Antonella Zanobetti

Inhalable metal-rich air particles and histone H3K4 dimethylation and H3K9 acetylation in a cross-sectional study of steel workers.

Background: Epidemiology investigations have linked exposure to ambient and occupational air particulate matter (PM) with increased risk of lung cancer. PM contains carcinogenic and toxic metals, including arsenic and nickel, which have been shown in in vitro studies to induce histone modifications that activate gene expression by inducing open-chromatin states. Whether inhalation of metal components of PM induces histone modifications in human subjects is undetermined. Objectives: We investigated whether the metal components of PM determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich PM. Methods: We determined histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and to total PM was estimated for each study subject. Results: Both H3K4me2 and H3K9ac increased in association with years of employment in the plant (p-trend = 0.04 and 0.006, respectively). H3K4me2 increased in association with air levels of nickel [β = 0.16; 95% confidence interval (CI), 0.03–0.3], arsenic (β = 0.16; 95% CI, 0.02–0.3), and iron (β = 0.14; 95% CI, 0.01–0.26). H3K9ac showed nonsignificant positive associations with air levels of nickel (β = 0.24; 95% CI, –0.02 to 0.51), arsenic (β = 0.21; 95% CI, –0.06 to 0.48), and iron (β = 0.22; 95% CI, –0.03 to 0.47). Cumulative exposures to nickel and arsenic, defined as the product of years of employment by metal air levels, were positively correlated with both H3K4me2 (nickel: β = 0.16; 95% CI, 0.01–0.3; arsenic: β = 0.16; 95% CI, 0.03–0.29) and H3K9ac (nickel: β = 0.27; 95% CI, 0.01–0.54; arsenic: β = 0.28; 95% CI, 0.04–0.51). Conclusions: Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.

Rapid DNA methylation changes after exposure to traffic particles.

RATIONALE Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis. OBJECTIVES We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome. METHODS We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction-pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter < or = 2.5 microm [PM2.5], or sulfate) in multiple time windows (4 h to 7 d) before the examination. We estimated standardized regression coefficients (beta) expressing the fraction of a standard deviation change in DNA methylation associated with a standard deviation increase in exposure. MEASUREMENTS AND MAIN RESULTS Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season. LINE-1 methylation decreased after recent exposure to higher black carbon (beta = -0.11; 95% confidence interval [CI], -0.18 to -0.04; P = 0.002) and PM2.5 (beta = -0.13; 95% CI, -0.19 to -0.06; P < 0.001 for the 7-d moving average). In two-pollutant models, only black carbon, a tracer of traffic particles, was significantly associated with LINE-1 methylation (beta = -0.09; 95% CI, -0.17 to -0.01; P = 0.03). No association was found with Alu methylation (P > 0.12). CONCLUSIONS We found decreased repeated-element methylation after exposure to traffic particles. Whether decreased methylation mediates exposure-related health effects remains to be determined.

Mortality risk attributable to high and low ambient temperature: a multicountry observational study.

Summary Background Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures. Methods We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature–mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5th temperature percentiles. Findings We analysed 74 225 200 deaths in various periods between 1985 and 2012. In total, 7·71% (95% empirical CI 7·43–7·91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80–90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7·29%, 7·02–7·49) than by heat (0·42%, 0·39–0·44). Extreme cold and hot temperatures were responsible for 0·86% (0·84–0·87) of total mortality. Interpretation Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios. Funding UK Medical Research Council.

Diabetes Enhances Vulnerability to Particulate Air Pollution–Associated Impairment in Vascular Reactivity and Endothelial Function

Background—Epidemiological studies suggest that people with diabetes are vulnerable to cardiovascular health effects associated with exposure to particle air pollution. Endothelial and vascular function is impaired in diabetes and may be related to increased cardiovascular risk. We examined whether endothelium-dependent and -independent vascular reactivity was associated with particle exposure in individuals with and without diabetes. Methods and Results—Study subjects were 270 greater-Boston residents. We measured 24-hour average ambient levels of air pollution (fine particles [PM2.5], particle number, black carbon, and sulfates [SO42−]) ≈500 m from the patient examination site. Pollutant concentrations were evaluated for associations with vascular reactivity. Linear regressions were fit to the percent change in brachial artery diameter (flow mediated and nitroglycerin mediated), with the particulate pollutant index, apparent temperature, season, age, race, sex, smoking history, and body mass index as predictors. Models were fit to all subjects and then stratified by diagnosed diabetes versus at risk for diabetes. Six-day moving averages of all 4 particle metrics were associated with decreased vascular reactivity among patients with diabetes but not those at risk. Interquartile range increases in SO42− were associated with decreased flow-mediated (−10.7%; 95% CI, −17.3 to −3.5) and nitroglycerin-mediated (−5.4%; 95% CI, −10.5 to −0.1) vascular reactivity among those with diabetes. Black carbon increases were associated with decreased flow-mediated vascular reactivity (−12.6%; 95% CI, −21.7 to −2.4), and PM2.5 was associated with nitroglycerin-mediated reactivity (−7.6%; 95% CI, −12.8 to −2.1). Effects were stronger in type II than type I diabetes. Conclusions—Diabetes confers vulnerability to particles associated with coal-burning power plants and traffic.

