2014 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: August 1, 2013 through July 31,2014
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 coexposure. 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:

Our studies have been designed to address GLACIER’s overarching hypothesis that the major criteria 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. Research in Year 4 addressed all four of these hypotheses by conducting both field-exposure studies and mechanism-driven experiments. These studies were 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. Our results in Years 1-4 have been designed to extend and complement the initial research of lean and obese human subjects (Project 1), by making invasive and prolonged measurements in laboratory rats/mice that could not be practically or ethically done in humans (e.g., repeated CAP exposures, semi-continuous cardiovascular recordings, and microscopic examination of multiple organs for exposure-related pathology). Our acute animal studies were also designed to contrast and complement the initial animal toxicology studies of long-term multipollutant exposures in Project 3. 
 
In Year 4, several research milestones were achieved that led directly to a better understanding of the health effects of both individual pollutant and multipollutant exposures in the face of experimentally induced facets of the cardiometabolic syndrome (CMS). Specifically these milestones included the following: 1) Our field study of rats fed normal or a high fructose (HFr) diet, and repeatedly exposed to O3 and concentrated PM2.5 aerosols in the urban/industrial community of Dearborn MI was published in the January issue of Environmental Health Perspectives (Jan;122:27-33, 2014); 2) We finished the telemetric, cardiovascular data analysis from rats in a similar inhalation toxicology study designed to investigate the toxicity of PM2.5, O3 and PM2.5/O3 exposures but in a rural/regional airshed (Dexter, MI); 3) We completed a laboratory study designed to determine the effects of O3 exposure on the development of insulin resistance and other health facets of the CMS in mice that are genetically prone to develop type two diabetes (T2D); 4) We initiated a study investigating the role of lymphocytes in the development of O3-induced eosinophilic rhinitis in mice; and 5) We continued our data analysis from an intraCLARC collaborative animal toxicology study with Harvard University that employed our rat model of diet-induced CMS and their inhalation exposure system to traffic emissions from the Boston Tunnel. A brief summary of specific Project 2 accomplishments in the last year and proposed future studies in Year 5 are briefly described below. 
 
Rat Inhalation Toxicology Study in Dexter, MI. In June 2013, we initiated a rat inhalation toxicology study at our rural/regional exposure site in Dexter, MI, that was similar in design to that previously conducted in Dearborn MI. Repeated acute inhalation exposures of rats, fed normal (ND) or HFr-diets (HFrD), to O3/PM2.5, were performed for 19 consecutive weekdays, 8 h/day, in our mobile air research laboratory (AirCARE I) parked in a rural setting in Dexter, MI. In contrast to the urban/industrial site in Dearborn MI with local traffic and industrial air pollutant emission sources, this Dexter exposure site is dominated by transferred air pollution from distant regional emission sources. Like the previous Dearborn study, cardiovascular responses (e.g., blood pressure, heart rate, heart rate variability) were measured every 5 minutes by radiotelemetry during and after daily exposures. The inhalation exposures were successfully completed in early July. 
 
Drs. Cathie Spino and Bin Nan from our Biostatistical and Data Management Core (BDM) at the University of Michigan completed a thorough quality control and statistical analysis of all the data collected from this study. We first used data from the first nine days from this study to compare the responses to O3/PM2.5 in Dexter to our previous data from rats exposed to O3 alone and to O3/PM2.5 in Dearborn. We found that inhalation of O3/PM2.5 in Dexter caused significant drops in mean arterial pressure (3-8 mm Hg) in rats fed ND that were maintained for most days of the exposures (Figure A, black circles). In contrast, both decreases and increases in blood pressure (3-5 mm Hg) were detected in HFrD rats during exposures (Fig 1A, white circles). These responses are in stark contrast to O3/PM2.5 exposure in urban/industrial Dearborn (Fig 1B) where ND rats had no exposure-related responses and HFrD quickly adapted after acute drops in blood pressure during the first day of exposure. In both rural Dexter and urban Dearborn, coexposure to PM2.5 diminished the vascular response induced by O3 exposure alone (compare Fig 1A and 1B to 1C). 
 
