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. Author manuscript; available in PMC: 2018 Apr 1.
Published in final edited form as: Environ Int. 2017 Jan 20;101:89–95. doi: 10.1016/j.envint.2017.01.010

Influence of exposure to coarse, fine and ultrafine urban particulate matter and their biological constituents on neural biomarkers in a randomized controlled crossover study

Ling Liu 1, Bruce Urch 2,3, Mieczyslaw Szyszkowicz 1, Mary Speck 2, Karen Leingartner 1, Robin Shutt 1, Guillaume Pelletier 1, Diane R Gold 4, James A Scott 2, Jeffrey R Brook 2,3,5, Peter S Thorne 6, Frances S Silverman 2,3,7,8
PMCID: PMC5348252  NIHMSID: NIHMS845714  PMID: 28117141

Abstract

Background

Epidemiological studies have reported associations between air pollution and neuro-psychological conditions. Biological mechanisms behind these findings are still not clear.

Objectives

We examined changes in blood and urinary neural biomarkers following exposure to concentrated ambient coarse, fine and ultrafine particles.

Methods

Fifty healthy non-smoking volunteers, mean age 28 years, were exposed to coarse (2.5-10 μm, mean 213 μg/m3) and fine (0.15-2.5 μm, mean 238 μg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (mean size 59.6 nm, range 47.0-69.8 nm, mean 136 μg/m3) and filtered medical air. Exposures lasted 130 minutes, separated by ≥2 weeks, and the biological constituents endotoxin and β-1,3-D-glucan of each particle size fraction were measured. Blood and urine samples were collected pre-exposure, and 1-hour and 21-hour post exposure to determine neural biomarker levels. Mixed-model regressions assessed associations between exposures and changes in biomarker levels.

Results

Results were expressed as percent change from daily pre-exposure biomarker levels. Exposure to coarse CAP was significantly associated with increased urinary levels of the stress-related biomarkers vanillylmandelic acid (VMA) and cortisol when compared with exposure to filtered medical air [20% (95% confidence interval: 1.0%, 38%) and 64% (0.2%, 127%), respectively] 21 hours post exposure. However exposure to coarse CAP was significantly associated with decreases in blood cortisol [-26.0% (-42.4%, -9.6%) and -22.4% (-43.7%, -1.1%) at 1 hr and 21 hr post exposure, respectively]. Biological molecules present in coarse CAP were significantly associated with blood biomarkers indicative of blood brain barrier integrity. Endotoxin content was significantly associated with increased blood ubiquitin C-terminal hydrolase L1 [UCHL1, 11 % (5.3%, 16%) per ln(ng/m3+1)] 1-hour post exposure, while β-1,3-D-glucan was significantly associated with increased blood S100B [6.3% (3.2%, 9.4%) per ln(ng/m3+1)], as well as UCHL1 [3.1% (0.4%, 5.9%) per ln(ng/m3+1)], one-hour post exposure. Fine CAP was marginally associated with increased blood UCHL1 when compared with exposure to filtered medical air [17.7% (-1.7%, 37.2%), p=0.07] 21 hours post exposure. Ultrafine CAP was not significantly associated with changes in any blood and urinary neural biomarkers examined.

Conclusion

Ambient coarse particulate matter and its biological constituents may influence neural biomarker levels that reflect perturbations of blood-brain barrier integrity and systemic stress response.

Keywords: Air pollution; particulate matter; endotoxin; β-1,3-D-glucan; neural biomarker; randomized controlled crossover trial

Introduction

Extensive epidemiological evidence has shown that daily increased particulate air pollution is associated with elevated risk of cardiovascular and respiratory mortality and hospital admissions (World Health Organization 2013). However, the effects of urban air pollution on nervous systems are not as well studied. This has been recognized by the US National Institute of Environmental Health Sciences/National Institute of Health as a priority for scientific research (Block et al. 2012). In recent years, epidemiological studies have reported associations between daily air pollution and hospital admissions or emergency room visits for Parkinson's disease (Zanobetti et al. 2014) and neuro-psychological responses such as depression and suicide attempt/mortality (Bakian et al. 2015; Kim et al. 2010; Szyszkowicz et al. 2009; Szyszkowicz et al. 2010; Yackerson et al. 2014). Long-term exposure to elevated air pollution in urban centres has been associated with hospital admissions for dementia, Parkinson's and Alzheimer's diseases (Kioumourtzoglou et al. 2016; Ritz et al. 2016).

