Final Report: Long Term Metabolic Consequences of Exposures to Multipollutant Atmospheres in the Great Lakes Region

EPA Grant Number: R834797C003
Subproject: this is subproject number 003 , 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: Long Term Metabolic Consequences of Exposures to Multipollutant Atmospheres in the Great Lakes Region
Investigators: Rajagopalan, Sanjay , Sun, Qinghua
Institution: The Ohio State University - Main Campus
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:

We have recently demonstrated that short-term exposure to inhaled concentrated airborne particulate (CAP) matter <2.5μm (PM2.5) results in components of cardiometabolic syndrome (CMS) including development of hypertension and insulin resistance. In this project, we had hypothesized that chronic inhalation of CAP in conjunction with gaseous components such as ozone from distinct multipollutant atmospheres synergistically interacts with diet and genetic susceptibility to influence development of CMS. Project 3 has been an integral component of the overarching theme of this center that primary air pollutants, fine PM (PM2.5) and ozone (O3), cause cardiometabolic health effects that are dependent on the local atmospheric multipollutant milieu, predisposing factors, and the interactive toxicity of multipollutant coexposure. The experiments proposed were natural extensions of human research outlined in Project 1 and acute experiments in Project 2 and focused on conducting chronic inhalation toxicology studies in diet fed and genetic models of obesity/diabetes. In Aim 1, simultaneous chronic exposure to multipollutant CAP from two locations in Columbus, OH representing near-roadside/traffic or remotely transported/aged emissions were examined in combination with high fat chow (HFC). The impact of CAP on glucose/insulin homeostasis, adipokines, insulin signaling, adipose and pulmonary inflammation and an analysis of dose dependence and CAP components were evaluated in diet sensitive (C57BL/6) and genetic models of Type II diabetes susceptibility (KKA/y). In Aim 2, we investigated the effect of co-exposure of multipollutant CAP with ozone on the temporal development of insulin resistance and adipose/lung inflammation using the KKA/y model. We will assess dose response relationship of multipollutant-O3 mixture on insulin resistance measures (HOMA-IR and IPGTT) and novel mediators of innate immune, pivotal to the development of metabolic derangement. Based on data from Aims 1 and 2, we designed experiments in Aim 3, which helped us assess chronic effects of multipollutant CAP in potentiating inflammatory monocyte activation and infiltration into tissue niches as a central mechanism for mediating adverse metabolic effects of CAP. Using state of the art multiple exposure systems available at OSU (OASIS-1 and OASIS-2) and MSU in conjunction the resources available at the ECC including the use of several novel and novel high-time resolution exposure characterization methods, we were able to elucidate and improved our understanding of the metabolic effects of PM2.5 alone and in conjunction with ozone.

Summary/Accomplishments (Outputs/Outcomes):

In the 5 years of GLACIER we have successfully conducted experiments to determine the temporal course of diabetes development in response to CAPS in genetic and high fat models of diabetes. In a series of studies in animals (Table 1) as part of this grant, we have provided firm experimental evidence linking PM2.5 exposure with multiple pathways that lead to insulin resistance and obesity. We have facilitated understanding of mechanisms more than any other group in the world. We have provided experimental evidence of the interaction of PM2.5 with other entities including metals and in conjunction with other gaseous entities such as ozone as part of complex mixtures, which was the goal of the proposal.
TABLE 1. Summary of Findings from our Animal Exposure Studies
Duration
Models
Exposures
Main Findings
 
 
10 wks
 
C57BL/6 mice
 
*PM2.5 (75 μg/m3)
PM2.5 exposure induces both oxidative stress and ER stress in mouse lung and liver tissues through PERK/eIF2α/ATF6/IRE1α-mediated UPR pathway
2010 1
 
10 wks
C57BL/6 &
p47-/- mice on HFD/NCD
 
*PM2.5 (111 μg/m3)
PM2.5 increases fat content, macrophage infiltration in adipose tissue and vascular function in young mice. P47 (phox) deficiency improves IR in response to PM2.5.
2010 2
 
10 mths
 
C57BL/6 mice
 
*PM2.5 (94 μg/m3)
PM2.5 induces IR in adipose tissue, liver and skeletal muscle possibly through increased cytokine, mitochondrial alteration, oxidation and decreased Akt.
2011 3
2 mths
ApoE -/- mice
*PM2.5 (97 μg/m3)
PM2.5 results in increased superoxide production and
2011 4

 

 
 
 
 
decrease of mitochondrial number/UCP1 expression in BAT. WAT/BAT-specific genes are also abnormal.
 