The Effect of Fine and Coarse Particulate Air Pollution on Mortality: A National Analysis

Background Although many studies have examined the effects of air pollution on mortality, data limitations have resulted in fewer studies of both particulate matter with an aerodynamic diameter of ≤ 2.5 μm (PM2.5; fine particles) and of coarse particles (particles with an aerodynamic diameter > 2.5 and < 10 μm; PM coarse). We conducted a national, multicity time-series study of the acute effect of PM2.5 and PM coarse on the increased risk of death for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory mortality for the years 1999–2005. Method We applied a city- and season-specific Poisson regression in 112 U.S. cities to examine the association of mean (day of death and previous day) PM2.5 and PM coarse with daily deaths. We combined the city-specific estimates using a random effects approach, in total, by season and by region. Results We found a 0.98% increase [95% confidence interval (CI), 0.75–1.22] in total mortality, a 0.85% increase (95% CI, 0.46–1.24) in CVD, a 1.18% increase (95% CI, 0.48–1.89) in MI, a 1.78% increase (95% CI, 0.96–2.62) in stroke, and a 1.68% increase (95% CI, 1.04–2.33) in respiratory deaths for a 10-μg/m3 increase in 2-day averaged PM2.5. The effects were higher in spring. For PM coarse, we found significant but smaller increases for all causes analyzed. Conclusions We conclude that our analysis showed an increased risk of mortality for all and specific causes associated with PM2.5, and the risks are higher than what was previously observed for PM10. In addition, coarse particles are also associated with more deaths.

The Time Course of Weather-Related Deaths

We carried out time-series analysis in 12 U.S. cities to estimate both the acute effects and the lagged influence of weather on total daily deaths. We fit generalized additive Poisson regressions for each city using nonparametric smooth functions to control for long time trend and barometric pressure. We also controlled for day of the week. We estimated the effect and the lag structure of both temperature and humidity on the basis of a distributed lag model. In cold cities, both high and low temperatures were associated with increased deaths. In general, the effect of cold temperatures persisted for days, whereas the effect of high temperatures was restricted to the day of the death or the immediately preceding day and was twice as large as the cold effect. The hot temperature effect appears to be primarily harvesting. In hot cities, neither hot nor cold temperatures had much effect on deaths. The magnitude of the effect of hot temperature varied with central air conditioning use and the variance of summertime temperatures. We saw no clear pattern for humidity effect. These dissimilarities indicate that analysis of the impact of any climatic change should take into account regional weather differences and harvesting.

Increasing CO2 threatens human nutrition

Dietary deficiencies of zinc and iron are a substantial global public health problem. An estimated two billion people suffer these deficiencies, causing a loss of 63 million life-years annually. Most of these people depend on C3 grains and legumes as their primary dietary source of zinc and iron. Here we report that C3 grains and legumes have lower concentrations of zinc and iron when grown under field conditions at the elevated atmospheric CO2 concentration predicted for the middle of this century. C3 crops other than legumes also have lower concentrations of protein, whereas C4 crops seem to be less affected. Differences between cultivars of a single crop suggest that breeding for decreased sensitivity to atmospheric CO2 concentration could partly address these new challenges to global health.

