concentrations. The highest weights for harmful effects were due to organic carbon, nickel, zinc, sulfate, and vanadium. CONCLUSIONS: Long-term exposure to PM2.5 species, as a mixture, increased the risk of all-cause, cardiovascular, and respiratory mortality.

Prenatal exposure to air pollution and BWGA Z-score: Modifying effects of placenta leukocyte telomere length and infant sex.

BACKGROUND: Air pollutants, such as fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), have been associated with adverse birth outcomes, including low birth weight, often exhibiting sex-specific effects. However, the modifying effect of placental telomere length (TL), reflecting cumulative lifetime oxidative stress in mothers, remains unexplored. METHOD: Using data from a Northeastern U.S. birth cohort (n = 306), we employed linear regression and weighted quantile sum models to assess trimester-average air pollution exposures and birth weight for gestational age (BWGA) z-scores. Placental TL, categorized by median split, was considered as an effect modifier. Interactions among air pollutants, placental TL, infant sex, and BWGA z-score were evaluated. RESULTS: Without placental TL as a modifier, only 1st trimester O3 was significantly associated with BWGA z-scores (coefficient: 0.33, 95% CI: 0.03, 0.63). In models considering TL interactions, a significant modifying effect was observed between 3rd trimester NO2 and BWGA z-scores (interaction p-value = 0.02). Specifically, a one interquartile range (1-IQR) increase in 3rd trimester NO2 was linked to a 0.28 (95% CI: 0.06, 0.52) change in BWGA z-score among shorter placental TL group, with no significant association among longer TL group. Among male infants, there were significant associations between 3rd trimester PM2.5 exposure and BWGA z-scores in the longer TL group (coefficient: -0.34, 95% CI: -0.61, -0.02), and between 1st trimester O3 exposure and BWGA z-scores among males in the shorter TL group (coefficient: 0.59, 95% CI: 0.06, 1.08). For females, only a negative association in 2nd trimester mixture model was observed within the longer TL group (coefficient: -0.10, 95% CI: -0.21, -0.01). CONCLUSION: These findings highlight the need to consider the complex interactions among prenatal air pollutant exposures, placental TL, and fetal sex to better elucidate those at greatest risk for adverse birth outcomes.

Relative humidity, temperature, and hypertensive disorders of pregnancy: Findings from the Project Viva cohort.

BACKGROUND: Preeclampsia is a multi-system hypertensive disorder of pregnancy that is a leading cause of maternal and fetal morbidity and mortality. Prior studies disagree on the cause and even the presence of seasonal patterns in its incidence. Using unsuitable time windows for seasonal exposures can bias model results, potentially explaining these inconsistencies. OBJECTIVES: We aimed to investigate humidity and temperature as possible causes for seasonal trends in preeclampsia in Project Viva, a prebirth cohort in Boston, Massachusetts, considering only exposure windows that precede disease onset. METHODS: Using the Parameter-elevation Relationships on Independent Slopes Model (PRISM) Climate Dataset, we estimated daily residential temperature and relative humidity (RH) exposures during pregnancy. Our primary multinomial regression adjusted for person-level covariates and season. Secondary analyses included distributed lag models (DLMs) and adjusted for ambient air pollutants including fine particulates (PM2.5). We used Generalized Additive Mixed Models (GAMMs) for systolic blood pressure (SBP) trajectories across hypertensive disorder statuses to confirm exposure timing. RESULTS: While preeclampsia is typically diagnosed late in pregnancy, GAMM-fitted SBP trajectories for preeclamptic and non-preeclamptic women began to diverge at around 20 weeks' gestation, confirming the need to only consider early exposures. In the primary analysis with 1776 women, RH in the early second trimester, weeks 14-20, was associated with significantly higher odds of preeclampsia (OR per IQR increase: 1.81, 95% CI: 1.10, 2.97). The DLM corroborated this window, finding a positive association from weeks 12-20. There were no other significant associations between RH or temperature and preeclampsia or gestational hypertension in any other time period. DISCUSSION: The association between preeclampsia and RH in the early second trimester was robust to model choice, suggesting that RH may contribute to seasonal trends in preeclampsia incidence. Differences between these results and those of prior studies could be attributable to exposure timing differences.