3/10 wks
C57BL/6 mice
*PM2.5 (77 μg/m3)
PM2.5 induces a NASH-like phenotype and impairs hepatic glucose metabolism
2013 5
17 wks
C57/CCR2-/- HFD
*PM2.5(117 μg/m3)
PM2.5 increases IR and hepatic lipids. CCR2-/- partially rescued the effect of PM2.5.
2013 6
10 mths
C57BL/6 mice
*PM2.5 (94 μg/m3)
PM2.5 induces macrophage infiltration, unfolded protein response, lipid deposition
2013 7
 
 
8 weeks
 
 
Sprague Dawley
 
 
PM2.5 + Ozone
PM2.5 +O3 resulted in increase of macrophage infiltration in both epicardial and perirenal adipose (EAT and PAT) of high-fructose fed rats. Tnf, Mcp-1 were upregulated while IL-10 and adiponectin, were reduced. Decreased mitochondrial area and increased macrophages noted in EAT and PAT.
20138
 
5-8 week
 
KKAy Mice
 
*PM2.5 (82 μg/m3)
PM2.5 decreased O2 consumption, CO2 production, respiratory exchange ratio and thermogenesis. Increased inflammation in insulin responsive organs.
20149
 
10 weeks
C57Bl/6 WT
or p47phox-/-
 
*PM2.5 (75 μg/m3)
Exposure to PM2.5 led to activation of the transforming growth factor β-SMAD3 signaling, increased liver collagen, suppression of PPAR gamma signaling
201510
 
18 weeks
 
LDLR-/- mice
 
PM2.5 (75 μg/m3)
Exposure to PM2.5 increases 7-ketocholesterol content in LDL/VLDL and increase atherosclerosis. This response is dependent on CD36 mediated uptake of ox- LDL in macrophages.
201411
 
 
 
2 weeks
 
 
 
KKAy Mice
 
 
 
0.5 ppm ozone
CD11b(+)Gr-1(lo)7/4(hi) macrophages increased by 200% in adipose but unchanged in blood. Glucose levels were not different in the insulin tolerance test between air- and ozone-exposed mice, whereas fasting insulin levels and HOMA-IR in ozone-exposed animals were significantly reduced. Increased insulin signaling in skeletal muscle and liver, but not adipose tissues. Ozone caused decrease in body weight and plasma leptin.
201612
 
 
 
2 weeks
 
 
 
KK mice
 
 
 
0.5 ppm ozone
Plasma insulin and leptin levels were reduced in O3- exposed mice. ncreased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. Multiple inflammatory genes including CXCL-11, IFN-gamma, TNFalpha, IL-12, and iNOS were up-regulated in visceral adipose tissue. Expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose
201613
 
 

Conclusions:

Our findings and reviews have fundamentally shaped the understanding of the effects of PM2.5 and its association with IR, T2DM and HTN. Low-grade systemic inflammation is considered a sine qua non in the pathogenesis of PM2.5-mediated health effects. There is now a large body of data including our own implicating innate immune activation in response to PM exposure in both humans and animals. Chronic PM exposure results in inflammatory cell recruitment and oxidative stress in organs such as the visceral adipose and CNS. Through a better understanding of the integrated mechanisms whereby PM instigates diverse responses culminating in multiple cardio-metabolic derangements) we have provided a body of knowledge that has advanced the field. In particular, in year 2 of the grant we have conclusively shown that PM2.5 exposure results in CNS inflammation and sympathetic activation that may contribute to the development of  hypertension and metabolic 
inhibitor, delivered intracerebroventricularly (ICV), alleviates deterioration of whole body insulin resistance seen in response to PM2.5. These findings have led to a paradigm shift in investigations in the field, where now the CNS is seen as playing an integrative role in air pollution responses. During year 3 of the proposal we began conducting detailed experiments in collaboration with Dr. Harkema on the effects of ozone exposure as well as other mixtures including PM2.5 and metals (Nickel). We isolated the effects of ozone and demonstrated that inhalational exposure to ozone results in systemic inflammation in adipose and alterations in insulin resistance. Finally, we conducted combined exposures to both Ozone and PM2.5. These results have suggested profound innate immune activation often accompanied by alterations in insulin signaling. However there appears to be a significant weight loss effect in response to ozone that may complicate interpretations of insulin and HOMA values that may also need to factor in species and strain differences (KK vs KKAY as well as rats versus mice). We have also provided important commentaries on the effects of ozone and have contributed substantially to the literature by authoring several state of the art reviews on the topic of air pollution.


