Grantee Research Project Results
2012 Progress Report: Long Term Metabolic Consequences of Exposures to Multipollutant Atmospheres in the Great Lakes Region
EPA Grant Number: R834797C003Subproject: 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: Center for Research on Early Childhood Exposure and Development in Puerto Rico
Center Director: Alshawabkeh, Akram
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 , University of Michigan
Current Institution: The Ohio State University
EPA Project Officer: Chung, Serena
Project Period: December 1, 2010 through November 30, 2015 (Extended to December 31, 2016)
Project Period Covered by this Report: December 1, 2011 through November 30,2012
RFA: Clean Air Research Centers (2009) RFA Text | Recipients Lists
Research Category: Human Health , 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 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 dose response relationship of multipollutant-O3 mixture on insulin resistance measures (HOMA-IR and IPGTT) and novel mediators of innate immune, pivotal in the development of metabolic derangement. Based on data from Aims 1 and 2, we will design experiments in 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 OSU (OASIS-1 and OASIS-2) and MI in conjunction 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:
Exposure Facilities:
Our prior experiments have suggested an effect of PM2.5 in increasing peripheral inflammation. We then investigate the effects of CAP exposure on inflammatory monocytes in blood and spleen in mice exposed to FA or PM2.5 for 14 weeks. Results demonstrated that the increase in inflammatory monocytes in response to PM2.5 were reversed in blood by CCR2 deficiency and the this monocyte subset was lower in CCR2 -/- mice than wild type mice (Figure 3). We next tested the effect of exposure on insulin signaling pathways and MAPK activation in the liver. A selective increase in p38 MAPK signaling in the liver was noted, an effect mediated likely by PM2.5 and attenuated by CCR2 deficiency. These results are portrayed in Figure 4. We also investigated endothelium function and vascular response to insulin in aorta, another target organ of insulin resistance. It demonstrated that CAP exposure impairs endothelium function and insulin-induced vasorelaxation, which were not modified by CCR2 deficiency (Figure 5).
To assess the effect of CAP exposure on insulin resistance, we further visceral adipose tissue, a major source of inflammatory cytokines and free fatty acids in insulin resistance. In contrast to the lack of alteration of insulin signaling in liver, phosphorylation of Akt at ser473 was decreased significantly in adipose tissue with deficiency. CCR2 deficiency markedly alleviated these changes. To investigate the mechanism of insulin resistance in visceral adipose tissue, we firstly measured macrophage infiltration (F4/80+ staining) and quantified VAT infiltration by inflammatory macrophages using flow cytometry. Our results indicated that CCR2 mediated infiltration of visceral adipose tissue by inflammatory macrophages defined as CD11b+F4/80+ and CD11c+F4/80+ cells plays a pivotal role in PM2.5- exaggarated insulin resistance (Figure 6).
Future Activities:
All aspects of the study protocol are approved by our IACUC. KKAY mice as specified in Aim 1 have undergone exposure at Polaris Exposure Facility (OASIS-2) in Columbus, OH, and the results are being summarized. We will thereafter begin specific aim 2.
Journal Articles on this Report : 3 Displayed | Download in RIS Format
Other subproject views: | All 45 publications | 34 publications in selected types | All 34 journal articles |
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Other center views: | All 148 publications | 72 publications in selected types | All 72 journal articles |
Type | Citation | ||
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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) R834797 (2015) R834797 (2016) R834797 (Final) R834797C003 (2012) R834797C003 (Final) |
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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) R834797 (2015) R834797 (2016) R834797 (Final) R834797C003 (2012) R834797C003 (Final) |
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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) R834797 (2015) R834797 (2016) R834797 (Final) R834797C003 (2012) R834797C003 (Final) |
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Supplemental Keywords:
Ozone (O3) PM2.5, Type II Diabetes Mellitus (DM), Insulin Resistance (IR), 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, cardiotoxicityProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R834797 Center for Research on Early Childhood Exposure and Development in Puerto Rico 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2016 Progress Report
- 2015 Progress Report
- 2014 Progress Report
- 2013 Progress Report
- 2011 Progress Report
- Original Abstract
34 journal articles for this subproject
Main Center: R834797
148 publications for this center
72 journal articles for this center