 
Figure 1. Daily Effect of Inhalation Exposure to O3/PM2.5 in Dexter, MI (A), O3/PM2.5 in Dearborn, MI (B) or O3 alone (C) on Blood Pressure in Rats Fed Normal (black circles) or High Fructose (white circles) Diets. Data is plotted as the effect estimate on blood pressure (mm Hg) of the indicated exposure compared to filtered air (indicated by dotted line – zero axis). *‐indicates significant difference from Air exposed rats on the same Diet; ** ‐ indicates significant difference from rats fed a Normal Diet. 
 
 
Changes in heart rate were initially similar in ND- and HFrD rats exposed O3/PM2.5 in Dexter, with acute drops (40-60 bpm) during the first two days, and followed by increases (10-30 bpm) by end of the week (Fig 2A). During the second week of exposure diet-related responses diverged, with drops in HR consistently greater in HFrD compared to ND rats. In Dearborn, exposure to O3/PM2.5 caused drops in heart rate were that were remarkable during the first two days (decreases of 40-70 bpm), but were less dramatic with repeated exposures (0-20 bpm decreases; Fig 2B). Coexposure to PM2.5 in either Dexter or Dearborn enhanced O3-induced drops in heart rate in ND rats the first two days of exposure (compare Fig 2A and 2B to 2C), but this effect diminished with repeated coexposure. Furthermore PM2.5 at both sites was associated with diminished ozone-induced cardiac responses by O3, with greater effects by urban PM in Dearborn. Overall responses to coexposures to O3 and PM2.5 were not greater than exposure to O3 alone. 
 
Figure 2. Exposure-related responses of decreased blood pressure and heart rate persisted during a third and fourth week of exposure to O3/PM2.5 (Fig 3). Depression on blood pressure was similar in NF and HFrD rats (5 mm Hg), but drops in heart rate were greater in HFrD rats (~40 bpm). 
 
 
Figure 3. Daily Effect of 4‐Week Inhalation Exposure to O3/PM2.5 in Dexter, MI on Blood Pressure (A) and Heart Rate (B) in Rats Fed Normal (black circles) or High Fructose (white circles) Diets. Data is plotted as the effect estimate on cardiovascular responses O3/PM2.5 exposure compared to filtered air (indicated by dotted line – zero axis). *‐indicates significant difference from Air exposed rats on the same Diet; ** ‐ indicates significant difference from rats fed a Normal Diet. 
 
 
Associations of Exposure/Health Outcomes in Rats, Dearborn, MI. With the help of Dr. Bin Nan in the Biostatistics and Data Management Core, and Dr. Morishita in the Exposure Core, cardiovascular responses and PM2.5 metrics (e.g., trace elements, gases, sources) collected over the same 30-minute timeframes were analyzed with linear mixed model approaches to determine the effect of PM2.5 emission sources on blood pressure and heart rate. Dr. Morishita determined that our field site at Salinas Elementary School in Dearborn, MI, was impacted by five major sources of PM2.5: secondary, urban dust, diesel/motor vehicle, refinery, and iron/steel. Depression in blood pressure in both ND and HFrD rats was related to diesel/motor vehicle sources, while iron/steel manufacturing was associated with increased blood pressure in ND rats (Fig 4A). Traffic sources were also associated with decreased heart rate in HFrD (Fig 4B), whereas urban dust was linked to increase heart rate in these same animals. These data suggest that subjects with metabolic syndrome may be more susceptible to traffic sources of PM2.5 than normal healthy subjects, and sensitivity for cardiovascular responses to specific PM sources is dependent on metabolic health.
 
Figure 4. Effect Estimates for Cardiovascular Responses to Inhalation Exposure to PM2.5 Derived From Specific Emission Sources. Data are expressed as change in blood pressure (A), and heart rate (B) per IQR of PM2.5 emission sources. Estimates with confidence intervals that do not intersect the 0‐axis are significant, p < 0.05.
 