The biological mechanisms behind these neuro-psychological responses are not well understood. Air pollution-induced systemic inflammation and oxidative stress have been implicated in field epidemiological and controlled human exposure studies (Behbod et al. 2013; Chuang et al. 2007; Delfino et al. 2009; Liu et al. 2015; Rückerl et al. 2007). Evidence from toxicological studies has contributed to the hypothesis that particulate matter (PM)-induced systemic inflammation and oxidative stress may damage cerebral vasculature, and compromise the tight junctions of the blood-brain barrier that controls the influx of neurotoxins and release of some neural mediators into the peripheral blood stream (Hartz et al. 2016). Thomson et al. observed that short-term exposure of rats to PM and ozone induced redox/glucocorticoid-sensitive gene responses and increased plasma levels of adrenocorticotropic hormone and the glucocorticoid corticosterone (Thomson et al. 2013). These observations led to the hypothesis that exposure to these air pollutants may activate the hypothalamic-pituitary-adrenal stress response axis, resulting in various metabolic and neurobehavioral changes (Thomson 2014). There is also evidence that long-term exposure to high levels of air pollution is associated with increased inflammatory gene expressions and disruption of the blood brain barrier in human brain autopsy samples (Calderón-Garcidueñas et al. 2008). Controlled human exposure studies examining neural biomarkers in blood and urine may contribute to evidence to elucidate how exposure to pollutants in ambient air may result in adverse neuro-psychological responses in human population.

Urban PM in ambient air is generally categorized into coarse [mass median aerodynamic diameter (MMAD) 2.5-10 μm, PM10-2.5], fine (MMAD ≤2.5 μm, PM2.5) and ultrafine (MMAD ≤0.1 μm) particles. Studies suggest that various particle size fractions may affect systemic inflammation and oxidative stress in a different manner, which might be explained by differences in particle delivery rate, route and deposition location in the body and by the presence of chemical and biological components of varying toxic potency [including neurotoxicity, (Lucchini et al. 2012)] in different PM size fractions. For example, Samet et al. reported that controlled exposures to concentrated ambient PM2.5 and PM10-2.5 were associated with increased airway inflammation and a trend of increased blood coagulation markers such as fibrinogen and plasminogen in human volunteers, but exposure to ultrafine particles had no such effects (Samet et al. 2007). Our findings in a controlled exposure study suggest that among the three size fractions, coarse concentrated ambient particles (CAP) had a stronger association with vascular endothelial growth factor (VEGF) in blood, fine CAP a stronger association with urinary marker of lipid peroxidation, and ultrafine CAP a stronger association with urinary marker of DNA oxidative damage (Liu et al. 2015). PM often carries biological components such as endotoxin, a major constituent of the outer membrane of the cell wall of Gram-negative bacteria, and β-1,3-D-glucan (β-glucan), a constituent of the cell wall of fungi and plants. They both are known to be associated with respiratory illness in children and adults (Dales et al. 2006; Douwes et al. 2000; Thorne et al. 2015). We have observed that endotoxin contained in coarse and fine CAPs were significantly associated with blood leukocytes (Behbod et al. 2013) and blood pressure (Zhong et al. 2015), as well as systemic changes in vasodilatory inflammatory marker VEGF and biomarkers of DNA and lipid oxidation (Liu et al. 2015), suggesting that endotoxin plays a role in the effects of coarse and fine CAPs on human health.

In this study, we tested the hypotheses that (1) a short-term exposure to concentrated ambient coarse, fine or ultrafine PM in a controlled environment is associated with changes in systemic neural biomarkers in the blood and urine of healthy individuals; and (2) endotoxin and β-glucan in these particles might play a role in the perturbation of these biomarkers. The neural biomarkers examined in this study are those that have been reported to be associated with: a) oxidative stress [brain-derived neurotrophic factor (BDNF) in blood] (Moylan et al. 2013); b) traumatic brain injury or degeneration [neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and ubiquitin C-terminal hydrolase L1 (UCHL1) in blood] (Arent et al. 2014; Lewis et al. 2010; Zetterberg et al. 2013); and c) systemic stress [cortisol in blood and urine, and urinary metabolites of dopamine and norepinephrine: homovanillic acid (HVA) and vanillylmandelic acid (VMA), respectively](Frankenhaeuser et al. 1986; Fukuda et al. 1996; Sapolsky et al. 2000).

Materials and Methods

The study design was a single-blind randomized cross-over trial. Detailed methods of participant recruitment were described by Liu et al. (Liu et al. 2015). Briefly, participants were non-smokers, 18-60 years of age, without history of coronary artery disease, myocardial infarction, peripheral vascular disease, angina, heart failure, hypertension or diabetes mellitus, and free of lipid abnormalities and respiratory tract infections. We excluded participants with baseline spirometry <75% of predicted normal values (forced vital capacity and forced expiratory 1-second volume), having clinically significant abnormalities in their resting electrocardiogram, as well as those who were pregnant or breast-feeding. All participants provided informed written consent prior to participating in the study. The Research Ethics Boards of Health Canada and Public Health Agency of Canada, St. Michael's Hospital, and the University of Toronto approved the study protocol.