Journal Articles on this Report : 35 Displayed | Download in RIS Format

Other subproject views: All 46 publications 35 publications in selected types All 35 journal articles
Other center views: All 147 publications 71 publications in selected types All 71 journal articles
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Journal Article Blazek A, Rutsky J, Osei K, Maiseyeu A, Rajagopalan S. Exercise-mediated changes in high-density lipoprotein: impact on form and function. American Heart Journal 2013;166(3):392-400. R834797 (2013)
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  • Journal Article Brook RD, Rajagopalan S. Can what you breathe trigger a stroke within hours? Comment on "ambient air pollution and the risk of acute ischemic stroke". Archives of Internal Medicine 2012;172(3):235-236. 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 Deiuliis JA, Kampfrath T, Zhong J, Oghumu S, Maiseyeu A, Chen LC, Sun Q, Satoskar AR, Rajagopalan S. Pulmonary T cell activation in response to chronic particulate air pollution. American Journal of Physiology:Lung Cellular and Molecular Physiology 2012;302(4):L399-L409. R834797 (2014)
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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 Liu C, Fonken LK, Wang A, Maiseyeu A, Bai Y, Wang T-Y, Maurya S, Ko Y-A, Periasamy M, Dvonch T, Morishita M, Brook RD, Harkema J, Ying Z, Mukherjee B, Sun Q, Nelson RJ, Rajagopalan S. Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes. Particle and Fibre Toxicology 2014;11:53. R834797 (2014)
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  • Journal Article Mendez R, Zheng Z, Fan Z, Rajagopalan S, Sun Q, Zhang K. Exposure to fine airborne particulate matter induces macrophage infiltration, unfolded protein response, and lipid deposition in white adipose tissue. American Journal of Translational Research 2013;5(2):224-234. R834797 (2016)
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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 Newby DE, Mannucci PM, Tell GS, Baccarelli AA, Brook RD, Donaldson K, Forastiere F, Franchini M, Franco OH, Graham I, Hoek G, Hoffmann B, Hoylaerts MF, Kunzli N, Mills N, Pekkanen J, Peters A, Piepoli MF, Rajagopalan S, Storey RF, ESC Working Group on Thrombosis, European Association for Cardiovascular Prevention and Rehabilitation, ESC Heart Failure Association. Expert position paper on air pollution and cardiovascular disease. European Heart Journal 2015;36(2):83-93b. R834797 (2014)
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  • Journal Article Rajagopalan S, Brook RD. Personalizing your airspace and your health. Journal of the American College of Cardiology 2015;65(21):2288-2290. 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 Rao X, Patel P, Puett R, Rajagopalan S. Air pollution as a risk factor for type 2 diabetes. Toxicological Sciences 2015;143(2):231-241. R834797 (2014)
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  • Journal Article Rao X, Montresor-Lopez J, Puett R, Rajagopalan S, Brook RD. Ambient air pollution:an emerging risk factor for diabetes mellitus. Current Diabetes Reports 2015;15(6):603. 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, Morishita M, Keeler GJ, Harkema JR. Divergent effects of urban particulate air pollution on allergic airway responses in experimental asthma:a comparison of field exposure studies. Environmental Health 2012;11:45 (13 pp.). R834797 (2014)
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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 Wellenius GA, Boyle LD, Wilker EH, Sorond FA, Coull BA, Koutrakis P, Mittleman MA, Lipsitz LA. Ambient fine particulate matter alters cerebral hemodynamics in the elderly. Stroke 2013;44(6):1532-1536. R834797 (2016)
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  • Journal Article Wold LE, Ying Z, Hutchinson KR, Velten M, Gorr MW, Velten C, Youtz DJ, Wang A, Lucchesi PA, Sun Q, Rajagopalan S. Cardiovascular remodeling in response to long-term exposure to fine particulate matter air pollution. Circulation:Heart Failure 2012;5(4):452-461. R834797 (2014)
