2014 Progress 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 , University of Michigan - Ann Arbor
Current 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)
Project Period Covered by this Report: August 1, 2013 through July 31,2014
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

We recently demonstrated that short-term exposure to inhaled concentrated airborne particulate (CAP) matter <2.5 μm (PM2.5) results in components of cardiometabolic syndrome (CMS) including development of hypertension and insulin resistance. In this project, we hypothesize 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 is 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 are natural extensions of human research outlined in Project 1 and acute experiments in Project 2 and will focus 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 will be 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 most likely associated with these effects will be evaluated in diet sensitive (C57BL/6) and genetic models of Type II diabetes susceptibility (KKA/y). In Aim 2, we will investigate 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 the dose response relationship of multipollutant-O3 mixture on insulin resistance measures (HOMA-IR and IPGTT) and novel mediators of innate immunity, pivotal in the development of metabolic derangement. Based on data from Aims 1 and 2, we will design experiments for Aim 3, which will help 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 Ohio State University (OASIS-1 and OASIS-2) and University of Michigan in conjunction with the resources available at the ECC, including the use of several novel and novel high-time resolution exposure characterization methods, GLACIER offers an unprecedented opportunity to elucidate relevant mechanisms responsible for the effects of multipollutant CAP on the pathogenesis of insulin resistance and inflammation. The insights gleaned from the acute studies planned in Projects 1 and 2 in conjunction with chronic studies in Project 3, have significant public health ramifications and may eventually lead to policy changes to avert environmental exposure to PM2.5

Progress Summary:

In our prior year, we successfully conducted experiments to determine the temporal course of diabetes development in response to CAPS and reported these results in several manuscripts. During Year 3 we began conducting detailed experiments in collaboration with Dr. Harkema on the effects of ozone exposure. We were interested in isolating the effects of ozone prior to conducting multipollutant exposures in combination with CAPS, which we had proposed performing as part of Aim 3. We hypothesized that ozone induces rapid effects on the cardiovascular system and proceeded to investigate this in a murine model of Type II diabetes. Inhalation exposure to O3 was conducted in whole body exposure chambers, and mice were exposed to nominal ozone concentrations of 0 (filtered room air), or 0.5 ppm, for 8 h/d, 7 d/wk for 13 wk (n = 8/group). Ozone was generated with two OREC Model OZONEV1-O ozonizers (Ozone Research and Equipment Corp., Phoenix, AZ), with compressed air used as a source of oxygen. The concentration of ozone within the chambers was monitored throughout the exposure with three Dasibi 1003 AH ambient-air ozone monitors (Dasibi Environmental Corp., Glendale, CA). The air-sampling probes were placed in the breathing zone of the rats. The chamber ozone concentration was automatically maintained through a computer-controlled closed-loop feedback system, which adjusted the amount of ozone delivered to the chamber through remotely controlled mass-flow valves. The effect of ozone exposure on body weight is depicted in Figure 1.


Figure 1. Depicts the effect of ozone exposure on body weight. After three weeks of inhalation exposure to control air or ozone, mice were sacrificed. The weights of whole body and organs were recorded. While the weights of whole body (A), visceral fat (C), and brown adipose tissue (D) were not significantly different between control and ozone-exposed groups, the weight of liver (B) in ozone-exposed group was significantly reduced.

Inhalational exposure to ozone over the short term resulted in infiltration of proinflammatory macrophages in the adipose tissue. These results are depicted in Figure 2.


Figure 2. Macrophage activation in response to ozone exposure. Cells were isolated from blood (A and B), mediastinal lymph nodes (C), visceral adipose tissues (D and E), and aortic perivascular adipose tissues. The richness of proinflammatory (CD11b+Gr-1low7/4hi) macrophages was analyzed with flow cytometry. Results show that while inhalation exposure to ozone did not increase the richness of proinflammatory macrophages in blood (B) and lymph nodes (C), it significantly increased the infiltration of proinflammatory macrophages in visceral (E) and aortic perivascular (F) adipose tissues. 

Interestingly these proinflammatory changes in adipose tissue were not paralleled by alteration in T cell subsets either in the mediastinal lymph nodes (data not shown) or in the visceral adipose tissue (Figure 3). In distinct contrast to the effects on macrophages in adipose, ozone exposure resulted in improvement in vascular function as evidenced by an improvement in response to endothelial-dependent agonist acetylcholine and a reduction in vasoconstrictor response to phenylephrine. There results were accompanied by a reduction in proinflammatory gene expression in the vessel wall (aorta). The conclusion of this experiment was that inhalation exposure to O3 has minimal effects on markers of T cell activation in adipose but increases the content of CD11b+Gr-1low7/4hi cells. 

 


Figure 3. The effect of ozone exposure on T cell subsets in adipose tissue. Because T cells regulate innate immune inflammatory response, and given that ozone exposure increased proinflammatory macrophage infiltration in adipose, we investigated CD3+ T cell content in perivascular fat and compared this with visceral adipose tissue. Stromal vascular cells were prepared from visceral adipose tissues and perivascular followed by profiling with flow cytometry. 

O3 exposure appears to have effects on endothelial function that appear paradoxical to its proinflammatory effects in the lung. The effect of ozone exposure on vascular function is depicted in Figure 4. These results suggest complex effects of O3 systemically, further suggesting that combination of O3 with PM may have effects that may be hard to predict based on their individual effects on vascular and inflammatory phenotype. There was minimal evidence of inflammatory gene expression in the vasculature when we assessed this by RT-PCR (data not shown). 


FIGURE 4. The effect of ozone exposure on vascular function. Thoracic aorta were isolated and mounted onto myograph. A, Dose response to phenylephrine; B, Dose response to U-46619; C, Dose response to Ach following pre-constriction with aphenylephrine (1 mM), D, Dose response to acetylcholine of aortic rings pre-contracted with phenylephrine (1 M). *p<0.05 vs Ctrl. Twoway ANOVA.

During this project cycle we have generated the following new findings and contributed to further understanding of the link between PM2.5 and inflammation:

  1. Began exposures in a near roadway site and performed characterization of the exposure milieu.
  2. CAP exaggerated Type II DM development in a genetic model with effects evident within 5 weeks including decreased thermogenesis and increased peripheral inflammation.
  3. PM2.5 exposure caused rapid effects (in KKay) of hypothalamic inflammation.
  4. Central inhibition of IKKβ but not TNFα blockade showed improvement in insulin resistance and metabolism.

 

Future Activities:

All aspects of the study protocol are approved by our IACUC. We anticipate beginning our CAPS + Ozone exposure this year. 


Journal Articles on this Report : 11 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
Type Citation Sub Project Document Sources
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 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 IKK╬▓ 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 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 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 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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  • Supplemental Keywords:

    ozone, O3, PM2.5, type II diabetes mellitus, DM, insulin resistance;, 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:

    GLACIER: Great Lakes Air Center for Integrated Environmental Research Exit

    Progress and Final Reports:

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

  • Main Center Abstract and Reports:

    R834797    Great Lakes Air Center for Integrative Environmental Research

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