Exposure facility

Details of the coarse, fine and ultrafine particle concentrator facility were described elsewhere (Rastogi et al. 2012). The controlled exposures to CAPs drew air from breathing height (1.8 m) adjacent to a downtown street in Toronto, Canada. We used the Harvard Ambient Fine and Coarse Particle Concentrators and an enclosed temperature-controlled exposure chamber for the study participants. Ambient aerosols were drawn through a size-selective inlet where particles >10 μm were removed. The fine PM concentrator delivered CAP 0.15-2.5 μm in MMAD (fine CAP), while the coarse PM concentrator delivered CAP 2.5-10 μm in MMAD (coarse CAP). Particle-free filtered ambient air (FA) was used as a control by inserting a high-efficiency particulate absorption (HEPA) filter inline downstream of the particle concentrator. For the study on coarse and fine CAPs, we enrolled 50 participants. Forty-one participants also had exposure to HEPA-filtered cylinder medical air as control that was particle- and ambient gas-free; the remaining 9 participants only had filtered ambient air as control. The study for the coarse and fine CAPs included up to five exposures for each participant when he or she was available: two exposures to coarse CAP, and one exposure to fine CAP, HEPA-filtered ambient air, and/or filtered medical air. Details on the regime of exposures were described elsewhere (Liu et al. 2015).

To generate ultrafine CAP, in the airstream of the ultrafine particle concentrator, particles larger than 0.3 μm were removed by inertial impaction, and the resulting concentrated ultrafine aerosol was delivered to the participant. For the study on ultrafine CAP, we used the HEPA-filtered medical air as control. We used a fast mobility particle sizer (FMPS, TSI model 3091) and a scanning mobility particle sizer (SMPS, TSI model 3034) to measure particle size distribution. Twenty five participants completed the ultrafine CAP study, twenty of whom also participated in the coarse and fine CAP study.

The exposure air stream was delivered directly to the participant who was seated at rest and breathing freely via a facemask (Baxter Airlife, aerosol mask) covering his/her nose and mouth. All exposures took place at the same time of the day, starting at approximately 9:00, and each lasted 130 minutes. PM in the airstream was collected on a 47 mm, 2 μm Teflon filter (Teflo, R2PJ047, Pall Corp, Ann Arbor, MI) during the 130-min exposure, and gravimetric determinations of mass concentrations reported. Between exposures there was a washout period of ≥ 2 weeks.

Measurement of endotoxin and β-glucan

Detailed methods for the measurements of endotoxin and β-glucan were previously described (Behbod et al. 2013). Endotoxin and β-glucan were collected on polycarbonate membrane filters during exposures to CAPs and filtered ambient air. Natural log transformation was performed on endotoxin and β-glucan concentrations [ln(ng/m3+1)] to obtain a normal distribution of the data.

Measurement of neural biomarkers in blood and urine

Upon arrival of the participants for the first exposure, we measured their height and weight and calculated body mass index (BMI) using the standard procedures. We collected urine and venous blood samples (20 ml) prior to, and at 1-hr and 21-hr after each exposure. The pre-exposure blood and urine samples from the participants were used to determine daily baseline values.

Blood biomarker assays: We obtained fasting blood samples by venipuncture and stored plasma at -70°C. S100B was measured using an ELISA kit from Millipore (Billerica, MA, USA), UCHL1 measured using an ELISA kit from EnCor Biotechnology Inc. (Gainesville, FL, USA), NSE and BDNF measured using ELISA kits from R&D Systems (Minneapolis, MN, USA), and total cortisol measured using the DetectX Cortisol ELISA kit (Arbor Assays, Ann Arbor, MI, USA).

Urinary biomarker assays: We collected and stored urine samples at -20°C. Urine samples were clarified by centrifugation (5000 rpm, 5 mins in an Eppendorf 5804 centrifuge) prior to analyses. VMA and HVA were determined using ELISA assay kits from Eagle Biosciences Inc. (Nashua, NH, USA). Free cortisol was assayed using the DetectX Cortisol ELISA kit (Arbor Assays, Ann Arbor, MI, USA). Creatinine concentrations were measured using a CREA kit (Roche Diagnostics, Laval, Quebec, Canada) to normalize urinary biomarker concentrations. All assays were carried out by following the instructions provided by the assay kit manufacturers.

We also measured blood concentrations of endothelin-1 (ET-1), interleukin-6 (IL-6), high sensitivity C-reactive protein (CRP), vascular endothelial growth factor (VEGF) and malondialdehyde (MDA), and urinary concentrations of VEGF, 8-hydroxydeoxyguanosine (8-OHdG) and MDA. Results were reported elsewhere (Liu et al. 2015).

Statistical analysis

We tested statistically significant differences in concentrations of endotoxin and β-glucan among exposure scenarios using Kruskal-Wallis one-way analysis of variance (ANOVA), followed by Dunn's test of pairwise multiple comparisons. We calculated percent change of biomarker values at 1-hr and 21-hr post exposure using the equation: [(post-exposure value minus pre-exposure value)/pre-exposure value]*100. This equation was used to adjust for the participant's potential day-to-day variations in factors such as daily diet, stress, exposure to ambient pollutants and environmental tobacco smoke, and other unknown factors that may also contribute to variations in systemic biomarker levels. We calculated the correlations between post-exposure changes in neural biomarkers and changes in blood VEGF and urinary 8-OHdG, VEGF and MDA levels using Spearman rank order correlation method.

