A cohort study of the multipollutant effects of PM2.5, NO2, and O3 on C-reactive protein levels during pregnancy.

Background: PM2.5, NO2, and O3 contribute to the development of adverse pregnancy complications. While studies have investigated the independent effects of these exposures, literature on their combined effects is limited. Our objective was to study the multipollutant effects of PM2.5, NO2, and O3 on maternal systemic C-reactive protein (CRP) levels. Methods: We used data from 1170 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals Study (MIREC) study in Canada. Air pollution exposures were assigned to each participant based on residential location. CRP was measured in third-trimester blood samples. We fit multipollutant linear regression models and evaluated the effects of air pollutant mixtures (14-day averages) using repeated-holdout Weighted Quantile Sum (WQS) regression and by calculating the Air Quality Health Index (AQHI). Results: In multipollutant models adjusting for NO2, O3, and green space, each interquartile range (IQR) increase in 14-day average PM2.5 (IQR: 6.9 µg/m3) was associated with 27.1% (95% confidence interval [CI] = 6.2, 50.7) higher CRP. In air pollution mixture models adjusting for green space, each IQR increase in AQHI was associated with 37.7% (95% CI = 13.9, 66.5) higher CRP; and an IQR increase in the WQS index was associated with 78.6% (95% CI = 29.7, 146.0) higher CRP. Conclusion: PM2.5 has the strongest relationship of the individual pollutants examined with maternal blood CRP concentrations. Mixtures incorporating all three pollutants, assessed using the AQHI and WQS index, showed stronger relationships with CRP compared with individual pollutants and illustrate the importance of conducting multipollutant analyses.

Ambient air pollution and inflammatory effects in a Canadian pregnancy cohort.

BACKGROUND: Epidemiologic studies have consistently reported associations between air pollution and pregnancy outcomes including preeclampsia and gestational diabetes. However, the biologic mechanisms underlying these relationships remain unclear as few studies have collected relevant biomarker data. We examined relationships between ambient PM2.5 and NO2 with markers of inflammation during pregnancy in a prospective cohort of Canadian women. METHODS: We analyzed data from 1170 women enrolled in the Maternal-Infant Research on Environmental Chemicals study. Daily residential PM2.5 and NO2 exposures during pregnancy were estimated using satellite-based and land-use regression models and used to create 14-day and 30-day exposure windows before blood-draw. Inflammatory markers C-reactive protein, interleukin-6, interleukin-8, and tumor necrosis factor-α were measured in third trimester plasma samples. Multivariable linear regression was used to estimate associations for an interquartile range (IQR) increase in PM2.5 and NO2 and markers of inflammation, while adjusting for individual-level confounders. RESULTS: Fourteen-day (IQR: 6.85 µg/m3) and 30-day (IQR: 6.15 µg/m3) average PM2.5 exposures before blood-draw were positively associated with C-reactive protein after adjustment for covariates (24.6% [95% CI = 9.4, 41.9] and 17.4% [95% CI = 1.0, 35.0] increases, respectively). This association was found to be robust in several sensitivity analyses. Neither PM2.5 nor NO2 exposures were associated with interleukin-6, interleukin-8, or tumor necrosis factor-α. CONCLUSION: Exposure to ambient PM2.5 is positively associated with maternal inflammatory pathways in late pregnancy. This may contribute to positive associations between ambient PM2.5 and risk of adverse pregnancy outcomes.

Associations between air pollution and cardio-respiratory physiological measures in older adults exercising outdoors.

We examined whether exercising indoors vs. outdoors reduced the cardio-respiratory effects of outdoor air pollution. Adults ≥55 were randomly assigned to exercise indoors when the Air Quality Health Index was ≥5 and outdoors on other days (intervention group, n = 37), or outdoors everyday (control group, n = 35). Both groups completed cardio-respiratory measurements before and after exercise for up to 10 weeks. Data were analyzed using linear mixed effect regression models. In the control group, an interquartile range increase in fine particulate matter (PM2.5) was associated with increases of 1.4% in heart rate (standard error (SE) = 0.7%) and 5.6% (SE = 2.6%) in malondialdehyde, and decreases of 5.6% (SE = 2.5%) to 16.5% (SE = 7.5%) in heart rate variability measures. While the hypothesized benefit of indoor vs. outdoor exercise could not be demonstrated due to an insufficient number of intervention days (n = 2), the study provides evidence of short-term effects of air pollution in older adults. ISRCTN #26552763.

Metals and oxidative potential in urban particulate matter influence systemic inflammatory and neural biomarkers: A controlled exposure study.

