2013 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, 2012 through December 31,2013
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 CAPinduced 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 in the study investigators or personnel in year 3 of this Project. Our objectives in Project 2 have also remained the same in Year 3. Specifically, 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 3 addressed all four of these hypotheses, and focused on field exposure studies during summer months, and was followed by mechanism-driven experiments during the winter months. 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 and 2 were 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 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 3 several research milestones were achieved that led directly to a better understanding of the health effects of multipollutant exposures in the face of experimentally induced facets of the cardiometabolic syndrome (CMS). Specifically, we 1) finished the statistical analyses of the data from a large inhalation 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, 2) used murine models of diet- and genetically induced CMS to investigate the effects of O3 exposure on the development of insulin resistance and other health facets of the CMS, and 3) started a new inhalation toxicology study in Dexter, MI to study the toxicity of PM2.5, O3 and PM2.5/O3 exposures in this rural/regional airshed. In addition, we started an intraCLARC collaborative animal toxicology study with Harvard University in the Fall of 2012 employing our rat model of diet-induced CMS and their inhalation exposure system to traffic emissions from the Boston Tunnel. A brief summary of our Project 3 accomplishments in the last year and future studies in Year 4 are briefly described below.
 
1) Results from our Rat Inhalation Toxicology Study in Dearborn MI.  Sprague-Dawley rats fed a diet with 60% fructose-derived calories induced multiple facets of the human CMS. These rats were insulin-resistant, hypertensive and dyslipidemic, which are three major facets of the CMS (Figure 1A, B, C). In addition, high fructose (HFr) fed rats developed hepatic steatosis and elevated heart rate. As such, HFr-fed rat model demonstrated cardiovascular and metabolic abnormalities that are consistent with human CMS, and provided a reproducible rodent model to further elucidate the adverse health effects of multi-pollutant exposures in a potentially susceptible population suffering from CMS.
 
Figure 1. Changes in Blood Pressure (A), Insulin Resistance (B) and Serum Triglycedrides (C) in Sprague Dawely Rats after 10 weeks on a High Fructose Diet. * - indicates significant difference from rats fed a Normal Diet.
 
We conducted a series of acute inhalation exposures of rats, on normal or HFr-diets (HFrD), to O3 and/or concentrated PM2.5 (CAP), for 9 days, 8 h/day, in our mobile air research laboratory (AirCARE I) parked in an urban/industrial setting in Dearborn, MI. Two 9-day exposure regimens were conducted in order to acquire data from all experimental groups. Inhalation exposures were coordinated with Drs. Dvonch and Morishita in the Exposure Characterization Core at the University of Michigan. They characterized the physicochemical composition of both ambient and concentrated PM2.5 at this exposure site. Initiated by Drs. Harkema, Wagner and Fink (MSU-Project 2), the details of the study design and data and tissue collection protocols were finalized after consultation with Drs. Rajagopalan (Project 3) and Brook (Project 1), so as to ensure cohesion of endpoints in acute and chronic rodent and acute human studies. Acute cardiovascular responses (e.g., blood pressure, heart rate, heart rate variability) were measured every 5 minutes by radiotelemetry during and after daily exposures. Twenty-four hours after the last exposure, tissue samples were taken at necropsy from a widerange of targeted organs, along with blood and bronchoalveolar lavage fluid samples, and analyzed for biochemical, molecular, and morphometric alterations related to the CMS.
 
This past year, 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 found that inhalation of either concentrated PM2.5 or O3 alone caused significant drops in mean arterial pressure (10-15 mmHg) in HFr-fed rats that were maintained for most days of the exposures (Figure 2A, B). These decreases persisted during post-exposure periods on the weekends (7:30AM-3:30PM) and during evening hours of weekdays (12:00-5:00AM) when rats were removed from the inhalation chambers. In comparison, vascular responses of rats fed a normal diet were minimal and less frequent, with episodic elevations in blood pressure on certain days. Interestingly, co-exposure to both pollutants caused marked decreases in blood pressure in HFr-fed rats on the first two days of exposure, yet this vascular response did not persist with repeated exposures, as was observed with single pollutant exposures (Figure 2C).
 
Figure 2. Daily Effect of PM2.5 (A), Ozone (B) and Ozone + PM2.5 Coexposure (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 exposed rats (indicated by dotted line, zero axis). * - indicates significant difference from Air-exposed rats given the same diet; # - indicates significant difference from rats fed a Normal Diet.
 
