2016 Progress Report: Cardiometabolic, Autonomic, and Airway Toxicity of Acute Exposures to PM2.5 from Multipollutant Atmospheres in the Great Lakes Region

EPA Grant Number: R834797C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R834797
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Great Lakes Air Center for Integrative Environmental Research
Center Director: Harkema, Jack
Title: Cardiometabolic, Autonomic, and Airway Toxicity of Acute Exposures to PM2.5 from Multipollutant Atmospheres in the Great Lakes Region
Investigators: Harkema, Jack , Fink, Greg , Wagner, James
Institution: Michigan State University
EPA Project Officer: Ilacqua, Vito
Project Period: December 1, 2010 through November 30, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: December 1, 2015 through November 30,2016
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Our objectives in Project 2 arise out of GLACIER’s overarching hypothesis that the major air pollutants, fine particulate matter (PM2.5) and ozone (O3), are 1) capable of eliciting multiple important adverse cardiometabolic health effects that are dependent on 2) the local multipollutant milieu, 3) an individual’s pre-existing cardiovascular (CV) and metabolic condition (susceptibility factors), and 4) the interactive toxicity of PM2.5 and O3 co-exposure. Goals of Project 2 are to determine the cardiovascular (CV), autonomic nervous system (ANS), and airway toxicity in rats acutely exposed to concentrated ambient PM2.5 (CAP) from distinct multipollutant atmospheres commonly found in the Great Lakes Region of the United States. Our studies are extensions of our previous findings that CAP-induced alterations in heart rate variability are dependent on specific PM2.5 emission sources in distinct locations in the Great Lakes Region. We will use a mobile air research facility (AirCARE 1) that is fully equipped with inhalation toxicology and atmospheric monitoring labs to conduct toxicology studies of rats exposed to CAP derived from real-world PM2.5 in three distinct locations dominated by industrial/urban, transported/regional, or near-roadway/residential emission sources. Blood pressure, heart rate, heart rate variability and direct measurements of autonomic nerve activity will be continuously monitored during CAP and/or O3 exposures in lean or obese rats with and without diet-induced facets of the cardiometabolic syndrome (CMS; hypertension, insulin resistance, endothelial dysfunction), respectively. Acute functional responses will be measured by radiotelemetry and will be correlated with specific PM constituents and their emission sources determined for the same highly resolved 30-minute timeframes, thereby making associations of exposure and health effects especially robust. Studies will feature novel real-time sympathetic nerve recordings during PM2.5 and/or O3 inhalation exposure. In addition, our project will highlight the unique integrative capabilities of our research team to link specific health cardiovascular effects in a sensitive obese population with PM content by a combined technological expertise that is unavailable elsewhere. Our GLACIER project will extend and complement the research of lean and obese human subjects (Project 1), conducted at the same exposure sites, by making invasive and prolonged measurements that could not be practically or ethically done in humans (e.g., repeated CAP exposures, continuous recordings of CV and autonomic nerve function, and microscopic examination of multiple organs for exposure-related pathology). Our acute animal studies will also overlap and integrate scientifically with the animal toxicology study of long-term multipollutant exposures in Project 3.

Progress Summary:

There have been no changes to our study investigators in year 6 of this project. Our objectives in Project 2 have also remained the same in Year 6. In this no-cost extension period, one of our primary aims was to submit manuscripts of our latest research to appropriate scientific journals for their peer review and consideration of publication. In collaboration with our investigators in Project 3, two of these manuscripts were accepted for publication and have been now published in the journal of Inhalation Toxicology (Zhong et al. 2016; Ying et al. 2016). In addition, Project 2 investigators have submitted two additional manuscripts to the American Journal of Respiratory Cell and Molecular Biology on the development of nasal type 2 immunity and eosinophilic rhinitis in mice repeatedly exposed to ozone. These papers have now been published in this journal (Ong et al. 2016; Kumagai et al. 2016). The paper by Kumagai et al. received the Society of Toxicology (SOT) Inhalation Toxicology Specialty Section’s Paper of the Year Award at the SOT’s annual conference in March 2016 (New Orleans, LA). This was a very important paper because it the first report that recently discovered innate lymphoid cells (ILCs) mediate air pollutant-induced nasal airway lesions in mice that mimic those found in children with non-atopic rhinitis and asthma.

