Final 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)
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Our objectives in Project 2 arose out of GLACIER’s overarching hypothesis that the major air pollutants, fine particulate matter (PM2.5) and ozone (O3), are capable of eliciting multiple important adverse cardiometabolic health effects that are dependent on 1) the local multipollutant milieu, 2) an individual’s pre-existing cardiovascular (CV) and metabolic condition (susceptibility factors), and 3) 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 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. We used a mobile air research facility (AirCARE 1) that was 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 were 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 were measured by radio-telemetry 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 featured novel real-time sympathetic nerve recordings during PM2.5 and/or O3 inhalation exposure. In addition, our project highlighted 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 extended and complemented 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 also overlapped and integrated scientifically with the animal toxicology studies in Project 3.

Summary/Accomplishments (Outputs/Outcomes):

There were no changes to our study investigators in the final project. Our objectives in Project 2 remained the same throughout the entirety of the 5-year funding period. In the no-cost extension period (sixth year of the Center), 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). Project 2 investigators also 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, a third manuscript focused on our unique mouse model of air pollution-induced nonatopic asthma and rhinitis was accepted in the Summer of 2016 and published in the January 2017 issue of the journal of Toxicologic Pathology (Strain Differences in a Murine Model of Air Pollutant-induced Nonatopic Asthma and Rhinitis. Toxicol Pathol. 2017 Jan; 45:161-171).

Besides the publication of these manuscripts, we 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. We will submit a manuscript for publication, describing these results, in February 2017.
A second study, completed in the 6th year, was designed to explore the effects of fine particulate matter (PM2.5) co-exposure on ozone-induced airway inflammatory and epithelial responses in the lungs of non-atopic mice. Male C57BL/6Tac mice were exposed to 0 or 0.8 ppm ozone, 4h/day, for 9 consecutive weekdays (our murine model of air pollution-induced nonatopic asthma). In the last four days, mice were also intranasally instilled with 0, 10 or 50 g of ambient PM2.5, in saline, prior to each daily ozone exposure. Ambient PM2.5 was collected with a high volume sampler, during the summer months, from the urban/industrial airshed in Dearborn, MI. One day after the end of the 9-day exposure, mice were sacrificed and bronchoalveolar lavage fluid (BALF) was collected for cellular analyses. Lung tissues were processed for histopathologic examination, digital quantitative pathology (morphometry) and molecular analyses (qRT-PCR). Ozone exposures caused both neutrophilic and eosinophilic inflammation and mucous cell metaplasia in the pulmonary airways. PM2.5 co-exposure did not enhance ozone-induced, type 2-associated inflammatory and epithelial responses, but it markedly enhanced ozone-induced neutrophilic inflammation at both the low and high doses (2x greater than ozone-exposures alone). These initial pathology findings in mice suggest that co-exposure to PM2.5 may enhance ozone-induced neutrophilic inflammation, rather than eosinophilic inflammation, in children or adults with new onset non-atopic asthma. Future molecular analyses of the lung tissue from these mice will be conducted to decipher the effects of PM2.5 on ozone-induced expression of inflammatory and epithelial genes associated with type 2 immunity and airway mucus production to better define this mixed air pollutant-induced asthmatic phenotype. We anticipate that these results will be submitted for publication in early Summer 2017.

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. The results of this collaborative interCLARC project have been submitted for publication to the journal Particle and Fibre Toxicology and revisions are being made based on the reviewer’s comments. We anticipate that this paper will be accepted for publication in the next few months.

 

Conclusions:

In the first years of this project, we focused our research on the development of a rat model of the human cardiometabolic syndrome (CMS) and then used this rodent model to elucidate the potential health effects of repeated multipollutant exposures (ozone and PM2.5 co-exposures). For these animal inhalation toxicology studies we utilized our mobile air research laboratory (AirCARE 1), equipped with an ambient air particle concentrator that is integrated with a whole body inhalation exposure system, in an urban/industrial community in Dearborn, MI, that is known for its high ambient concentrations of fine particulate matter (PM2.5). Though several publications on health effects and atmospheric characterization/source apportionment resulted from this body of work (see publication list below), there are two publications that should be highlighted in this concluding report.
In a seminal study, that was published in the journal Experimental Health Perspectives (Wagner et al. 2014), we tested the hypothesis that cardiovascular responses to ozone and PM2.5 will be enhanced in rats with diet-induced CMS. Male Sprague-Dawley rats were fed a high-fructose diet (HFrD) to induce the CMS and then exposed to ozone, concentrated ambient PM2.5, or the combination of ozone plus PM2.5 for 9 days. Data related to heart rate (HR), HR variability (HRV), and blood pressure (BP) were collected. Consistent with the CMS, HFrD rats were hypertensive and insulin resistant, and had elevated fasting levels of blood glucose and triglycerides. Decreases in HR and BP, which were found in all exposure groups, were greater and more persistent in HFrD rats compared with those fed a normal diet (ND). Coexposure to O3 plus PM2.5 induced acute drops in HR and BP in all rats, but only ND rats adapted after 2 days. HFrD rats had little exposure-related changes in HRV, whereas ND rats had increased HRV during ozone exposure, modest decreases with PM2.5, and dramatic decreases during ozone plus PM2.5 coexposures. Cardiovascular depression in ozone- and PM2.5-exposed rats was enhanced and prolonged in rats with HFrD-induced CMS. These results in rodents suggest that people with CMS may be prone to similar exaggerated BP and HR responses to inhaled air pollutants.
We also explored the effect of multipollutant exposure on the rodent’s regional adipose tissue, a major regulator of metabolic and immune/inflammatory function in the body (Sun et al. 2013, Part Fibre Toxicol). Inflammation and oxidative stress play critical roles in the pathogenesis of inhaled air pollutant-mediated metabolic disease. Inflammation in adipose tissues niches are widely believed to exert adverse effects on organ function (e.g., cardiac dysfunction). Recent data from both human and animal models suggest a role for inflammation and oxidative stress in epicardial adipose tissue (EAT) as a risk factor for the development of cardiovascular disease. We hypothesized that inhalation exposure to concentrated ambient fine particulates (PM2.5) and ozone exaggerates inflammation and oxidative stress in EAT and perirenal adipose tissue (PAT).

Eight- week-old Male Sprague-Dawley rats were fed a normal diet (ND) or high fructose diet (HFr) for 8 weeks, and then exposed to filtered air, PM2.5 at a mean of 356 μg/m3, ozone at 0.485 ppm, or PM2.5 (441 μg/m3) + ozone (0.497 ppm) in Dearborn, MI, 8 hours/day, 5 days/week, for 9 days over 2 weeks. EAT and PAT showed whitish color in gross, and less mitochondria, higher mRNA expression of white adipose specific and lower brown adipose specific genes than in brown adipose tissues. Exposure to PM2.5 and ozone resulted in the increase of macrophage infiltration in both EAT and PAT of HFr groups. Pro-inflammatory genes of Tnf-α, Mcp-1 and leptin were significantly upregulated while IL-10 and adiponectin, known as anti-inflammatory genes, were reduced after the exposures. PM2.5 and ozone exposures also induced an increase in inducible nitric oxide synthase (iNOS) protein expression, and decrease in mitochondrial area in EAT and PAT. We also found significant increases in macrophages of HFr-ozone rats. The synergetic interaction of HFr and polluted air exposure on inflammation was found in most of the experiments. Surprisingly, exposure to CAPs or O3 induced more significant inflammation and oxidative stress than co-exposure of PM2.5 and O3 in EAT and PAT. In conclusion, short-term exposure to PM2.5 and O3, especially with high fructose diet, induced inflammation and oxidative stress in EAT and PAT in rats. These findings may provide a link between air-pollution exposure and accelerated susceptibility to cardiovascular disease and metabolic complications.
In the latter years of Project 2, our research was focused on understanding the cellular mechanisms and mode of action that underlie the effects of repeated ozone exposure on the development (early onset) of two important chronic diseases 1) non-atopic asthma (and rhinitis) and 2) type 2 diabetes mellitus. Though this body of work has also resulted in several peer-reviewed publications, only three major studies that have been recently published will be highlighted here. In a recently reported study from our laboratory (Ong et al. 2016), lymphoid cell-sufficient, C57BL/6 mice were exposed to 0 or 0.5 ppm ozone for 1, 2, 4, or 9 consecutive weekdays (4 h/day). Lymphoid cell-deficient (no ILCs, T or B cells), Rag2-/-Il2rg-/- mice were similarly exposed for 9 weekdays. Nasal tissues were taken at 2 h or 24 h post-exposure for morphometric and gene expression analyses. C57BL/6 mice exposed to ozone for 1 day had acute neutrophilic rhinitis with airway epithelial necrosis and over-expression of mucosal Ccl2 (MCP-1), Ccl11 (eotaxin), Cxcl1 (KC), Cxcl2 (MIP-2), Hmox1, Il1b, Il5, Il6, Il13 and Tnf mRNA. In contrast, 9-day-ozone exposure elicited type 2 immune/inflammatory responses in C57BL/6 mice with mucosal mRNA overexpression of Arg1, Ccl8 (MCP-2), Ccl11, Chil4 (Ym2), Clca1 (Gob5), Il5, Il10, and Il13, increased density of mucosal eosinophils, and nasal epithelial remodeling (e.g., mucous cell metaplasia). Rag2-/-Il2rg-/- mice exposed to ozone for 9 days, however, had no nasal pathology or overexpression of transcripts related to type 2 immunity.
In a subsequent study (Kumagai et al. 2016), we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2-/- mice that are devoid of T cells and B cells (but have ILCs), and Rag2-/-Il2rg-/- mice that are depleted of all lymphoid cells including ILCs. Animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/day). Mice were sacrificed 24 h post-exposure and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2-/- mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., mucous cell metaplasia). Alarmins (IL-33, IL-25, and TSLP) were also morphometrically increased in the nasal epithelium of ozone-exposed C57BL/6 and Rag2-/- mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, Ccl8 (MCP-2), Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2-/- mice. In contrast, ozone-exposed ILC-deficient Rag2-/-Il2rg-/- mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs (most likely group 2 ILCs). This was the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.
In a more recent study (not yet published), we investigated the role of ILCs in the pathogenesis of ozone-induced pulmonary lesions by using C57BL/6, Rag2-/-, and Rag2-/-Il2rg-/- mice. Animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/day). Ozone-exposed C57BL/6 and Rag2-/- mice had increased BALF eosinophils and mucous cell metaplasia in the bronchiolar epithelium. Repeated exposure to ozone elicited overexpression of Il13, Muc5ac, Muc5b, Clca1 (Gob5), Chil4 (Ym2) mRNA in C57BL/6 and Rag2-/- mice. Ozone-exposed Rag2-/-Il2rg-/- mice had no pulmonary airway pathology or overexpression of transcripts related to type 2 immunity. These initial results in mice provide a plausible ILC2-dependent paradigm for activation of eosinophilic inflammation and type 2 immunity in the pulmonary airways of non-atopic children repeatedly exposed to ozone (i.e., induction of new-onset, non-atopic asthma).