Health benefits of decreases in on-road transportation emissions in the United States from 2008 to 2017.

Decades of air pollution regulation have yielded enormous benefits in the United States, but vehicle emissions remain a climate and public health issue. Studies have quantified the vehicle-related fine particulate matter (PM2.5)-attributable mortality but lack the combination of proper counterfactual scenarios, latest epidemiological evidence, and detailed spatial resolution; all needed to assess the benefits of recent emission reductions. We use this combination to assess PM2.5-attributable health benefits and also assess the climate benefits of on-road emission reductions between 2008 and 2017. We estimate total benefits of $270 (190 to 480) billion in 2017. Vehicle-related PM2.5-attributable deaths decreased from 27,700 in 2008 to 19,800 in 2017; however, had per-mile emission factors remained at 2008 levels, 48,200 deaths would have occurred in 2017. The 74% increase from 27,700 to 48,200 PM2.5-attributable deaths with the same emission factors is due to lower baseline PM2.5 concentrations (+26%), more vehicle miles and fleet composition changes (+22%), higher baseline mortality (+13%), and interactions among these (+12%). Climate benefits were small (3 to 19% of the total). The percent reductions in emissions and PM2.5-attributable deaths were similar despite an opportunity to achieve disproportionately large health benefits by reducing high-impact emissions of passenger light-duty vehicles in urban areas. Increasingly large vehicles and an aging population, increasing mortality, suggest large health benefits in urban areas require more stringent policies. Local policies can be effective because high-impact primary PM2.5 and NH3 emissions disperse little outside metropolitan areas. Complementary national-level policies for NOx are merited because of its substantial impacts-with little spatial variability-and dispersion across states and metropolitan areas.

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

Association of low and high ambient temperature with mortality for cardiorespiratory diseases in Brazil.

Extreme temperatures are a major public health concern, as they have been linked to an increased risk of mortality from circulatory and respiratory diseases. Brazil, a country with vast geographic and climatic variations, is particularly vulnerable to the health impacts of extreme temperatures. In this study, we examined the nationwide (considering 5572 municipalities) association of low and high ambient temperature (1st and 99th percentiles) with daily mortality for circulatory and respiratory diseases in Brazil between 2003 and 2017. We used an extension of the two-stage time-series design. First, we applied a case time series design in combination with distributed lag non-linear modeling (DLMN) framework to assess the association by Brazilian region. Here, the analyses were stratified by sex, age group (15-45, 46-65, and >65 years), and cause of death (respiratory and circulatory mortality). In the second stage, we performed a meta-analysis to estimate pooled effects across the Brazilian regions. Our study population included 1,071,090 death records due to cardiorespiratory diseases in Brazil over the study period. We found increased risk of respiratory and circulatory mortality associated with low and high ambient temperatures. The pooled national results for the whole population (all ages and sex) suggest a relative risk (RR) of 1.27 (95% CI: 1.16; 1.37) and 1.11 (95% CI: 1.01; 1.21) associated with circulatory mortality during cold and heat exposure, respectively. For respiratory mortality, we estimated a RR of 1.16 (95% CI: 1.08; 1.25) during cold exposure and a RR of 1.14 (95% CI: 0.99; 1.28) during heat exposure. The national meta-analysis indicated robust positive associations for circulatory mortality on cold days across several subgroups by sex and age, while only a few subgroups presented robust positive associations for circulatory mortality on warm days and respiratory mortality on both cold and warm days. These findings have important public health implications for Brazil and suggest the need for targeted interventions to mitigate the adverse effects of extreme temperatures on human health.

Measurement error correction for ambient PM2.5 exposure using stratified regression calibration: Effects on all-cause mortality.