Extreme Temperatures and Mortality: Assessing Effect Modification by Personal Characteristics and Specific Cause of Death in a Multi-City Case-Only Analysis

Background Extremes of temperature are associated with short-term increases in daily mortality. Objectives We set out to identify subpopulations and mortality causes with increased susceptibility to temperature extremes. Methods We conducted a case-only analysis using daily mortality and hourly weather data from 50 U.S. cities for the period 1989–2000, covering a total of 7,789,655 deaths. We used distributions of daily minimum and maximum temperature in each city to define extremely hot days (≥ 99th percentile) and extremely cold days (≤ 1st percentile), respectively. For each (hypothesized) effect modifier, a city-specific logistic regression model was fitted and an overall estimate calculated in a subsequent meta-analysis. Results Older subjects [odds ratio (OR) = 1.020; 95% confidence interval (CI), 1.005–1.034], diabetics (OR = 1.035; 95% CI, 1.010–1.062), blacks (OR = 1.037; 95% CI, 1.016–1.059), and those dying outside a hospital (OR = 1.066; 95% CI, 1.036–1.098) were more susceptible to extreme heat, with some differences observed between those dying from a cardiovascular disease and other decedents. Cardiovascular deaths (OR = 1.053; 95% CI, 1.036–1.070), and especially cardiac arrest deaths (OR =1.137; 95% CI, 1.051–1.230), showed a greater relative increase on extremely cold days, whereas the increase in heat-related mortality was marginally higher for those with coexisting atrial fibrillation (OR = 1.059; 95% CI, 0.996–1.125). Conclusions In this study we identified several subpopulations and mortality causes particularly susceptible to temperature extremes. This knowledge may contribute to establishing health programs that would better protect the vulnerable.

The effect of particulate air pollution on emergency admissions for myocardial infarction: a multicity case-crossover analysis.

Recently, attention has focused on whether particulate air pollution is a specific trigger of myocardial infarction (MI). The results of several studies of single locations assessing the effects of ambient particular matter on the risk of MI have been disparate. We used a multicity case-crossover study to examine risk of emergency hospitalization associated with fine particulate matter (PM) with aerodynamic diameter < 10 μm (PM10) for > 300,000 MIs during 1985–1999 among elderly residents of 21 U.S. cities. We used time-stratified controls matched on day of the week or on temperature to detect possible residual confounding by weather. Overall, we found a 0.65% [95% confidence interval (CI), 0.3–1.0%] increased risk of hospitalization for MI per 10 μg/m3 increase in ambient PM10 concentration. Matching on apparent temperature yielded a 0.64% increase in risk (95% CI, 0.1–1.2%). We found that the effect size for PM10 doubled for subjects with a previous admission for chronic obstructive pulmonary disease or a secondary diagnosis of pneumonia, although these differences did not achieve statistical significance. There was a weaker indication of a larger effect on males but no evidence of effect modification by age or the other diagnoses. We also found that the shape of the exposure–response relationship between MI hospitalizations and PM10 is almost linear, but with a steeper slope at levels of PM10 < 50 μg/m3. We conclude that increased concentrations of ambient PM10 are associated with increased risk of MI among the elderly.

Fine particulate air pollution and its components in association with cause-specific emergency admissions

BackgroundAlthough the association between exposure to particulate matter and health is well established, there remains uncertainty as to whether certain chemical components are more harmful than others. We explored whether the association between cause-specific hospital admissions and PM2.5 was modified by PM2.5 chemical composition.MethodsWe estimated the association between daily PM2.5 and emergency hospital admissions for cardiac causes (CVD), myocardial infarction (MI), congestive heart failure (CHF), respiratory disease, and diabetes in 26 US communities, for the years 2000-2003. Using meta-regression, we examined how this association was modified by season- and community-specific PM2.5 composition, controlling for seasonal temperature as a surrogate for ventilation.ResultsFor a 10 μg/m3 increase in 2-day averaged PM2.5 concentration we found an increase of 1.89% (95% CI: 1.34- 2.45) in CVD, 2.25% (95% CI: 1.10- 3.42) in MI, 1.85% (95% CI: 1.19- 2.51) in CHF, 2.74% (95% CI: 1.30- 4.2) in diabetes, and 2.07% (95% CI: 1.20- 2.95) in respiratory admissions. The association between PM2.5 and CVD admissions was significantly modified when the mass was high in Br, Cr, Ni, and Na+, while mass high in As, Cr, Mn, OC, Ni, and Na+ modified MI, and mass high in As, OC, and SO42- modified diabetes admissions. For these species, an interquartile range increase in their relative proportion was associated with a 1-2% additional increase in daily admissions per 10 μg/m3 increase in mass.ConclusionsWe found that PM2.5 mass higher in Ni, As, and Cr, as well as Br and OC significantly increased its effect on hospital admissions. This result suggests that particles from industrial combustion sources and traffic may, on average, have greater toxicity.