Both PM2.5 and O3 exposure alone caused drops in heart rate that were consistently greater and persistent in HFr-fed rats (Figure 3A, B). Decreases of up to 25 beats per minute (bpm) in normal chow-fed rats and up to 60 bpm in HFr-fed rats were observed. During co-exposures to both O3 and PM2.5, drops in heart rate were remarkable during the first two days (decreases of 40-70 bpm), but were less dramatic with repeated exposures (0-20 bpm decreases; Figure 3C). Thus decreases in both blood pressure and heart rate were greater and more sustained with single pollutant exposures, whereas cardiovascular responses during co-exposures appeared to attenuate more quickly. The reason for this difference in the persistence of these cardiovascular responses to repeated single or multiple pollutant exposures is unknown. We speculate that the rapid adaptation of co-pollutant-induced blood pressure and heart rate responses in HFr-fed rats may have been the result of a greater adaptive defense mechanism(s) due to a greater total pollutant dose with the co-pollutant exposures. The biological mechanisms underlying these physiologic responses to exposure will be the focus of future studies.
 
Figure 3. Daily Effect of PM2.5 (A), Ozone (B) and Ozone + PM2.5 Coexposure (C) on Heart Rate In Rats Fed Normal (black circles) or High Fructose (white circles) Diets. Data is plotted as the effect estimate on heart rate (bpm) of the indicated exposure compared to filtered air exposed rats (indicated by dotted line, zero axis). * - indicates significant difference from Air-exposed rats given the same diet; # - indicates significant difference from rats fed a Normal Diet.
 
From these results, we conclude that cardiovascular depression in response to exposures to O3 and PM2.5 was enhanced and prolonged in rats with HFrD-induced CMS. This suggests that people with CMS may be prone to similar exaggerated BP and HR responses to inhaled air pollutants. We have submitted a manuscript describing this study to Environmental Health Perspectives (EHP) for peer review publication. Initial reviews were encouraging and a revised paper will be submitted to EHP in July or early August 2013.
 
2) Effects of Ozone Exposure on Facets of the Cardiometabolic Syndrome in Mice. In year 3, we conducted two mouse inhalation toxicology studies. In the first study, we exposed C57BL/6 male mice to 0 or 0.5 ppm O3, 4h/day, for 24 consecutive weekdays. Half of the mice were fed a high fructose diet (HFrD) and the other half a normal rodent chow diet (ND). We found that O3 induced upper and lower respiratory tract inflammation that was more marked in ND-fed mice. However, O3 exposure induced insulin resistance and increased blood insulin levels (facets of the CMS and diabetes) only in mice fed the HFrD. Insulin resistance (HOMA-IR) was not found in the HFrD-fed mice exposed only to filtered air (0 ppm O3). In addition, O3 enhanced the severity of diet-induced fatty liver (hepatic steatosis) and levels of total liver triglycerides in the HFrD-fed mice. Figure 4 graphically summarizes selected O3-specific metabolic changes. These initial results suggest that metabolic and pre-diabetic facets of HFrD-induced CMS can be enhanced by subacute inhalation exposure to this common gaseous air pollutant. These health effect findings caused by O3 exposure are similar in nature to those previously reports in mice fed a high fat diet and chronically exposed to PM2.5.
 
Figure 4. Effects of 24-day exposure of ozone on plasma insulin levels, insulin resistance (HOMA-IR) and total liver triglycerides in C57BL/6 mice fed a normal or high fructose diet, white and black bars respectively. Bars represent the mean ± the standard error of the mean (SEM). * Statistical difference between groups, p ≤ 0.05.
 
In collaboration with our colleagues in Project 3, we also conducted a second O3 inhalation toxicology study using murine strains, KK and KKAy, which are genetically prone to develop different severities of type two diabetes mellitus (T2D). KKAy develop obesity and have more severe facets of T2D compared to KK mice. Both strains of mice (8-10 weeks of age) were exposed to 0 or 0.5 ppm O3, 4h/day, for 13 consecutive weekdays. O3 caused pulmonary inflammation (as measured in the collected bronchoalveolar lavage fluid – BALF) in both strains of mice, but the severity was greatest in the KKAy mice due to striking increases in BALF eosinophils and lymphocytes that was not found in the lungs of O3-exposed KK mice (Figure 5).
 
Figure 5. Changes in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) collected from the lungs of KK and KKAy mice after exposure to either 0 or 0.5 ppm O3 for 13 consecutive weekdays. Bars represent the group means ± SEM.
* statistical difference between groups, p ≤ 0.05.
 