 

In addition, to the publication of manuscripts we have finished two important studies that further define our ozone-induced mouse model of non-atopic rhinitis and asthma that is dependent on ILC mediation of type 2 immunity and eosinophilic airway inflammation in both the nose and lungs. Epidemiological associations have been found between elevated ambient concentrations of ozone and the onset of eosinophilic airway inflammation in children. Recently we have reported that repeated exposure to 0.8 ppm ozone induces eosinophilic rhinitis, nasal epithelial remodeling (e.g., mucous cell metaplasia), and type-2 immune-related transcripts in the nasal airways of ILC-sufficient Rag2-/- mice, that are also devoid of T and B lymphoid cells, and in C57BL/6 mice (genetic background for knockout mice) that are sufficient for all lymphoid cells, including ILC. In contrast, these type-2 immune nasal responses were completely absent in similarly exposed Rag2-/-Il2rg-/- mice that are devoid of all types of lymphoid cells, including ILC. In the first study of the sixth year of Project 2, we elucidated the role of ILC in the pathogenesis of ozone-induced pulmonary airway lesions by using ILC-sufficient C57BL/6 and Rag2-/- mice, and ILC-deficient Rag2-/-Il2rg-/- mice. Mice were exposed to 0 ppm (filtered air) or 0.8 ppm ozone for 1 day (a single 4-h exposure) or 9 consecutive weekdays (repeated 4h/day exposures). Bronchoalveolar lavage fluid (BALF) was collected and lung tissues were processed for light microscopy, morphometry, and mRNA expression analyses.

 

All three strains of mice had increased numbers of neutrophils in BALF and bromodeoxyuridine-positive nuclei (marker of reparative DNA synthesis following toxicant-induced cell death) in the bronchiolar epithelium after 1-day exposure to ozone, as compared to filtered air-exposed control mice. Ozone-exposed, ILC-sufficient C57BL/6 and Rag2-/- mice had increased numbers of BALF eosinophils and mucous cell metaplasia in the bronchiolar epithelium after 9 days of exposure. Repeated exposures to ozone also elicited overexpression of Il13, Muc5ac, Muc5b, Gob5 (Clca1), and Ym2 (Chil4) mRNA in ILC-sufficient C57BL/6 and Rag2-/- mice. In contrast, ozone-exposed, ILC-depleted Rag2-/-Il2rg-/- mice had no pulmonary airway pathology or overexpression of transcripts related to type-2 immunity after the 9-day exposure.

These results indicate that ILC (most likely group 2 ILC) play a key role in the development of innate-type allergy caused by repeated, but not single, ozone exposure. This study in mice also provides a plausible biological paradigm for the activation of eosinophilic inflammation and type-2 immunity in the airways of children repeatedly exposed to high ambient levels of ozone.

 

Our second study of the 6th year was designed to test the hypothesis that there are murine strain-dependent differences in pulmonary and nasal pathologic responses to repeated ozone exposure (i.e., murine model of non-atopic asthma and rhinitis). Male, 7-8 week-old, C57BL/6 and BALB/c mice were exposed to 0 or 0.8 ppm ozone, 4 h/day, for 9 consecutive week-days. One day after the end of the inhalation exposures, mice were sacrificed and bronchoalveolar lavage fluid (BALF) was collected for cytologic analyses. The left lung lobe and nose were processed for histopathologic examination and morphometric analysis. The right caudal lung lobe was analyzed for gene expression analysis using qRT-PCR. In both strains of mice, ozone induced eosinophilic inflammation and mucous cell metaplasia in the nasal and pulmonary airways. Lungs of ozone-exposed C57BL/6 mice, however, had greater eosinophilic inflammation, mucous cell metaplasia, and the expression of genes related to type 2 immunity and airway mucus production/secretion, as compared to ozone-exposed BALB/c mice. Ozone-exposed C57BL/6 mice also had greater eosinophilic rhinitis, but a similar degree of mucous cell metaplasia in nasal epithelium, as compared to similarly exposed BALB/c mice. Results of this study indicate that the magnitude of ozone-induced non-atopic asthma and rhinitis vary depending on the strain of mouse. This suggests that individuals may vary in their inflammatory and epithelial responses to repeated ozone exposures that are due, in part, to genetic factors.