BACKGROUND: Previous studies on the impact of measurement error for PM2.5 were mostly simulation studies, did not control for other pollutants, or used a single regression calibration model to correct for measurement error. However, the relationship between actual and error-prone PM2.5 concentration may vary by time and region. We aim to correct the measurement error of PM2.5 predictions using stratified regression calibration and investigate how the measurement error biases the association between PM2.5 and mortality in the Medicare Cohort. METHODS: The "gold-standard" measurements of PM2.5 were defined as daily monitoring data. We regressed daily monitoring PM2.5 on modeled PM2.5 using the simple linear regression by strata of season, elevation, census division and time period. Calibrated PM2.5 was calculated with stratum-specific calibration parameters ß0 (intercept) and ß1 (slope) for each strata and aggregated to annual level. Associations between calibrated and error-prone annual PM2.5 and all-cause mortality among Medicare beneficiaries were estimated with Quasi-Poisson regression models. RESULTS: Across 208 strata, the median of ß0 and ß1 were 0.62 (25% 0.0.20, 75% 1.06) and 0.93 (25% 0.87, 75% 0.99). From calibrated and error-prone PM2.5 data, we estimated that each 10 µg/m3 increase in PM2.5 was respectively associated with 4.9% (95%CI 4.6-5.2) and 4.6% (95%CI 4.4-4.9) increases in the mortality rate among Medicare beneficiaries, conditional on confounders. CONCLUSIONS: Regression calibration parameters of PM2.5 varied by time and region. Using error-prone measures of PM2.5 underestimated the association between PM2.5 and all-cause mortality. Modern exposure models produce relatively small bias.

Short-term air pollution exposure and hospital admissions for cardiorespiratory diseases in Brazil: A nationwide time-series study between 2008 and 2018.

The established evidence associating air pollution with health is limited to populations from specific regions. Further large-scale studies in several regions worldwide are needed to support the literature to date and encourage national governments to act. Brazil is an example of these regions where little research has been performed on a large scale. To address this gap, we conducted a study looking at the relationship between daily PM2.5, NO2, and O3, and hospital admissions for circulatory and respiratory diseases across Brazil between 2008 and 2018. A time-series analytic approach was applied with a distributed lag modeling framework. We used a generalized conditional quasi-Poisson regression model to estimate relative risks (RRs) of the association of each air pollutant with the hospitalization for circulatory and respiratory diseases by sex, age group, and Brazilian regions. Our study population includes 23, 791, 093 hospital admissions for cardiorespiratory diseases in Brazil between 2008 and 2018. Among those, 53.1% are respiratory diseases, and 46.9% are circulatory diseases. Our findings suggest significant associations of ambient air pollution (PM2.5, NO2, and O3) with respiratory and circulatory hospital admissions in Brazil. The national meta-analysis for the whole population showed that for every increase of PM2.5 by 10 µg/m3, there is a 3.28% (95%CI: 2.61; 3.94) increase in the risk of hospital admission for respiratory diseases. For O3, we found positive associations only for some sub-group analyses by age and sex. For NO2, our findings suggest that a 10 ppb increase in this pollutant, there was a 35.26% (95%CI: 24.07; 46.44) increase in the risk of hospital admission for respiratory diseases. This study may better support policymakers to improve the air quality and public health in Brazil.

Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

BACKGROUND: The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical consequences. OBJECTIVES: To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles. METHODS: Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis. RESULTS: We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease. CONCLUSION: Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.

Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.

BACKGROUND: Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources. METHODS: We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways. RESULTS: We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic. CONCLUSIONS: Our findings showed that the effects of PM2.5 on DNAm varied by its PMCs and sources.

Air Pollutants and Asthma Hospitalization in the Medicaid Population.