We used mixed-effects linear regression models (restricted maximum likelihood estimation) to analyze: (1) associations between exposure to CAPs and changes in biomarkers; exposure type was a dummy variable, with filtered medical air as reference, and regression results expressed as percent change in biomarker concentrations [95% confidence interval (CI)] when compared with exposure to filtered medical air; and (2) the associations between biomarkers and concentrations of endotoxin or β-glucan collected during exposures to coarse CAP; regression results were expressed as percent change in biomarker concentrations (95% CI) per unit of biological content [ln(ng/m3+1)]. Mixed models accounted for the repeated measures, assuming random participant intercepts and random slopes. We used an autoregressive model of order-one to adjust for serial autocorrelation. We used multi-variable linear regressions to analyze the associations between biomarkers and concentrations of endotoxin or β-glucan in fine CAPs, since in this dataset each participant only had one exposure to fine CAP. Age, sex (binary variable, male=1), BMI, and season [binary variable, warm season (May to October) =1] were included in all models. Since temperature was controlled and relative humidity was constant in the testing facility, we did not adjust for them in the models. The statistical software used was S-PLUS® version 6.2 (TIBCO Software Inc., Palo Alto, CA, USA). A two tailed value of p≤0.05 was considered statistically significant.

Results

As previously reported (Liu et al. 2015), fifty participants were included in the study on coarse and fine CAPs. Twenty of them also participated in the ultrafine CAP study, along with five additional participants, bringing the total number of participants to the ultrafine CAP study to 25. In total 55 participants were enrolled including 29 females and 26 males. The characteristics of the cohort are presented in Table 1.

Table 1. Baseline characteristics of subjects (N=55).

Characteristic Mean ± standard deviation, unless otherwise noted
Age (years) 28 ± 9
Sex (female/male, numbers) 29/26
Race (Asian/Caucasian/other, numbers) 24/23/8
BMI (kg/m2) 23.2 ± 2.7
Blood biomarkers*
S100B (pg/ml) 19.0 ± 10.2
NSE (ng/ml) 4.0 ± 1.0
UCHL1 (ng/ml) 3.2 ± 2.1
Cortisol (ng/ml) 105.1 ± 65.8
BDNF (ng/ml) 21.1 ± 6.1
Urinary biomarkers*
VMA (mg/g Creatinine) 5.7 ± 3.6
HVA (mg/g Creatinine) 7.2 ± 5.0
Cortisol (μg/g Creatinine) 2.3 ± 1.8
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*

S100B, S100 calcium-binding protein B. NSE, neuron-specific enolase. UCHLI, Ubiquitin carboxy-terminal hydrolase L1. BDNF, Brain-derived neurotrophic factor. VMA, Vanillylmandelic acid. HVA, Homovanillic acid.

Table 2 presents air pollutant concentrations in the exposure airstreams of CAP, filtered ambient and filtered medical air delivered to the participants. The temperature and relative humidity were stable (mean ± standard deviation=24.0°C ± 1.2°C and 25.0% ± 12.4%, respectively). Although there was a slight overlap in the cut-off sizes of fine CAP (0.15-2.5 μm) and ultrafine CAP (≤0.3 μm), the mean ± standard deviation of median ultrafine CAP diameter during the 130-min exposures was 59.6 ± 5.7 nm (range 47 - 69.8 nm). Moreover, Table 2 shows higher concentrations of endotoxin and β-glucan in fine CAP than in ultrafine CAP, indicating that there is a clear distinction between these two size fractions.

Table 2. Pollutant concentrations in the exposure airstream.

Exposure Pollutant N Mean ± Standard deviation
Study of coarse and fine CAPs
Filtered ambient air PM (μg/m3) 29 -0.4 ± 13.5
Endotoxin [ln(ng/m3+1)] 29 0.5 ± 0.3
β-Glucan [ln(pg/m3+1)] 29 7.1 ± 1.9
Filtered medical air PM (μg/m3) 41 2.0 ± 8.8
Endotoxin [ln(ng/m3+1)] 15 0.3 ± 0.3
β-Glucan [ln(pg/m3+1)] N/Ab N/Da
Coarse CAP PM (μg/m3) 76 212.9 ± 52.0#
Endotoxin [ln(ng/m3+1)] 74 2.0 ± 1.1*#
β-Glucan [ln(pg/m3+1)] 61 10.5 ± 2.3*
Fine CAP PM (μg/m3) 29 238.4 ± 62.0#
Endotoxin [ln(ng/m3+1)] 28 2.00 ± 0.6*#
β-Glucan [ln(pg/m3+1)] 25 9.3 ± 1.1*
Study of ultrafine CAP
Filtered medical air PM (μg/m3) 25 8.8 ± 21.1
Particle number count 25 16,405 ± 53,152
Endotoxin [ln(ng/m3 + 1)] N/Ab N/Da
β-Glucan [ln(pg/m3+1)] N/Ab N/Da
Ultrafine CAP PM (μg/m3) 25 135.8 ± 67.2#
Particle number count 25 227,767 ± 63,902#
Endotoxin [ln(ng/m3 + 1)] 6 0.12 ± 0.01
β-Glucan [ln(pg/m3+1)] 6 9.0 ± 1.3
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*

Significantly different from filtered ambient air, p<0.05.