 

Collaborative Research Effort with the Harvard Clean Air Research Center.

 

Toxicity of Traffic-Based Air Pollution in Rats with Diet-Induced Cardiometabolic Syndrome: In the Fall of 2012, investigators from GLACIER and Harvard University CLARC initiated an intraCLARC collaborative toxicology study under the principal direction of Drs. Jack Harkema (GLACIER) and John Godleski (Harvard University). Using our established high fructose-diet-fed rat model of CMS, the collaborative study was designed to determine if this dysfunctional cardiometabolic condition predisposes to the toxic effects of traffic-related air pollution and to identify underlying toxicological modes of action by which this may occur. Our goal is to discern if CMS renders the laboratory animal more susceptible to the cardiovascular, autonomic and airway toxicity of a multipollutant mixture of primary particles and secondary organic aerosols derived from traffic emissions in the Boston Tunnel. Data analysis was completed in 2016 and a manuscript will be submitted for publication shortly. A brief description of the rationale, design and results of this study are presented below.

 

Epidemiological studies have linked exposures to ambient fine particulate matter (PM2.5) and vehicular traffic with autonomic nervous system imbalance and adverse cardiac outcomes, especially in individuals with preexisting disease. It is unclear whether metabolic syndrome (MetS) confers susceptibility to the cardiovascular or autonomic effects of PM2.5. We hypothesized that exposure to traffic-derived primary and secondary organic aerosols (P+SOA) at ambient levels would cause pronounced autonomic and cardiovascular dysfunction in rats exhibiting features of MetS. Male Sprague Dawley rats were fed a high-fructose diet (HFrD) to induce MetS, and exposed to either P+SOA (20.4 ± 1.2 µg/m3) or filtered air (FA) for 12 days and compared to similarly-exposed normal diet (ND) rats.

 

In MetS rats P+SOA decreased HRV, QTc, PR, and expiratory time overall, increased breathing rate overall, decreased baroreflex sensitivity (BRS) on three exposure days, and increased spontaneous atrioventricular (AV) block Mobitz Type II arrhythmia on exposure day 4 relative to FA. Among ND rats, P+SOA decreased HRV only on day 1 and did not significantly alter BRS despite overall hypertensive responses relative to FA. Correlations between HRV, ECG, BRS, and breathing parameters suggested a role for autonomic imbalance in the adverse cardiophysiologic effects of P+SOA among MetS rats. Autonomic cardiovascular responses to P+SOA at ambient PM2.5 levels were pronounced among MetS rats and indicated impaired vagal regulation of cardiovascular physiology. Results support epidemiologic findings that MetS confers susceptibility to the adverse cardiac effects of ambient-level PM, potentially through autonomic nervous system imbalance.

Future Activities:

We anticipate that at least two additional manuscripts will be submitted and accepted for publication before the end of the year.