Rationale: Risk of asthma hospitalization and its disparities associated with air pollutant exposures are less clear within socioeconomically disadvantaged populations, particularly at low degrees of exposure. Objectives: To assess effects of short-term exposures to fine particulate matter (particulate matter with an aerodynamic diameter of ⩽2.5 µm [PM2.5]), warm-season ozone (O3), and nitrogen dioxide (NO2) on risk of asthma hospitalization among national Medicaid beneficiaries, the most disadvantaged population in the United States, and to test whether any subpopulations were at higher risk. Methods: We constructed a time-stratified case-crossover dataset among 1,627,002 hospitalizations during 2000-2012 and estimated risk of asthma hospitalization associated with short-term PM2.5, O3, and NO2 exposures. We then restricted the analysis to hospitalizations with degrees of exposure below increasingly stringent thresholds. Furthermore, we tested effect modifications by individual- and community-level characteristics. Measurements and Main Results: Each 1-µg/m3 increase in PM2.5, 1-ppb increase in O3, and 1-ppb increase in NO2 was associated with 0.31% (95% confidence interval [CI], 0.24-0.37%), 0.10% (95% CI, 0.05 - 0.15%), and 0.28% (95% CI, 0.24 - 0.32%) increase in risk of asthma hospitalization, respectively. Low-level PM2.5 and NO2 exposures were associated with higher risk. Furthermore, beneficiaries with only one asthma hospitalization during the study period or in communities with lower population density, higher average body mass index, longer distance to the nearest hospital, or greater neighborhood deprivation experienced higher risk. Conclusions: Short-term air pollutant exposures increased risk of asthma hospitalization among Medicaid beneficiaries, even at concentrations well below national standards. The subgroup differences suggested individual and contextual factors contributed to asthma disparities under effects of air pollutant exposures.

Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.

Long-Term Association of Air Pollution and Hospital Admissions Among Medicare Participants Using a Doubly Robust Additive Model.

BACKGROUND: Studies examining the nonfatal health outcomes of exposure to air pollution have been limited by the number of pollutants studied and focus on short-term exposures. METHODS: We examined the relationship between long-term exposure to fine particulate matter with an aerodynamic diameter <2.5 micrometers (PM2.5), NO2, and tropospheric ozone and hospital admissions for 4 cardiovascular and respiratory outcomes (myocardial infarction, ischemic stroke, atrial fibrillation and flutter, and pneumonia) among the Medicare population of the United States. We used a doubly robust method for our statistical analysis, which relies on both inverse probability weighting and adjustment in the outcome model to account for confounding. The results from this regression are on an additive scale. We further looked at this relationship at lower pollutant concentrations, which are consistent with typical exposure levels in the United States, and among potentially susceptible subgroups. RESULTS: Long-term exposure to fine PM2.5 was associated with an increased risk of all outcomes with the highest effect seen for stroke with a 0.0091% (95% CI, 0.0086-0.0097) increase in the risk of stroke for each 1-µg/m3 increase in annual levels. This translated to 2536 (95% CI, 2383-2691) cases of hospital admissions with ischemic stroke per year, which can be attributed to each 1-unit increase in fine particulate matter levels among the study population. NO2 was associated with an increase in the risk of admission with stroke by 0.00059% (95% CI, 0.00039-0.00075) and atrial fibrillation by 0.00129% (95% CI, 0.00114-0.00148) per ppb and tropospheric ozone was associated with an increase in the risk of admission with pneumonia by 0.00413% (95% CI, 0.00376-0.00447) per parts per billion. At lower concentrations, all pollutants were consistently associated with an increased risk for all our studied outcomes. CONCLUSIONS: Long-term exposure to air pollutants poses a significant risk to cardiovascular and respiratory health among the elderly population in the United States, with the greatest increase in the association per unit of exposure occurring at lower concentrations.

Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition.

BACKGROUND: Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. METHODS: Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. RESULTS: At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure-but not pulsatile pressure-and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. CONCLUSIONS: This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.

Short-term PM2.5 exposure and early-readmission risk: a retrospective cohort study in North Carolina heart failure patients.

BACKGROUND: Short-term changes in ambient fine particulate matter (PM2.5) increase the risk for unplanned hospital readmissions. However, this association has not been fully evaluated for high-risk patients or examined to determine if the readmission risk differs based on time since discharge. Here we investigate the relation between ambient PM2.5 and 30-day readmission risk in heart failure (HF) patients using daily time windows and examine how this risk varies with respect to time following discharge. METHODS: We performed a retrospective cohort study of 17,674 patients with a recorded HF diagnosis between 2004 and 2016. The cohort was identified using the EPA CARES electronic health record resource. The association between ambient daily PM2.5 (µg/m3) concentration and 30-day readmissions was evaluated using time-dependent Cox proportional hazard models. PM2.5 associated readmission risk was examined throughout the 30-day readmission period and for early readmissions (1-3 days post-discharge). Models for 30-day readmissions included a parametric continuous function to estimate the daily PM2.5 associated readmission hazard. Fine-resolution ambient PM2.5 data were assigned to patient residential address and hazard ratios are expressed per 10 µg/m3 of PM2.5. Secondary analyses examined potential effect modification based on the time after a HF diagnosis, urbanicity, medication prescription, comorbidities, and type of HF. RESULTS: The hazard of a PM2.5-related readmission within 3 days of discharge was 1.33 (95% CI 1.18-1.51). This PM2.5 readmission hazard was slightly elevated in patients residing in non-urban areas (1.43, 95%CI 1.22-1.67) and for HF patients without a beta-blocker prescription prior to the readmission (1.35; 95% CI 1.19-1.53). CONCLUSION: Our findings add to the evidence indicating substantial air quality-related health risks in individuals with underlying cardiovascular disease. Hospital readmissions are key metrics for patients and providers alike. As a potentially modifiable risk factor, air pollution-related interventions may be enacted that might assist in reducing costly and burdensome unplanned readmissions.