#

Significantly different from filtered medical air, p<0.05.

a

N/D, not detectable.

b

N/A, not applicable.

Endotoxin and β-glucan concentrations in coarse and fine CAPs were similar, and significantly higher than in filtered ambient air and filtered medical air. β-Glucan levels in filtered medical air were non-detectable. Endotoxin and β-glucan concentrations were measured during six ultrafine CAP exposures. The ultrafine CAP appears to contain the lowest concentrations of endotoxin and β-glucan among the three particle size fractions. The correlation coefficients between particle mass concentrations and endotoxin and β-glucan were reported in our previous publication (Liu et al. 2015), which showed a relatively strong correlation (r= 0.59-0.75, p<0.001).

Correlations between percent changes in neural biomarkers and percent changes in blood VEGF, and urinary VEGF, 8-OHdG and MDA post exposure to coarse and fine CAPs were weak although in some cases statistically significant (Supplementary Tables S1-S3), r values ranging from -0.31 between urinary 8-OHdG and urinary cortisol 21 hours post exposure to ultrafine CAP, to 0.27 between blood VEGF and blood S100B 1-hour post exposure to fine CAP, and urinary VMA 21 hours post exposure to ultrafine CAP (p<0.05). Only 1-hour post exposure values of blood and urinary VEGF and urinary 8-OHdG and MDA were used for correlation analyses, because in the previous study only these markers at 1-hr post exposure were significantly associated with exposure to CAPs (Liu et al. 2015).

Table 3 presents the mixed effects linear regression results for percent changes in blood and urinary neural biomarkers from daily pre-exposure levels after exposure to coarse, fine and ultrafine CAPs, using filtered medical air as a reference (a control). Exposure to coarse CAP was significantly associated with increased urinary VMA and cortisol measured at 21-hour post exposure, while similar trends were seen at 1-hour post exposure but statistically not significant. Exposure to fine CAP was marginally significantly associated with increased blood UCHL1 at 21-hour post exposure (p=0.07). Exposure to coarse CAP was significantly associated with a decrease in blood cortisol 1-hour and 21-hour post exposure. This trend was also observed for exposure to fine and ultrafine CAPs, although the changes were not statistically significant. Exposure to filtered ambient air was not significantly associated with changes in any neural biomarkers examined (data not shown). The number count variable for ultrafine CAP yielded similar regression outcomes (see Supplemental Material, Table S4).

Table 3.

Percent change (95% confidence interval) in blood and urinary neural biomarkers after exposure to concentrated coarse, fine and ultrafine ambient particles. Percent change was calculated using the equation: [(post minus pre-exposure)/pre-exposure]*100. Exposure type was an indicator variable, with exposure to filtered medical air as reference. Models were adjusted for age, sex, BMI, and season.

Biomarker Time post exposure Coarse CAP Fine CAP Ultrafine CAP
Blood markers
S100B 1 hr 0.1 (-10.0, 10.2) -6.8 (-19.6, 6.0) 5.8 (-6.1, 17.7)
21 hr -10.5 (-21.7, 0.7)* -9.2 (-23.3, 4.9) 3.5 (-14.4, 21.5)
NSE 1 hr -1.5 (-20.8, 17.7) -4.8 (-29.2, 19.6) 6.7 (-10.0, 23.5)
21 hr -13.2 (-28.0, 1.6)* 1.8 (-16.8, 20.3) -9.0 (-30.6, 12.5)
UCHL1 1 hr 4.5 (-6.7, 15.6) 11.5 (-2.6, 25.5) -11.9 (-30.9, 7.1)
21 hr 4.3 (-11.3, 19.8) 17.7 (-1.7, 37.2)* -0.2 (-23.2, 22.7)
Cortisol 1 hr -26.0 (-42.4, -9.6)** -11.0 (-32.1, 10.0) -16.2 (-37.9, 5.5)
21 hr -22.4 (-43.7, -1.1)** -15.5 (-42.3, 11.2) -8.0 (-29.2, 13.2)
BDNF 1 hr 4.0 (-8.6, 16.5) -6.8 (-22.7, 9.2) 17.4 (-13.4, 48.1)
21 hr 1.0 (-11.3, 13.3) 2.8 (-12.6, 18.2) 56.4 (-35.0, 147.8)
Urinary markers
VMA 1 hr 23.0 (-0.5, 46.4)* 24.8 (-5.3, 54.8) 21.2 (-2.8, 45.1)*
21 hr 19.5 (1.0, 37.9)** 16.8 (-6.5, 40.2) -3.0 (-35.4, 29.4)
HVA 1 hr 9.3 (-17.1, 35.7) 5.9 (-27.4, 39.3) 43.4 (-80.8, 167.6)
21 hr -1.0 (-24.3, 22.3) 21.0 (-8.4, 50.4) 33.4 (-68.4, 135.1)
Cortisol 1 hr 50.6 (-20.4, 121.6) 19.9 (-70.1, 109.9) -26.2 (-73.8, 21.4)
21 hr 63.5 (0.2, 126.8)** 20.4 (-59.0, 99.8) 5.6 (-25.8, 37.0)
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*

p<0.1;