In terms of metabolic indices, both KK and KKAy had hyperglycemia that was not affected by the O3 exposure. Interestingly, KK mice exposed to filtered air (controls) had normal insulin tolerance tests (ITT) indicating no insulin resistance (Figure 6). In contrast KK mice exposed to O3 had abnormal ITT indicating insulin resistance (a major factor in the development of CMS and diabetes). KKAy mice exposed to filtered air or O3 (0 or 0.5 ppm O3, respectively) had insulin resistance (abnormal ITT). These results indicate that subacute exposure to O3 can induce insulin resistance in KK mice that is similar to the induction of insulin resistance that is genetically induced by the transfer of the yellow obesity gene AY in KK mice (Figure 6). We will continue this line of research next year by exploring the effects of subacute PM2.5 and O3/PM2.5 exposures of both the diet- and genetically induced murine models of the CMS and diabetes.
 
Figure 6. Results of insulin tolerance tests (ITT) in KK and KKAy mice after exposure to 0 or 0.5 ppm O3 for 13 consecutive weekdays. Mice were intraperitoneally injected with 0.5 IU/Kg body weight of insulin (Novolin) and blood glucose measurements were taken via the tail vein at 1, 30, 60, 90 and 120 minutes after insulin administration. KK mice exposed to filtered air (0 ppm O3) had normal blood glucose responses to insulin, while the other groups of mice had abnormal ITT indicating insulin resistance. * Statistically different from all groups. # Statistically different from O3-exposed groups, p ≤ 0.05.
 
3) 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 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. Twenty-four hours after the last exposure, tissue samples were taken at necropsy from a wide-range of targeted organs, along with blood and bronchoalveolar lavage fluid samples, and are being analyzed for biochemical, molecular, and morphometric alterations related to CMS. Collected data is currently being analyzed and results are not yet available.
 
4) Collaborative Research Effort with Other Clean Air Research Centers: 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 is still underway and results from this study will be compared to similar studies in GLACIER’s Project 2. A brief description of the study design is presented below.
 
Animals: Twelve 200 gram Sprague-Dawley rats were obtained from Taconic Farms with implanted DSI telemeters capable of monitoring blood pressure, heart rate, and temperature. Another 36 animals were obtained from Taconic Farms without telemeters. All rats were fed a high fructose diet (Harlan TD.89247; 60% of calories comes from fructose) for 8 weeks prior to use in any experiments. The high fructose diet was provided by the GLACIER CLARC. Inhalation exposures were conducted at Harvard’s Boston Tunnel site (see below). Rats were weighed weekly, and 4 hrs of continuous data was collected from the telemeters in the animals at two week intervals. Rats were without food or water during the 5 hours of daily exposure, but when returned to their housing during nonexposure hours they were fed their
specified diets.
 
Traffic-Related Urban Aerosol Particles (TRUAP) exposure protocol: Rats were continuously exposed to TRUAP or filtered air (FA) in single-animal plethysmographs for 5 hrs/day. TRUAP inhalation exposures are derived from the realtime ventilation exhaust of a moderate traffic density tunnel (with small positive road grade, approximately 2°), in the northeast United States. TRUAP consists of primary and secondary traffic-derived fine and ultrafine particles (1nm to 2.5 μm (PM2.5)). Twelve (12) animals (6/group TRAUP; 6/group filtered air all with implanted telemeters continuously monitoring blood pressure, heart rate, and temperature) were exposed each day, four days/week for three consecutive weeks. Another group of animals without telemeters, will also be exposed to filtered air or TRAUP for studies as described below. In prior TRUAP studies, concentrations average approximately 50 μg/m3 (combined primary and secondary particles), with standard deviations less than 25% of the mean for any component; however during these Fall exposures the mass concentrations were unusually low averaging approximately 30 μg/m3. Exposures were initiated at the same time each day, limiting variability due to diurnal traffic patterns.
 