 
Metabolic and Respiratory Effects of Ozone Exposure in Mice Genetically Prone to Type II Diabetes (T2D). Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects of air pollution. Mice chronically exposed to particulate air pollutants induce insulin resistance (IR), an early indicator of type II diabetes (T2D). In this study we tested the hypothesis that episodic inhalation exposures to a common gaseous air pollutant, ozone (O3), will induce early onset of IR in mice genetically prone to develop T2D. Male C57BL/6, KK, and KKAy mice were exposed to 0 ppm (filtered air; FA) or 0.5 ppm O3, 4 h/day, for 13 weekdays. Two hours after the last exposure, mice were subjected to insulin tolerance tests (ITT) and then sacrificed 24 hours postexposure. Mice received a single intraperitoneal injection of insulin and blood glucose levels were measured at 0, 10, 20, 30, 60, 90, 120 and 130 minutes after injection. Bronchoalveolar lavage fluid (BALF) was analyzed for inflammatory cells, and lungs were processed for light microscopy. 
 
Normoglycemic, C57BL/6 mice exposed to FA or O3 had normal ITT. Marked IR was present in O3- but not FA-exposed KK mice. Both FA- and O3-exposed, hyperglycemic KKAy mice developed IR. In C57BL/6 mice, O3 caused modest increases in the number of BALF inflammatory cells and minimal to mild pulmonary pathology. In contrast, O3 induced greater increases in BALF inflammatory cells in the hyperglycemic KK mice, along with more severe pulmonary pathology. KKAy mice exposed to O3 had the greatest numbers of BALF inflammatory cells and the most severe pulmonary pathology of all the mice. 
 
In conclusion, episodic Oexposures caused an early onset of IR in mice genetically prone to T2D. These hyperglycemic animals had greater O3-induced lung injury and inflammation compared to normoglycemic, insulin responsive mice. These results suggest that people at risk for T2D may be more susceptible to respiratory and metabolic health effects caused by elevated concentrations of ambient O3
 
Figure 5. Insulin tolerance tests (ITT) in C57/BL/6, KK and KKAy mice after exposure to 0 or 0.5 ppm O3 for 13 consecutive weekdays. 
 
 
Development of Ozone-Induced Eosinophilic Rhinitis is Lymphoid-Dependent. While nasal epithelial injury and remodeling have been reported in laboratory animals repeatedly exposed to O3, associated granulocytic rhinitis and pro-inflammatory cytokine expression have not been fully characterized. We investigated the temporal changes in granulocyte influx, cytokine gene expression, and epithelial remodeling in the nasal mucosa of mice episodically exposed to O3
 
C57BL/6 male mice were exposed to 0 or 0.5 ppm Ofor 1, 2, 4, or 9 weekdays (4 h/day). Airway mucosa from nasal turbinates and lateral wall were analyzed for cytokine and epithelial gene expression. Nasal tissues were prepared for light microscopy and morphometry. Immunohistochemistry was used to identify neutrophils, eosinophils, and chitinase-like proteins (Ym1/Ym2). Epithelial mucosubstances were histochemically detected. 
 
Figure 6. Total inflammatory cells in the bronchoalveolar lavage fluid of mice exposed to ozone or air for 13 consecutive weekdays.
 
 
1-day-O3 exposure induced a marked neutrophilic influx and concurrent epithelial necrosis (Figure 7). These responses were associated with overexpression of KC, MIP-2, IL-1, IFN, IL-5, IL-6 and eotaxin genes. After repeated O3 exposures, neutrophils waned and eosinophils increased, along with epithelial regeneration and remodeling. 9-day-O3 exposed mice had marked eosinophilic rhinitis with few neutrophils, mucous cell metaplasia and increased epithelial Ym1/Ym2 proteins (Figure 7). Concurrently there was overexpression of Gob5, Muc5AC, IL4, IL5, eotaxin and Ym2 genes. 24-day-O3 mice developed marked eosinophilic rhinitis, epithelial hyperplasia, mucous cell metaplasia, hyalinosis, and increased Ym1/Ym2 expression. 
 