**

p<0.05

Tables 4 and 5 show the regression results for percent changes in blood and urinary neural biomarkers post exposure to endotoxin and β-glucan in CAPs. Endotoxin in coarse CAP was significantly associated with increased blood UCHL1 1-hour and 21-hour post exposure, while β-glucan in coarse CAP was significantly associated with increased blood S100B and UCHL1 1-hour post exposure. Endotoxin in fine CAP was significantly associated with decreased urinary cortisol, whereas β-glucan in fine CAP was not associated with any biomarker changes.

Table 4.

Percent change (95% confidence interval) in blood and urinary neural biomarkers post exposure to one unit [ln(ng/m3+1)] of endotoxin in concentrated coarse and fine ambient particles. Percent change was calculated using the equation: [(post minus pre-exposure)/pre-exposure]*100. Models were adjusted for age, sex, BMI, and season.

Biomarker Time post exposure endotoxin in coarse CAP endotoxin in fine CAP
Blood markers
S100B 1 hr 1.8 (-5.5, 9.0) -1.3 (-17.4, 14.7)
21 hr 3.4 (-3.3, 10.1) -1.1 (-20.2, 17.9)
NSE 1 hr 6.4 (-7.3, 20.1) 2.8 (-29.1, 34.6)
21 hr 5.1 (-3.1, 13.3) 17.7 (-5.9, 41.3)
UCHL1 1 hr 10.6 (5.3,15.9)** -7.2 (-36.6, 22.2)
21 hr 15.9 (7.4, 24.4)** -15.3 (-58.1, 27.5)
Cortisol 1 hr -7.1 (-14.7, 0.5)* -33.1 (-75.9, 9.7)
21 hr -1.0 (-9.8, 7.9) 4.5 (-26.0, 34.9)
BDNF 1 hr -0.5 (-9.2, 8.1) 10.8 (-13.5, 35.1)
21 hr 0.7 (-7.0, 8.4) 7.4 (-22.2, 37.0)
Urinary markers
VMA 1 hr 6.5 (-7.6, 20.6) -6.3 (-72.0, 59.3)
21 hr 4.0 (-8.1, 16.1) -1.5 (-39.2, 36.3)
HVA 1 hr 15.7 (-0.2, 31.7)* 3.7 (-53.4, 60.7)
21 hr -9.3 (-21.9, 3.3) -3.5 (-52.4, 45.3)
Cortisol 1 hr -12.4 (-68.8, 44.0) -130.8 (-228.5, -33.1)**
21 hr -4.2 (-63.1, 54.6) -60.9 (-105.3, -16.5)**
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*

p<0.1;

**

p<0.05

Table 5.

Percent change (95% confidence interval) in blood and urinary neural biomarkers post exposure to one unit [ln(pg/m3+1)] of β-glucan in coarse and fine ambient particles. Percent change was calculated using the equation: [(post minus pre-exposure)/pre-exposure]*100. Models were adjusted for age, sex, BMI, and season.

Biomarker Time post exposure β-Glucan in coarse CAP β-Glucan in fine CAP
Blood markers
S100B 1 hr 6.3 (3.2, 9.4)** -0.7 (-10.6, 9.2)
21 hr 2.2 (-0.9, 5.4) 6.1 (-3.9, 16.1)
NSE 1 hr 2.2 (-3.7, 8.2) -0.4 (-20.1, 19.4)
21 hr 0.4 (-3.6, 4.3) 3.5 (-11.7, 18.6)
UCHL1 1 hr 3.1 (0.4, 5.9)** 9.2 (-6.5, 24.9)
21 hr 4.2 (-0.3, 8.6)* 9.1 (-14.9, 33.1)
Cortisol 1 hr -2.0 (-5.8, 1.9) -15.6 (-36.7, 5.4)
21 hr -2.1 (-6.6, 2.4) -9.8 (-27.9, 8.2)
BDNF 1 hr 0.6 (-3.0, 4.3) 9.4 (-5.0, 23.7)
21 hr 1.1 (-2.2, 4.5) 2.0 (-15.7, 19.7)
Urinary markers
VMA 1 hr 1.3 (-6.0, 8.6) 2.5 (-37.6, 42.6)
21 hr 1.4 (-4.5, 7.3) 3.9 (-19.2, 27.1
HVA 1 hr 4.7 (-3.5, 13.0) 22.1 (-10.0, 54.2)
21 hr -1.9 (-8.2, 4.5) 10.1 (-18.9, 39.2)
Cortisol 1 hr -0.1 (-29.4, 29.2) -8.7 (-37.2, 19.8)
21 hr -23.1 (-53.9, 7.6) 3.0 (-20.5, 26.5)
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*

p<0.1;