PM2.5 exposure during pregnancy is associated with altered placental expression of lipid metabolic genes in a US birth cohort.

Inhalation of ambient PM2.5, shown to be able to cross the placenta, has been linked to adverse obstetric and postnatal metabolic health outcomes. The placenta regulates fetal growth and influences postnatal development via fetal programming. Placental gene expression may be influenced by intrauterine exposures to PM2.5. Herein, we explore whether maternal PM2.5 exposure during pregnancy alters placental gene expression related to lipid and glucose metabolism in a U.S. birth cohort, the Rhode Island Child Health Study (RICHS). Average PM2.5 exposure level was estimated linking residential addresses and satellite data across the three trimesters using spatio-temporal models. Based on Gene Ontology annotations, we curated a list of 657 lipid and glucose metabolism genes. We conducted a two-staged analysis by leveraging placental RNA-Seq data from 148 subjects to identify top dysregulated metabolic genes associated with PM2.5 (Phase I) and then validated the results in placental samples from 415 participants of the cohort using RT-qPCR (Phase II). Associations between PM2.5 and placental gene expression were explored using multivariable linear regression models in the overall population and in sex-stratified analyses. The average level of PM2.5 exposure across pregnancy was 8.0µg/m3, which is below the national standard of 12µg/m3. Phase I revealed that expression levels of 32 out of the curated list of 657 genes were significantly associated with PM2.5 exposure (FDR P<0.01), 28 genes showed differential expression modified by sex of the infant. Five of these genes (ABHD3, ATP11A, CLTCL1, ST6GALNAC4 and PSCA) were validated using RT-qPCR. Associations were stronger in placentas from male births compared to females, indicating a sex-dependent effect. These genes are involved in inflammation, lipid transport, cell-cell communication or cell invasion. Our results suggest that gestational PM2.5 exposure may alter placental metabolic function. However, whether it confers long-term programming effects postnatally, especially in a sex-specific matter, warrants further studies.

Maternal exposure to black carbon and nitrogen dioxide during pregnancy and birth weight: Using machine-learning methods to achieve balance in inverse-probability weights.

BACKGROUND: Low birth weight is associated with increased risks of health problems in infancy and later life. Among the epidemiological analyses suggesting an association between air pollution and birth weight, few have estimated the effects of black carbon (BC) or together with nitrogen dioxide (NO2), and even fewer studies have used causal modelling. METHODS: We examined 1,119,011 birth records between 2001/01/01 and 2015/12/31 from the Massachusetts Birth Registry to investigate causal associations between prenatal exposure to BC and NO2 and birth weight. We calculated mean residential BC and NO2 exposures 0-30, and 31-280 days prior to birth from validated spatial-temporal models. We fit generalized propensity score models with gradient boosting tuned by a new algorithm to achieve covariate balance, then fit marginal structural models with stabilized inverse-probability weights. RESULTS: Throughout pregnancy, the average birth weight would drop by 17.0 g (95% CI: 15.4, 18.6) for an IQR increase of 0.14 µg/m3 in BC and would independently drop by 19.9 g (95% CI: 18.6, 21.3) for an IQR increase of 9.8 ppb in NO2. Most of the negative effects of BC on birth weight are from 0 to 30 days before the delivery date. The estimated odds ratio of low birth weight for every IQR increase during the entire pregnancy was 1.131 (95% CI: 1.106, 1.156) for BC and 1.082 (95% CI: 1.062, 1.103) for NO2. CONCLUSIONS: We found that prenatal exposures to both BC and NO2 were associated with lower birth weight.