Based on these initial findings, a second study was conducted to investigate the role of lymphocytes (hypothesized cellular sources of Th1 and Th2 cytokines) in the development of eosinophilic rhinitis and associated nasal epithelial remodeling. Male Rag2 x common gamma chain (γc) - deficient [RAG2(-/-) x γc(-/-)] mice, that are lymphoid-deficient (lack both T and B lymphocytes, as well as innate lymphoid cells) were exposed to 0.5 ppm O3 for 9 consecutive weekdays (4 h/day). Unlike the O3-exposed and lymphoid-sufficient C57 Bl/6 mice that developed a marked Th2-associated eosinophilic rhinitis with nasal epithelial remodeling, the similarly exposed RAG2(-/-) x γc(-/-) mice did not develop an eosinophilic rhinitis or O3-induced nasal epithelial lesions (Figure 8). In addition, these lymphoid-depleted mice had no O3-induced overexpression of Th-2 cytokine mRNA like that found in the O3-exposed and lymphoid-sufficient C57 Bl/6 mice. 
Figure 7. Density of granulocytes (neutrophils and eosinophils) in the nasal mucosa of C57 BL/6 mice exposed to 0.5 ppm O3 or filtered air (0 ppm O3, controls) for 1, 2, 4, or 9 consecutive weekdays (4 h/day) and sacrificed 2 or 24 h postexposure.
 
 
All tissues sections were immunohistochemically processed using a polyclonal antibody for mouse eosinophil-specific major basic protein (red chromagen; arrow). An influx of major basic protein-laden eosinophils is found only in lymphoid-sufficient C57 BL/6 mice exposed to O3 (C). Lymphoid-depleted RAG2(-/-) x γc(-/-) mice similarly exposed to O3 had no eosinophilic influx in the nasal mucosa (D). 
 
These results confirmed our hypothesis that lymphocytes are a crucial component to O3-induced eosinophilic rhinitis and nasal epithelial remodeling. Furthermore, these findings in mice provide biological plausibility for previous epidemiological studies that found associations of increased ambient O3 concentrations and increased incidence of eosinophilic rhinitis in atopic and nonatopic children, suggesting that chronic exposure to this gaseous air pollutant may cause nasal lesions that mimic those of allergic rhinitis. Studies are ongoing to identify the type of lymphoid cells (e.g., T lymphocytes, innate lymphoid cells) that mediate these O3-induced inflammatory and epithelial lesions in the nasal airways of mice. 
 
We further extended this line of research by examining O3-induced eosinophilic rhinitis in KK, KKAy and C57BL/6 mice exposed for 13 consecutive weekdays. Standard morphometric techniques were used to measure the density of major basic protein-laden eosinophils in the nasal mucosa (a quantitative assessment of the severity of eosinophilic rhinitis). The diabetes prone, hyperglycemic KKAy and KK mice exposed to O3 had remarkably more severe eosinophilic rhinitis compared to similarly exposed normoglycemic C57BL/6 mice (Figure 9). Interestingly, a similar stain-dependent increase in eosinophils also was found in the lungs of these mice. These results suggest that diabetics or those suffering from facets of the metabolic syndrome (e.g., hyperglycemia) may be more susceptible to airway injury caused by repeated ambient O3 exposure. 
 
Figure 8. Light photomicrographs of the nasal mucosa of mice exposed to 0.5 ppm O3 or filtered air (0 ppm O3) for 9 consecutive weekdays (4 h/day). 
 
 
Figure 9. Density of major basic protein-laden eosinophils in the nasal mucosa and lung of mice exposed to 0.5 ppm O3 or filtered air (0 ppm O3; controls) for 13 consecutive weekdays (4 h/day). O3-exposed KKAy and KK mice had a greater influx of eosinophils compared to C57BL/6 mice that were similarly exposed. 

 

Future Activities:

Our main goal in the final year of this project is to complete the ongoing studies and prepare manuscripts for peer-review publication. No new field studies will be initiated in Dearborn or Dexter, MI. Important analyses that need to be completed are listed below along with a few small, short-term laboratory studies that need to be conducted to complete the body of work necessary for manuscripts to be of publication quality. 
 