**

p<0.05

Discussion

In this randomized crossover controlled exposure study, we set out to investigate whether a 130-minute exposure to concentrated ambient coarse, fine or ultrafine PM would be associated with changes in human systemic neural biomarkers that may indicate perturbation of blood-brain barrier and systemic stress. We also sought to determine if endotoxin and β-glucan contained in these particles might play a role in the changes in these biomarkers. The results demonstrate that coarse CAP was significantly associated with increased urinary VMA and cortisol. Endotoxin and β-glucan measured in coarse CAP were significantly associated with increased blood UCHL1, and β-glucan associated with S100B as well. Unexpectedly, we also observed a significant reduction in blood cortisol post exposure to coarse CAP. Urinary cortisol was also significantly inversely associated with endotoxin in fine CAP. Exposure to fine and ultrafine CAPs revealed similar but less remarkable trends of changes in these neural biomarkers, with large confidence intervals suggesting large uncertainties likely due to smaller sample sizes (Table 2). The number count variable for ultrafine CAP yielded similar regression outcomes. Lack of response to ultrafine CAP might be explained by the lower exposure concentration and smaller number of participants compared to those of coarse CAP exposures. These biomarker changes were acute, with blood markers seen almost immediately post exposure, while urinary biomarker changes appeared to be more delayed, as they were mostly observed 21 hours post exposure. VMA is the major end-product of epinephrine and norepinephrine metabolism, while HVA is the major end-product of dopamine, a precursor of norepinephrine (Eisenhofer et al. 2004). Neurotransmitters epinephrine and norepinephrine, together with glucocorticoids such as cortisol, are regarded as stress hormones, and play a complex role in regulating cardiovascular function, energy-production and inflammation (Axelrod and Reisine 1984). UCHL1 is a neuron-specific protein that regulates ubiquitin protein modification, and has been implicated in brain injury (Li et al. 2015; Zetterberg et al. 2013). S100B is a glial-specific protein that is expressed primarily by astroglial cells (Zetterberg et al. 2013). Increased UCHL1 and S100B in peripheral blood have been postulated to be indicators of damage to the blood-brain barrier (Blyth et al. 2011; Zetterberg et al. 2013). Taken together, our findings in the present study suggest that exposure to coarse CAPs and its biological constituents may affect blood-brain barrier integrity and systemic stress levels.

Relatively few studies have reported the influence of air pollution on neural biomarkers in humans. Cliff et al. conducted a controlled diesel exhaust inhalation study (a 2-hour exposure, mean PM2.5 concentration = 289 μg/m3) (Cliff et al. 2016). Consistent with our results, they did not find any change in blood S100B, NSE, BDNF, IL-6 and TNF-α concentrations in healthy participants after the exposure. Exposure to heavy traffic (mean PM2.5 concentration = 24.6 μg/m3) while cycling for 20 minutes also did not result in increased blood BDNF levels compared to cycling in an air-filtered room (mean PM2.5 concentration = 2.0 μg/m3) (Bos et al. 2011). Long-term exposure to elevated air pollution in Mexico City has been associated with neuroinflammation and disruption of blood-brain barrier (Calderón-Garcidueñas et al. 2008; Calderón-Garcidueñas et al. 2015; Calderón-Garcidueñas et al. 2016). An in vivo study using rats showed that inhalation of diesel exhaust particles (0.5 and 2 mg/m3) for 4 weeks and a single intratracheal administration of diesel exhaust particles (20 mg/kg) caused an increase in a whole host of inflammatory cytokines and microglial (immune cells) reaction in the brain, indicating neuroinflammation, but the exposure concentration was much higher than that used in our study (Levesque et al. 2011). Exposing cultured PC-12 cells to ultrafine particles in diesel exhaust significantly increased intracellular concentrations of dopamine and its metabolites HVA and dihydroxyphenylacetic acid, as well as oxidative stress biomarkers (Kim et al. 2014).

As documented by Block and Calderon-Garciduenas (Block and Calderón-Garcidueñas 2009), multiple studies have linked air pollution to neuroinflammation in humans and animals, and suggested systemic inflammation and oxidative stress as a possible route of effects on central nervous system. In previous studies on the same cohort of participants, we found that exposure to these concentrated ambient particles and their biological constituents were significantly associated with increased blood and urinary VEGF [a mediator that regulates endothelial progenitor cells and also induces microvascular permeability (Ribatti 2004)], increased urinary 8-OHdG [a marker of DNA oxidative damage (Park and Floyd 1992)] and MDA [a marker of lipid oxidative degradation (Janero 1990)] (Liu et al. 2015). To examine whether post-exposure inflammatory and oxidative stress markers had any relationship with neural biomarkers, we conducted correlation analyses. The results show that post-exposure changes in urinary VEGF and 8-OHdG were weakly albeit statistically significantly correlated with changes in urinary VMA and HVA (r ranging between 0.17 and 0.27, p<0.05), while changes in blood VEGF were weakly correlated with changes in blood S100B and NSE (r ranging between 0.19 and 0.27, p<0.05). These results suggest a limited linkage between particle exposure-induced oxidative stress and inflammation and changes in neural biomarkers in the current experimental setting.