Modification of associations between indoor particulate matter and systemic inflammation in individuals with COPD.

RATIONALE: Little is known about personal characteristics and systemic responses to particulate pollution in patients with COPD. OBJECTIVES: Assess whether diabetes, obesity, statins and non-steroidal anti-inflammatory medications (NSAIDs) modify associations between indoor black carbon (BC) and fine particulate matter ≤2.5 µm in diameter (PM2.5) on systemic inflammation and endothelial activation. METHODS: 144 individuals with COPD without current smoking and without major in-home combustion sources were recruited at Veterans Affairs Boston Healthcare System. PM2.5 and BC were measured in each participant's home seasonally for a week (up to 4 times; 482 observations) and plasma biomarkers of systemic inflammation [C-reactive protein (CRP); interleukin-6 (IL-6)] and endothelial activation [soluble vascular adhesion molecule-1 (sVCAM-1)] measured. Linear mixed effects regression with a random intercept was used, and effect modification assessed with multiplicative interaction terms and stratum specific estimates. RESULTS: Median (25%ile, 75%ile) indoor BC and PM2.5 were 0.6 (0.5,0.7) µg/m3 and 6.8 (4.8,10.4) µg/m3, respectively. Although p-values for effect modification were not statistically significant, there were positive associations (%-increase/interquartile range; 95% CI) between CRP and BC greater among non-statin (18.8%; 3.6-36.3) than statin users (11.1%; 2.1-20.9). There were also positive associations greater among non-statin users between PM2.5 and CRP. For IL-6, associations with BC and PM2.5 were also greater among non-statin users. Associations between CRP and BC were greater (20.3%; 4.5-38.5) in persons with diabetes than without diabetes (10.3%; 0.92-20.6) with similar effects of PM2.5. There were no consistent associations that differed based on obesity. Effect modification was not observed for NSAID use, or with any factor considered with sVCAM-1. CONCLUSIONS: Associations between indoor BC and PM2.5 and CRP were greater in patients with diabetes and those not taking statins, and with IL-6 if not taking statins. These results suggest that these characteristics may modify the systemic response to indoor BC and PM2.5 in persons with COPD.

Short term exposure to air pollution and mortality in the US: a double negative control analysis.

RATIONALE: Studies examining the association of short-term air pollution exposure and daily deaths have typically been limited to cities and used citywide average exposures, with few using causal models. OBJECTIVES: To estimate the associations between short-term exposures to fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) and all-cause and cause-specific mortality in multiple US states using census tract or address exposure and including rural areas, using a double negative control analysis. METHODS: We conducted a time-stratified case-crossover study examining the entire population of seven US states from 2000-2015, with over 3 million non-accidental deaths. Daily predictions of PM2.5, O3, and NO2 at 1x1 km grid cells were linked to mortality based on census track or residential address. For each pollutant, we used conditional logistic regression to quantify the association between exposure and the relative risk of mortality conditioning on meteorological variables, other pollutants, and using double negative controls. RESULTS: A 10 µg/m3 increase in PM2.5 exposure at the moving average of lag 0-2 day was significantly associated with a 0.67% (95%CI: 0.34-1.01%) increase in all-cause mortality. 10 ppb increases in NO2 or O3 exposure at lag 0-2 day were marginally associated with and 0.19% (95%CI: -0.01-0.38%) and 0.20 (95% CI-0.01, 0.40), respectively. The adverse effects of PM2.5 persisted when pollution levels were restricted to below the current global air pollution standards. Negative control models indicated little likelihood of omitted confounders for PM2.5, and mixed results for the gases. PM2.5 was also significantly associated with respiratory mortality and cardiovascular mortality. CONCLUSIONS: Short-term exposure to PM2.5 and possibly O3 and NO2 are associated with increased risks for all-cause mortality. Our findings delivered evidence that risks of death persisted at levels below currently permissible.