BACKGROUND: Oxidative stress and inflammation are considered to be important pathways leading to particulate matter (PM)-associated disease. In this exploratory study, we examined the effects of metals and oxidative potential (OP) in urban PM on biomarkers of systemic inflammation, oxidative stress and neural function. METHODS: Fifty-three healthy non-smoking volunteers (mean age 28 years, twenty-eight females) were exposed to coarse (2.5-10 µm, mean 213 µg/m3), fine (0.15-2.5 µm, 238 µg/m3), and/or ultrafine concentrated ambient PM (<0.3 µm, 136 µg/m3). Exposures lasted 130 min, separated by ≥2 weeks. Metal concentrations and OP (measured by ascorbate and glutathione depletion in synthetic airway fluid) in PM were analyzed. Blood and urine samples were collected pre-exposure, and 1-h and 21-h post exposure for assessment of biomarkers. We used mixed-regression models to analyze associations adjusting for PM size and mass concentration. RESULTS: Results for metals were expressed as change (%) from daily pre-exposure biomarker levels after exposure to a metal at a level equivalent to the mean concentration. Exposure to various metals (silver, aluminum, barium, copper, iron, potassium, lithium, nickel, tin, and/or vanadium) was significantly associated with increased levels of various blood or urinary biomarkers. For example, the blood inflammatory marker vascular endothelia growth factor (VEGF) increased 5.3% (95% confidence interval: 0.3%, 10.2%) 1-h post exposure to nickel; the traumatic brain injury marker ubiquitin C-terminal hydrolase L1 (UCHL1) increased 11% (1.2%, 21%) and 14% (0.3%, 29%) 1-h and 21-h post exposure to barium, respectively; and the systemic stress marker cortisol increased 1.5% (0%, 2.9%) and 1.5% (0.5%, 2.8%) 1-h and 21-h post exposure to silver, respectively. Urinary DNA oxidation marker 8­hydroxy­deoxy­guanosine increased 14% (6.4%, 21%) 1-h post exposure to copper; urinary neural marker vanillylmandelic acid increased 29% (3%, 54%) 1-h post exposure to aluminum; and urinary cortisol increased 88% (0.9%, 176%) 1-h post exposure to vanadium. Results for OP were expressed as change (%) from daily pre-exposure biomarker levels after exposure to ascorbate-related OP at a level equivalent to the mean concentration, or for exposure to glutathione-related OP at a level above the limit of detection. Exposure to ascorbate- or glutathione-related OP was significantly associated with increased inflammatory and neural biomarkers including interleukin-6, VEGF, UCHL1, and S100 calcium-binding protein B in blood, and malondialdehyde and 8-hydroxy-deoxy-guanosine in urine. For example, UCHL1 increased 9.4% (1.8%, 17%) in blood 21-h post exposure to ascorbate-related OP, while urinary malondialdehyde increased 19% (3.6%, 35%) and 8-hydroxy-deoxy-guanosine increased 24% (2.9%, 48%) 21-h post exposure to ascorbate- and glutathione-related OP, respectively. CONCLUSION: Our results from this exploratory study suggest that metal constituents and OP in ambient PM may influence biomarker levels associated with systemic inflammation, oxidative stress, perturbations of neural function, and systemic physiological stress.

Exposure to air pollution near a steel plant is associated with reduced heart rate variability: a randomised crossover study.

BACKGROUND: Epidemiological studies have shown that as ambient air pollution (AP) increases the risk of cardiovascular mortality also increases. The mechanisms of this effect may be linked to alterations in autonomic nervous system function. We wished to examine the effects of industrial AP on heart rate variability (HRV), a measure of subtle changes in heart rate and rhythm representing autonomic input to the heart. METHODS: Sixty healthy adults were randomized to spend five consecutive 8-h days outdoors in one of two locations: (1) adjacent to a steel plant in the Bayview neighbourhood in Sault Ste Marie Ontario or (2) at a College campus, several kilometers from the plant. Following a 9-16 day washout period, participants spent five consecutive days at the other site. Ambient AP levels and ambulatory electrocardiogram recordings were collected daily. HRV analysis was undertaken on a segment of the ambulatory ECG recording during a 15 min rest period, near the end of the 8-h on-site day. Standard HRV parameters from both time and frequency domains were measured. Ambient AP was measured with fixed site monitors at both sites. Statistical analysis was completed using mixed-effects models. RESULTS: Compared to the College site, HRV was statistically significantly reduced at the Bayview site by 13% (95%CI 3.6,19.2) for the standard deviation of normal to normal, 8% (95%CI 0.1, 4.9) for the percent normal to normal intervals differing by more than 50 ms, and 15% (95%CI 74.9, 571.2) for low frequency power. Levels of carbon monoxide, sulphur dioxide, nitrogen dioxide, and fine and ultrafine particulates were slightly, but statistically significantly, elevated at Bayview when compared to College. Interquartile range changes in individual air pollutants were significantly associated with reductions in HRV measured on the same day. The patterns of effect showed a high degree of consistency, with nearly all pollutants significantly inversely associated with at least one measure of HRV. CONCLUSIONS: The significant associations between AP and changes in HRV suggest that ambient AP near a steel plant may impact autonomic nervous system control of the heart.