Journal Articles on this Report : 23 Displayed | Download in RIS Format

Other subproject views: All 73 publications 28 publications in selected types All 28 journal articles
Other center views: All 147 publications 71 publications in selected types All 71 journal articles
Type Citation Sub Project Document Sources
Journal Article Brandenberger C, Li N, Jackson-Humbles DN, Rockwell CE, Wagner JG, Harkema JR. Enhanced allergic airway disease in old mice is associated with a Th17 response. Clinical & Experimental Allergy 2014;44(10):1282-1292. R834797 (2014)
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  • Journal Article Brook RD, Bard RL, Kaplan MJ, Yalavarthi S, Morishita M, Dvonch JT, Wang L, Yang H-Y, Spino C, Mukherjee B, Oral EA, Sun Q, Brook JR, Harkema J, Rajagopalan S. The effect of acute exposure to coarse particulate matter air pollution in a rural location on circulating endothelial progenitor cells: results from a randomized controlled study. Inhalation Toxicology 2013;25(10):587-592. R834797 (2013)
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  • Journal Article Brook RD, Xu X, Bard RL, Dvonch JT, Morishita M, Kaciroti N, Sun Q, Harkema J, Rajagopalan S. Reduced metabolic insulin sensitivity following sub-acute exposures to low levels of ambient fine particulate matter air pollution. The Science of the Total Environment 2013;448:66-71. R834797 (2012)
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  • Journal Article Brook RD, Bard RL, Morishita M, Dvonch JT, Wang L, Yang HY, Spino C, Mukherjee B, Kaplan MJ, Yalavarthi S, Oral EA, Ajluni N, Sun Q, Brook JR, Harkema J, Rajagopalan S. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environmental Health Perspectives 2014;122(6):624-630. R834797 (2013)
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  • Journal Article Byrd JB, Morishita M, Bard RL, Das R, Wang L, Sun Z, Spino C, Harkema J, Dvonch JT, Rajagopalan S, Brook RD. Acute increase in blood pressure during inhalation of coarse particulate matter air pollution from an urban location. Journal of the American Society of Hypertension 2016;10(2):133-139. R834797 (2016)
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  • Journal Article Liu C, Ying Z, Harkema J, Sun Q, Rajagopalan S. Epidemiological and experimental links between air pollution and type 2 diabetes. Toxicologic Pathology 2013;41(2):361-373. R834797 (2013)
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  • Journal Article Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. Air pollution-mediated susceptibility to inflammation and insulin resistance:influence of CCR2 pathways in mice. Environmental Health Perspectives 2014;122(1):17-26. R834797 (2013)
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  • Journal Article Liu C, Bai Y, Xu X, Sun L, Wang A, Wang TY, Maurya SK, Periasamy M, Morishita M, Harkema J, Ying Z, Sun Q, Rajagopalan S. Exaggerated effects of particulate matter air pollution in genetic type II diabetes mellitus. Particle and Fibre Toxicology 2014;11:27. R834797 (2014)
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  • Journal Article Maiseyeu A, Yang H-Y, Ramanathan G, Yin F, Bard RL, Morishita M, Dvonch JT, Wang L, Spino C, Mukherjee B, Badgeley MA, Barajas-Espinosa A, Sun Q, Harkema J, Rajagopalan S, Araujo JA, Brook RD. No effect of acute exposure to coarse particulate matter air pollution in a rural location on high-density lipoprotein function. Inhalation Toxicology 2014;26(1):23-29. R834797 (2014)
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  • Journal Article Morishita M, Bard RL, Kaciroti N, Fitzner CA, Dvonch T, Harkema JR, Rajagopalan S, Brook RD. Exploration of the composition and sources of urban fine particulate matter associated with same-day cardiovascular health effects in Dearborn, Michigan. Journal of Exposure Science & Environmental Epidemiology 2015;25(2):145-152. R834797 (2014)
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  • Journal Article Morishita M, Bard RL, Wang L, Das R, Dvonch JT, Spino C, Mukherjee B, Sun Q, Harkema JR, Rajagopalan S, Brook RD. The characteristics of coarse particulate matter air pollution associated with alterations in blood pressure and heart rate during controlled exposures. Journal of Exposure Science & Environmental Epidemiology 2015;25(2):153-159. R834797 (2014)
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  • Journal Article Ong CB, Kumagai K, Brooks PT, Brandenberger C, Lewandowski RP, Jackson-Humbles DN, Nault R, Zacharewski TR, Wagner JG, Harkema JR. Ozone-induced type 2 immunity in nasal airways. Development and lymphoid cell dependence in mice. American Journal of Respiratory Cell and Molecular Biology 2016;54(3):331-340. R834797 (2014)