Outcomes: In this coming year we will complete the data analyses. We will compare filtered air vs TRUAP exposures in rats on a high fructose diet which produces hypertension and other facets of the metabolic syndrome (e.g., insulin resistance, hyperglycemia, dyslipidemia). From the telemetered animals, we will assess the following outcomes: 1) Cardiovascular parameters, including blood pressure, heart rate, heart rate variability, and body temperature all derived from the telemetry system; Respiratory parameters including respiratory rate, times of inspiration, expiration, inspiratory pause, expiratory pause and relaxation, peak air flows during inspiration and expiration, average air flow during expiration, tidal and minute volumes, inspiratory duty cycle, and minute ventilation. From the non-telemetered rats, we will assess differences in in vivo chemiluminescence of the heart and lungs after one day of exposure in 6 animals/TRUAP or filtered air group. In another group of non-telemetered animals, we will also assess bronchoalveolar lavage fluid (BALF) parameters after 4 days of exposure including total cells and cell types as well as total protein and ß-N-Acetyl-Glucuronidase determinations in the lavage fluid using 6 animals/ TRUAP or fitered air group. From the rats on which BAL is done, we will also collect heart blood from which complete blood count and differential as well as platelet counts will be done, and blood chemistry (chem 17) including blood glucose, electrolytes, insulin, triglycerides, and hepatic function assessment.
 
The third group of non-telemetered 6 animals per TRUAP or Filtered air group will be exposed for a length of time to be determined for specific outcomes to be assessed by collaboratoring CLARC investigators at Havard University CLARC, GLACIER, and the University of Washington Center for Clean Air Research.
 
Proposed Collaborative Effort with the University of Washington Center for Clean Air Research (UWCCAR): Pulmonary and Systemic Inflammatory Potentials of Inhaled Ozone and Fine PM in Mice. In years 4 and 5, we are planning to conduct collaborative research with Dr. Matt Campen at UW CCAC to identify biochemical markers of inflammation in blood, bronchoalveolar lavage fluid, and tissues from lung, blood vessels, liver and other organs from mice exposed to ozone and/or fine particulate matter. GLACIER with conduct the initial animal exposures and samples for analysis will be sent to Dr. Campen for analysis. A detailed project plan is being developed. GLACIER will dedicate a total of $75,000 over project years 4 and 5 for this CLARC collaboration (see GLACIER’s year 4 financial report).

 

Future Activities:

Ongoing Analyses in Year 3
  1. Cardiotelemetry Data: Data analysis of heart rate and blood pressure responses in rats exposed to the O3/PM2.5 mixture, 5 days/wk for four weeks (Dexter inhalation exposure study) should be finished by the end of the year. In addition, data analysis of heart rate variability is being calculated for all cardiotelemetry studies and ECG waveform analyses are being planned.
  2. Associations of Exposure/Health Outcomes: With the help of the Biostatistics and Data Management Core, we will use data of cardiovascular responses (e.g., heart rate, mean arterial pressure, heart rate variability) and PM2.5 metrics (e.g., trace elements, gases, sources) collected over the same 30-minute timeframes to provide a high resolution correlation of specific PM2.5 components to the cardiovascular health effects. We will conduct these correlative analyses using data from both our Dearborn and Dexter studies.
  3. Brain Neurochemistry: With the help of collaborators and neuroscientists Drs. P.S. and Sheba MohanKumar at MSU, exposure- and diet-related responses in specific brain regions that control autonomic functions are being examined. For example, neurochemical and molecular analyses in the paraventricular nucleus of the hypothalamus are being conducted for neurotransmitters and inflammatory cytokines after inhalation exposures in both normal and high fructose-fed rats.
  4. Effects of Subchronic Ozone Exposure on the Development of Cardiometabolic Sydrome in C57Bl/6, KK and KKAy mice. With the help of the Biostatistics and Data Management Core, we will be completing the statistical analyses of data collected from our initial O3 studies in which we used three mouse strains to more fully understand the impact of genetics and O3 exposure on facets of CMS and diabetes.
  5. Initial studies on Sympathetic Neural Recordings in Rats exposed to Ozone. Dr. Fink and colleagues have been working on perfecting the surgical implantation of radiotelemetric transmitters in the renal sympathetic nerves of Sprague-Dawley rats. In late summer or early Fall 2013, we will conduct pilot studies in telemeterized rats to record changes in nerve activity during acute O3 exposure. Once successful recordings are achieved, we will move to similar studies but using acute inhalation exposures to PM2.5 and PM2.5/O3.
 