Hypothermia increases the gain of excitation-contraction coupling in guinea pig ventricular myocytes.

Components of excitation-contraction (EC)-coupling were compared at 37 degrees C and 22 degrees C to determine whether hypothermia altered the gain of EC coupling in guinea pig ventricular myocytes. Ca(2+) concentration (fura-2) and cell shortening (edge detector) were measured simultaneously. Hypothermia increased fractional shortening (8.3+/-1.7 vs. 2.6+/-0.3% at 37 degrees C), Ca(2+) transients (157+/-33 vs. 35+/-5 nM at 37 degrees C), and diastolic Ca(2+) (100+/-9 vs. 60+/-6 nM at 37 degrees C) in field-stimulated myocytes (2 Hz). In experiments with high-resistance microelectrodes, the increase in contractions and Ca(2+) transients was accompanied by a twofold increase in action potential duration (APD). When voltage-clamp steps eliminated changes in APD, cooling still increased contractions and Ca(2+) transients. Hypothermia increased sarcoplasmic reticulum (SR) Ca(2+) stores (83+/-17 at 37 degrees C to 212+/-50 nM, assessed with caffeine) and increased fractional SR Ca(2+) release twofold. In contrast, peak Ca(2+) current was much smaller at 22 degrees C than at 37 degrees C (1.3+/-0.4 and 3.5+/-0.7 pA/pF, respectively). In cells dialyzed with sodium-free pipette solutions to inhibit Ca(2+) influx via reverse-mode Na(+)/Ca(2+) exchange, hypothermia still increased contractions, Ca(2+) transients, SR stores, and fractional release but decreased the amplitude of Ca(2+) current. The rate of SR Ca(2+) release per unit Ca(2+) current, a measure of EC-coupling gain, was increased sixfold by hypothermia. This increase in gain occurred regardless of whether cells were dialyzed with sodium-free solutions. Thus an increase in EC-coupling gain contributes importantly to positive inotropic effects of hypothermia in the heart.

Increases in diastolic [Ca2+] can contribute to positive inotropy in guinea pig ventricular myocytes in the absence of changes in amplitudes of Ca2+ transients.

Increases in contraction amplitude following rest or in elevated extracellular Ca(2+) concentration ([Ca(2+)]) have been attributed to increased sarcoplasmic reticulum (SR) Ca(2+) stores and/or increased trigger Ca(2+). However, either manipulation also may elevate diastolic [Ca(2+)]. The objective of this study was to determine whether elevation of diastolic [Ca(2+)] could contribute to positive inotropy in isolated ventricular myocytes. Voltage-clamp experiments were conducted with high-resistance microelectrodes in isolated myocytes at 37 degrees C. Intracellular free [Ca(2+)] was measured with fura-2, and cell shortening was measured with an edge detector. SR Ca(2+) stores were assessed with 10 mM caffeine (0 mM Na(+), 0 mM Ca(2+)). Following a period of rest, cells were activated with trains of pulses, which generated contractions of increasing amplitude, called positive staircases. Positive staircases were accompanied by increasing diastolic [Ca(2+)] but no change in Ca(2+) transient amplitudes. When extracellular [Ca(2+)] was elevated from 2.0 to 5.0 mM, resting intracellular [Ca(2+)] increased and resting cell length decreased. Amplitudes of contractions and L-type Ca(2+) current increased in elevated extracellular [Ca(2+)], although SR Ca(2+) stores, assessed by rapid application of caffeine, did not increase. Although Ca(2+) transient amplitude did not increase in 5.0 mM extracellular [Ca(2+)], diastolic [Ca(2+)] continued to increase with increasing extracellular [Ca(2+)]. These data suggest that increased diastolic [Ca(2+)] contributes to positive inotropy following rest or with increasing extracellular [Ca(2+)] in guinea pig ventricular myocytes.