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  • Journal Article Pancras JP, Landis MS, Norris GA, Vedantham R, Dvonch JT. Source apportionment of ambient fine particulate matter in Dearborn, Michigan, using hourly resolved PM chemical composition data. The Science of the Total Environment 2013;448:2-13. R834797 (2013)
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  • Journal Article Vital M, Harkema JR, Rizzo M, Tiedje J, Brandenberger C. Alterations of the murine gut microbiome with age and allergic airway disease. Journal of Immunology Research 2015;2015:892568 (8 pp.). R834797 (2015)
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  • Journal Article Wagner JG, Allen K, Yang HY, Nan B, Morishita M, Mukherjee B, Dvonch JT, Spino C, Fink GD, Rajagopalan S, Sun Q, Brook RD, Harkema JR. Cardiovascular depression in rats exposed to inhaled particulate matter and ozone: effects of diet-induced metabolic syndrome. Environmental Health Perspectives 2014;122(1):27-33. R834797 (2013)
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  • Journal Article Wagner JG, Kamal AS, Morishita M, Dvonch JT, Harkema JR, Rohr AC. PM2.5-induced cardiovascular dysregulation in rats is associated with elemental carbon and temperature-resolved carbon subfractions. Particle and Fibre Toxicology 2014;11:25 (10 pp.). R834797 (2014)
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  • Journal Article Wellenius GA, Boyle LD, Wilker EH, Sorond FA, Coull BA, Koutrakis P, Mittleman MA, Lipsitz LA. Ambient fine particulate matter alters cerebral hemodynamics in the elderly. Stroke 2013;44(6):1532-1536. R834797 (2016)
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  • Journal Article Xu X, Liu C, Xu Z, Tzan K, Zhong M, Wang A, Lippmann M, Chen LC, Rajagopalan S, Sun Q. Long-term exposure to ambient fine particulate pollution induces insulin resistance and mitochondrial alteration in adipose tissue. Toxicological Sciences 2011;124(1):88-98. R834797 (2014)
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  • Journal Article Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of sympathetic nervous system:a role for hypothalamic inflammation. Environmental Health Perspectives 2014;122(1):79-86. R834797 (2013)
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  • Journal Article Kumagai K, Lewandowski R, Jackson-Humbles DN, Li N, Van Dyken SJ, Wagner JG, Harkema JR (2016). Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells. American Journal of Respiratory Cell and Molecular Biology 2016;54(6):782-791. R834797 (Final)
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  • Journal Article Ong CB, Kumagai K, Brooks PT, Brandenberger C, Lewandowski RP, Jackson-HumblesDN, Nault R, Zacharewski TR, Wagner JG, Harkema JR. (2016) Ozone-Induced Type 2 Immunity in Nasal Airways: Development and Lymphoid Cell Dependence in Mice. American Journal of Respiratory Cell and Molecular Biology 2016;54(3):331-340. R834797 (Final)
    R834797C002 (2016)
    R834797C002 (Final)
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  • Journal Article Ying Z, Allen K, Zhong J, Chen M, Williams KM, Wagner JG, Lewandowski R, Sun Q, Rajagopalan S, Harkema JR. Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. Inhalation Toxicology 2016;28(4):155-163. R834797 (Final)
    R834797C002 (2016)
    R834797C002 (Final)
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  • Journal Article Zhong J, Allen K, Rao X, Ying Z, Braunstein Z, Kankanala SR, Xia C, Wang X, Bramble LA, Wagner JG, Lewandowski R, Sun Q, Harkema JR, Rajagopalan S (2016). Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. Inhal Toxicol. 28(9):383-92. PubMed PMID:27240593. R834797C002 (2016)
    R834797C002 (Final)
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    Supplemental Keywords:

    inhalation toxicology, acute multipollutant exposures, high-fructose diet, rats, PM, ozone, cardiometabolic syndrome., Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, air toxics, Health Risk Assessment, Biochemistry, Biology, Risk Assessment, ambient air quality, particulate matter, aerosol particles, susceptible populations, human exposure, physiology, acute cardiovascualr effects, cardiopulmonary, cardiotoxicity, human health

    Relevant Websites:

    Great Lakes Air Center Exit  

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R834797    Great Lakes Air Center for Integrative Environmental Research

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834797C001 Cardiometabolic Effects of Exposure to Differing Mixtures and Concentrations of PM2.5 in Obese and Lean Adults
    R834797C002 Cardiometabolic, Autonomic, and Airway Toxicity of Acute Exposures to PM2.5 from Multipollutant Atmospheres in the Great Lakes Region
    R834797C003 Long Term Metabolic Consequences of Exposures to Multipollutant Atmospheres in the Great Lakes Region