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  • Journal Article Xu X, Liu C, Xu Z, Tzan K, Wang A, Rajagopalan S, Sun Q. Altered adipocyte progenitor population and adipose-related gene profile in adipose tissue by long-term high-fat diet in mice. Life Sciences 2012;90(25-26):1001-1009. R834797 (2014)
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  • Journal Article Ying Z, Xu X, Chen M, Liu D, Zhong M, Chen L-C, Sun Q, Rajagopalan S. A synergistic vascular effect of airborne particulate matter and nickel in a mouse model. Toxicological Sciences 2013;135(1):72-80. R834797 (2013)
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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 Ying Z, Xie X, Bai Y, Chen M, Wang X, Zhang X, Morishita M, Sun Q, Rajagopalan S. Exposure to concentrated ambient particulate matter induces reversible increase of heart weight in spontaneously hypertensive rats. Particle and Fibre Toxicology 2015;12:15 (10 pp.). R834797 (2014)
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  • Journal Article Zheng Z, Xu X, Zhang X, Wang A, Zhang C, Huttemann M, Grossman LI, Chen LC, Rajagopalan S, Sun Q, Zhang K. Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model. Journal of Hepatology 2013;58(1):148-154. R834797 (2014)
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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. Inhalation Toxicology 2016;28(9):383-392. R834797 (Final)
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  • Journal Article Rajagopalan S, Brook RD. (2012) Air Pollution and Type II Diabetes:Mechanistic Insights Diabetes. 2012 Dec;61(12):3037-45. PMCID:PMC3501850. R834797C003 (Final)
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    Journal Article Xu X, Rao X, Wang TY, Jiang SY, Ying Z, Liu C, Wang A, Zhong M, Deiuliis JA, Maiseyeu A, Rajagopalan S, Lippmann M, Chen LC, Sun Q. (2012) Effect of co-exposure to nickel and particulate matter on insulin resistance and mitochondrial dysfunction in a mouse model. Part Fibre Toxicol. 2012 Nov 5;9:40. PMCID:PMC3545913. R834797C003 (Final)
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    Journal Article Münzel T, Sørensen M, Gori T, Schmidt FP, Rao X, Brook J, Chen LC, Brook RD, Rajagopalan S. (2016) Environmental stressors and cardio-metabolic disease:part I-epidemiologic evidence supporting a role for noise and air pollution and effects of mitigation strategies. Eur Heart J. 2016 Jul 26. pii:ehw269. PMID:27460892. R834797C003 (Final)
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    Journal Article Münzel T, Sørensen M, Gori T, Schmidt FP, Rao X, Brook FR, Chen LC, Brook RD, Rajagopalan S. (2016) Environmental stressors and cardio-metabolic disease:part II-mechanistic insights.Eur Heart J. 2016 Jul 26. pii:ehw294. [Epub ahead of print] PMID:27460891. R834797C003 (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. (2016) Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. Inhal Toxicol. 2016;28(4):155-63. PMCID:PMC4836866. R834797C003 (Final)
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    Journal Article Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. Ying Z, Allen K, Zhong J, Chen M, Williams KM, Wagner JG, Lewandowski R, Sun Q, Rajagopalan S, Harkema JR. Inhal Toxicol. 2016;28(4):155-63. R834797C003 (2016)
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    Journal Article Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. 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. Inhal Toxicol. 2016 Aug;28(9):383-92. R834797C003 (2016)
    R834797C003 (Final)
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    Supplemental Keywords:

    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

    Relevant Websites:

    Great Lakes Air Research 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