In the present study, exposure to coarse CAP was inversely significantly associated with total blood cortisol concentrations measured at both time points. Endotoxin in fine CAP was also inversely significantly associated with free urinary cortisol concentrations. Contrary to these findings, exposure to coarse CAP was significantly positively associated with urinary free cortisol concentrations at 21-hour post exposure. Since all exposures were carried out at the same time of the day, it is unlikely that the circadian rhythm of cortisol had a significant influence on the blood and urine cortisol responses. Lower cortisol levels are at odds with the literature, as most studies reported an immediate increase in blood and urinary cortisol levels after an acute mental (Morgan,C.A.3rd et al. 2002) or physiological (intravenous injection of hydrocortisone or endotoxin) (Jung et al. 2014; Vedder et al. 1999) stress on humans, returning to a near baseline level 24 hours later. Post-acute stress elevated urinary cortisol levels can last for a longer period of time (Jung et al. 2014). A 2-hour exposure to 0.3 ppm ozone resulted in a significant increase in plasma cortisol levels in human subjects (Miller et al. 2016). Likewise, exposing rats to particulate matter and ozone also caused a significant increase in plasma glucocorticoide corticosterone immediately post exposure (Thomson et al. 2016; Thomson et al. 2013). Regulation of cortisol is a complex issue, which involves numerous hormones, systems and feedback loops that may be affected by various pathophysiological conditions (Axelrod and Reisine 1984; Keenan et al. 2001). Hypothalamo-pituitary-adrenal axis functions were not assessed in this study, and the ELISA assay only measured total cortisol in blood and free cortisol in urine, providing no information on the fraction of cortisol bound to blood proteins or on the hepatic metabolism of cortisol into inactive metabolites (Hellhammer et al. 2009). Although our observation of increased urinary concentrations of cortisol and VMA suggest an elevated systemic stress level post exposure to coarse CAP, our findings on blood cortisol are not in line with these previous studies, and warrant further investigation on the reproducibility of these observations and on the involved molecular mechanisms.

Although the levels of endotoxin and β-glucan in coarse and fine CAPs were similar, neural biomarker changes were only significantly associated with endotoxin and β-glucan measured in coarse CAP. One explanation for this may be that coarse and fine CAPs are different in airway deposition locations and rates (Heyder 2004), which may have influenced the varying effects of biological constituents carried by these particle size fractions. It is also possible that the sample size for fine CAP exposure, which was smaller than for coarse CAP exposure, may have resulted in a lower statistical power to detect a statistically significant difference.

In conclusion, in this study we found that a 130-minute exposure to concentrated ambient coarse PM was associated with increased urinary biomarkers indicating stress hormone response, while endotoxin and β-glucan measured in coarse CAP were associated with increased blood neural biomarkers that may indicate perturbations of blood-brain barrier integrity. These results may help provide some biological basis to interpret epidemiological findings that have observed associations between short-term exposure to ambient air pollution and adverse neuro-psychological responses.

Supplementary Material

1
2

Highlight.

  • Healthy non-smoking volunteers were exposed to filtered clean air, and coarse, fine and ultrafine particles that came from outdoor air.

  • Biological constituents endotoxin and β -1,3-D-glucan in the particles, and neural biomarker levels in blood and urine were measured.

  • Associations between exposure to particulate matter and changes in neural biomarkers were examined.

  • Coarse particulate matter and its biological constituents may influence neural biomarker levels that reflect perturbations of blood-brain barrier and systemic stress response.

Acknowledgments

The authors wish to thank the staff at the Division of Occupational and Environmental Health, University of Toronto, for their technical work on controlled exposures; Yasmin Dirieh at Health Canada for her work on biomarkers; Rachel Cliff at the University of British Columbia for her insight on neural biomarkers.

Funding: This work was supported by Health Canada's Clean Air Regulatory Agenda, USEPA RD-83241601, NIH Grant P30 ES005605, Environment and Climate Change Canada, and AllerGen NCE. Infrastructure for concentrated ambient particle exposure facility was provided by SOCAAR through funding from the Canada Foundation for Innovation. The contents of this publication are solely the responsibility of the grantee and do not necessarily represent the official views of the funding agencies. The funding agencies do not endorse the purchase of any commercial products or services mentioned in the publication.

Footnotes

Competing Financial Interests Declaration: The authors have no competing financial interests in this work.

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