Ongoing Analyses:

  1. Cardiotelemetry Data Analysis: Data analysis of heart rate variability (HRV) in rats exposed to the O3/PM2.5 mixture, 5 days/wk for 4 weeks (Dexter inhalation exposure study) will be completed this year. A comparison of responses to O3/PM2.5 in Dexter vs. Dearborn will be conducted for HRV, heart rate and blood pressure. Lastly, we will assess exposure-related arrhythmias and ECG abnormalities in rats fed ND vs HFrD and exposed to O3, PM2.5, and O3/PM2.5 (coexposure) in all studies. These data will form the basis of two manuscripts.
  2. Associations of Exposure/Health Outcomes: Working in close collaboration with colleagues in the Exposure Core and the Biostatistics and Data Management Core, we will continue the correlation analyses to determine associations between acute cardiovascular responses (e.g., heart rate, mean arterial pressure, heart rate variability) and PM2.5 metrics (e.g., trace elements, gases, sources). We will conduct these correlative analyses to determine modifications by ozone coexposure on the source-induced cardiovascular health effects. These data will form the basis for at least one manuscript.
  3. Morphometric, Biochemical, and Molecular Analyses: We will complete these analyses of tissue (nose, lung, liver) and fluid (BALF and serum/plasma) samples taken from C57BL/6, KKAy, KK, RAG2(-/-) x γc(-/-) and RAG2(-/-) mice in our ongoing O3/PM2.5 studies. In addition, we will complete similar analyses taken from Sprague-Dawley rats in our collaborative study with colleagues in the Harvard CLARC (see below).

Short-term Studies:

  1. Study to identify the type of lymphoid cells responsible for the development of O3-induced eosinophilic rhinitis. We have demonstrated that lymphoid cells play a crucial role in the development of eosinophilic rhinitis in mice exposed to O3, but the type of lymphocytes involved is yet unknown. Based on our previous data and recently published articles in the scientific literature, we hypothesize that innate lymphoid cells (e.g., innate lymphoid 2 cells) are the primary effector cells. RAG2(-/-) mice (T and B lymphocyte deficient, but innate lymphoid cell sufficient) and RAG2(-/-) x γc(-/-) mice (deficient of all lymphoid cell types) will be exposed to O3 for 9 consecutive weekdays. If innate lymphoid cells do play a role in the development of O3-induced eosinophilic rhinitis, we anticipate that eosinophilic rhinitis will be induced in O3-exposed Rag 2(-/-) mice, but not in O3-exposed RAG2(-/-) x γc(-/-) mice.
  2. Study the role of insulin resistance in the enhanced sensitivity of diabetes-prone KKAy mice to O3-induced nasal and lung toxicity. Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes, and the only anti-diabetic therapy that has been demonstrated to attenuate the cardiovascular complications of diabetes and metabolic syndrome. It also helps to reduce LDL cholesterol and triglyceride levels in the blood and improves insulin sensitivity. We will conduct a short-term inhalation study designed to determine if Metformin will protect diabetes-prone and hyperglycemic KKAy mice from O3-induced insulin resistance and O3-induced rhinitis and pneumonitis.
  3. Study to assess autonomic changes in rats exposed to ozone or PM2.5 by microneurographic recording. We will measure direct sympathetic nerve activity in rats pre-exposed to ozone or PM2.5. In these studies we will administer sympathomimetic and vasoactive agents to determine the association of changes in sympathetic activity with blood pressure in exposed versus nonexposed rats, and in rats fed normal versus high fructose diets.

 


Journal Articles on this Report : 14 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
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Journal Article Balasubramanian P, Sirivelu MP, Weiss KA, Wagner JG, Harkema JR, Morishita M, Mohankumar PS, Mohankumar SM. Differential effects of inhalation exposure to PM 2.5 on hypothalamic monoamines and corticotrophin releasing hormone in lean and obese rats. NeuroToxicology 2013;36:106-111. R834797 (2013)
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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 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 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 Sun L, Liu C, Xu X, Ying Z, Maiseyeu A, Wang A, Allen K, Lewandowski RP, Bramble LA, Morishita M, Wagner JG, Dvonch JT, Sun Z, Yan X, Brook RD, Rajagopalan S, Harkema JR, Sun Q, Fan Z. Ambient fine particulate matter and ozone exposures induce inflammation in epicardial and perirenal adipose tissues in rats fed a high fructose diet. Particle and Fibre Toxicology 2013;10:43. R834797 (2013)
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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 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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  • 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, acute cardiovascualr effects, human exposure, physiology, cardiopulmonary, cardiotoxicity, human health

    Relevant Websites:

    Great Lakes Air Center For Integrated Environmental Research Exit

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2015 Progress Report
  • 2016 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