New Studies in Year 4:
  1. Effects of Subacute PM2.5 and PM2.5/O3 Exposures on the Development of Cardiometabolic Sydrome in C57Bl/6 mice. We will test the effects of subacute PM2.5 and PM2.5/O3 inhalation exposure (4h/day, 4d/wk, for 24 consecutive weekdays) on the development of HFr-diet-induced cardiometabolic syndrome in mice. Animals
  2. will be fed a normal chow or an HFr diet during the inhalation exposures.
  3. Effects of Subacute PM2.5 and PM2.5/O3 Exposures on the Development of Cardiometabolic Sydrome in KK and KKAy mice. Based on the encouraging findings with our initial subacute O3 exposures, we will extend the inhalation toxicology studies with KK and KKAy mice by exposing these pre-diabetic strains of mice for 24 consecutive weekdays to PM2.5 and PM2.5/O3 at either our Dexter or MSU East Lansing exposure site, depending on available resources.
  4. Sympathetic Neural Recordings in Rodents Exposed to Ozone. We will continue to work on refining the technique of radiotelemetric microneurography in order to apply this measurement in future inhalation studies of PM2.5 and O3.
  5. Inhalation Toxicology Studies in Dexter, MI. In the spring and summer of 2014, we will resume inhalation toxicology studies in our rural Dexter, MI (predominantly regionally transported air pollution) to determine the cardiopulmonary, airway and metabolic effects of acute PM2.5±O3 exposures on normal- and HFr-fed rats.

 


Journal Articles on this Report : 7 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 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)
R834797 (2014)
R834797 (2015)
R834797 (2016)
R834797 (Final)
R834797C002 (2012)
R834797C002 (2013)
R834797C002 (2014)
R834797C002 (2015)
R834797C002 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
    R834797 (2014)
    R834797 (2015)
    R834797 (2016)
    R834797 (Final)
    R834797C001 (2013)
    R834797C001 (2014)
    R834797C001 (2015)
    R834797C001 (2016)
    R834797C001 (Final)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (2016)
    R834797C002 (Final)
    R834797C003 (2013)
    R834797C003 (Final)
    R833740 (2012)
    R833740 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Taylor&Francis-Abstract
    Exit
  • 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)
    R834797 (2013)
    R834797 (2014)
    R834797 (2015)
    R834797 (Final)
    R834797C001 (2012)
    R834797C001 (2013)
    R834797C001 (2014)
    R834797C001 (2015)
    R834797C001 (2016)
    R834797C001 (Final)
    R834797C002 (2012)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (2016)
    R834797C002 (Final)
    R834797C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: ScienceDirect-Full Text HTML
    Exit
  • Abstract: ScienceDirect-Abstract
    Exit
  • Other: ScienceDirect-Full Text PDF
    Exit
  • 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)
    R834797 (2014)
    R834797 (2015)
    R834797 (2016)
    R834797 (Final)
    R834797C002 (2012)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (2016)
    R834797C002 (Final)
    R834797C003 (2013)
    R834797C003 (2014)
    R834797C003 (2015)
    R834797C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Sage Journals-Full Text HTML
    Exit
  • Abstract: Sage Journals-Abstract
    Exit
  • Other: Sage Journals-Full Text PDF
    Exit
  • 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)
    R834797 (2014)
    R834797 (2015)
    R834797 (Final)
    R834797C001 (2013)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (Final)
    R834797C003 (2013)
    R834797C003 (2014)
    R834797C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Particle and Fibre Toxicology-Full Text HTML
    Exit
  • Abstract: Particle and Fibre Toxicology-Abstract
    Exit
  • Other: Particle and Fibre Toxicology-Full Text PDF
    Exit
  • 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)
    R834797 (2014)
    R834797 (2015)
    R834797 (2016)
    R834797 (Final)
    R834797C001 (2013)
    R834797C001 (Final)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (2016)
    R834797C002 (Final)
    R834797C003 (2013)
    R834797C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text PDF
  • Abstract: EHP-Abstract & Full Text HTML
  • Other: ResearchGate-Abstract & Full Text-PDF
    Exit
  • 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)
    R834797 (2014)
    R834797 (2015)
    R834797 (2016)
    R834797 (Final)
    R834797C002 (2013)
    R834797C002 (2014)
    R834797C002 (2015)
    R834797C002 (2016)
    R834797C002 (Final)
    R834797C003 (2013)
    R834797C003 (2014)
    R834797C003 (2015)
    R834797C003 (Final)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: EHP-Full Text HTML
  • Abstract: EHP-Abstract
  • Other: EHP-Full Text PDF
  • Supplemental Keywords:

    inhalation toxicology, acute multipollutant exposures, high-fructose diet, rats, CAP, 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:

    GLACIER: Great Lakes Air Center For Integrated Environmental Research Exit

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • 2014 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