Furthermore we explored and expanded the knowledge base regarding the pathobiologic effects of ozone exposure on the development of type 2 diabetes, a global and increasing health problem related to the CMS. Inhaled ozone has been epidemiologically associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which ozone mediates harmful effects are poorly understood. The overall objective of this study was to investigate the effect of ozone exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model of diabetes (Zhong et al. 2016). Diabetes-prone KK mice were exposed to filtered air (FA), or ozone (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR. KK mice exposed to ozone displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in ozone-exposed mice. Three-week exposure to ozone induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of ozone although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of ozone-exposed mice. In conclusion we found that repeated ozone inhalation induced oxidative stress, adipose inflammation and insulin resistance in mice genetically prone to develop type 2 diabetes. Our findings suggest that these metabolic and inflammatory responses to ozone exposure may be critical in the early onset of diabetes in people genetically prone to this devastating chronic disease.
In summary, these highlighted studies illustrate the major contributions this project has made on expanding our understanding of how multi-pollutant and individual-pollutant exposures may impact the CMS and associated chronic diseases such as type 2 diabetes, asthma, rhinitis and cardiovascular disease. Numerous collaborative studies with Projects 1 and 3, and supported by the Exposure Core and Biostatistics & Data Management Core, also resulted in major contributions to this field of environmental/public health research and are highlighted in their individual reports.


Journal Articles on this Report : 24 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 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 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 Rao X, Zhong J, Maiseyeu A, Gopalakrishnan B, Villamena FA, Chen LC, Harkema JR, Sun Q, Rajagopalan S. CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure. Circulation Research 2014;115(9):770-780. 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 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 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)
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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)
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  • Journal Article Harkema JR, Hotchkiss LA, Vetter NA, Jackson-Humbles DN, Lewandowski RP, Wagner JG. Strain Differences in a Murine Model of Air Pollutant-induced Nonatopic Asthma and Rhinitis. Toxicologic Pathology 2017;45(1):161-171. R834797 (Final)
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  • Journal Article Carll, A.P., Crespo, S.M., Filho, M.S., Zati, D.H., Coull, B.A., Diaz, E.A., Raimundo, R.D., Jaeger, T.N.G., Ricci-Vitor, A.L., Papapostolou, V., Lawrence, J.E., Garner, D.M., Perry, B.S., Harkema, J.R., and Godleski, J.J. (2017). Inhaled Ambient-level Traffic-derived Particulates Decrease Cardiac Vagal Influence and Baroreflexes and Increase Arrhythmia in a Rat Model of Metabolic Syndrome. Particle and Fibre Toxicology 14, 16. 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)
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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 Exit   Exit

    Progress and Final Reports:

    Original Abstract
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • 2016 Progress 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