2014 Progress Report: Cardiometabolic Effects of Exposure to Differing Mixtures and Concentrations of PM2.5 in Obese and Lean Adults

EPA Grant Number: R834797C001
Subproject: this is subproject number 001 , 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 Effects of Exposure to Differing Mixtures and Concentrations of PM2.5 in Obese and Lean Adults
Investigators: Brook, Robert D. , Araujo, Jesus , Kaplan, Marianna J. , Oral, Elif
Institution: University of Michigan - Ann Arbor , University of California - Los Angeles
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 have elucidated the existence of an important confluence between key facets of the cardiometabolic syndrome (CMS) and fine particulate matter (PM2.5). Brief exposure to concentrated PM2.5 (fine CAP) for 2 hours has proven capable of triggering vasoconstriction, raising diastolic blood pressure (BP), and impairing vascular endothelial function (VEF) 1 day later – the latter occurring in a location-dependent manner suggesting that particle constituents/sources are important determinants of the responses. Two distinct mechanistic pathways were implicated – with altered autonomic nervous system (ANS) balance responsible for the increased BP and systemic inflammatory responses for the slower impairment in VEF. Though these findings are important as they help to explain how PM2.5 might cause acute cardiovascular (CV) events, several important issues remain to be clarified. Moreover, our studies also suggest that a more-encompassing, yet unappreciated, convergence between PM2.5 and the CMS might exist. Not only could obesity enhance the susceptibility for adverse health effects induced by PM2.5 exposure, but PM2.5 might promote the development of metabolic insulin resistance (IR), a central factor in the pathogenesis of obesity and the CMS itself (i.e., reciprocal relationship).

We propose to build upon our previous research on the effect of short-term PM2.5 exposure on key facets of the CMS. The broad objectives are to investigate: 1) if exposure to fine CAP mixtures is capable of acutely instigating metabolic IR in addition to elevating diastolic BP and impairing VEF; 2) whether obesity confers enhanced susceptibility for these adverse responses; 3) details of the mechanistic pathways involved; 4) the extent and nature of the dose-response relationships even to levels below current 24-hour PM2.5 standards; and 5) if fine CAP derived from 2 dissimilar multi-pollutant ambient PM2.5 mixtures elicit differing CMS responses and the specific pollutants responsible. We will achieve these aims by examining the BP and VEF responses, along with additional/novel outcomes, in obese versus healthy adults induced by fine CAP exposures in two separate locals comprised of dissimilar PM2.5 mixtures (industrial/urban versus a near-roadway/residential). The concentrations of fine CAP will be varied to include levels from below 35 to above 100 µg/m3. Using state-of-the-art physiological testing and novel biomarkers (including adipocytokines, HDL function, endothelial progenitor cell levels and function), the mechanisms responsible for the alterations in the CMS responses will be explored. The role of the ANS in the etiology of the BP increase and the effectiveness of a prophylactic measure, α+β adrenergic blockade, in obviating this response also will be tested. Finally, we will evaluate whether exposure to fine CAP can acutely elicit metabolic IR, the underlying cause of the CMS itself. This project addresses several RFA questions (Q) in an experimental fashion with humans exposed to real-world PM2.5, thereby providing findings of tremendous health/regulatory importance. The expected results will elucidate pivotal new insights into: the enhanced susceptibility of obese individuals (Q#3), the extent of the concentration-response relationship (Q#4), the mixtures of PM2.5 and their constituents/sources responsible (Q#2), and the mechanisms underlying the CV responses (Q#6). Finally, we will explore for the first time the evidence for a novel PM2.5 health effect (Q#6) – instigation of metabolic IR by PM2.5 mixtures – of critical health importance given the rising global epidemics of obesity and the CMS. 

Progress Summary:

We began urban exposures per protocol design in Dearborn after the end of winter season starting in April 2013. Randomized exposures continued until April of 2014. During this period (year 4), we completed 30 subjects having both CAP and FA exposure done at the urban Dearborn site. All health outcomes and exposures/monitoring were completed per study design without deviation from the protocol, pitfalls, or adverse events reportable to IRB. (Due to concerns about performing human exposure to concentrated PM2.5 (fine particles) we chose to re-design study #2 of project 1 without using fine CAP.) Though the study was approved by the IRB to perform fine CAP exposures, we re-designed the protocol for study #2 to involve only ambient level exposures in a panel study. In June of 2013, the re-designed panel study of obese and lean individuals (n = 50) undergoing 2 separate non-scripted exposure window periods (7 days of local site pollution monitoring; 1 day of personal PM2.5 monitoring using pDR-1500) was approved by our IRB at the University of Michigan. The health outcomes collected have not changed from the original study design; however, they will be obtained on 2 separate mornings (from 1-4 weeks apart) and associated with daily 24-hour average PM2.5 levels measured from personal (pDR-1500) and local ambient PM2.5 levels during the prior 1 and 7 days, respectively. 

Future Activities:

We will begin study #2 of project 1 (re-designed panel study) during July 2014. The plan is to complete all 50 subjects (2 exposure periods each = 100 exposure windows) before the end of the project (Year 5 end). We will complete analyses of our controlled urban Dearborn CAP exposure study outcomes by September 2014, and submit manuscripts to journals regarding these results by December 2014. We will aim to complete analyses and submit manuscripts of the study #2 results within a few months of the trial completion. 


Journal Articles on this Report : 6 Displayed | Download in RIS Format

Other subproject views: All 17 publications 13 publications in selected types All 13 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 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 Maiseyeu A, Yang H-Y, Ramanathan G, Yin F, Bard RL, Morishita M, Dvonch JT, Wang L, Spino C, Mukherjee B, Badgeley MA, Barajas-Espinosa A, Sun Q, Harkema J, Rajagopalan S, Araujo JA, Brook RD. No effect of acute exposure to coarse particulate matter air pollution in a rural location on high-density lipoprotein function. Inhalation Toxicology 2014;26(1):23-29. 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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  • Supplemental Keywords:

    human exposures, susceptible populations, acute cardiovascular effects, particulate matter, human exposures, cardiometabolic syndrome 
    , Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, air toxics, Health Risk Assessment, Exposure, Biochemistry, Biology, Risk Assessment, ambient air quality, particulate matter, aerosol particles, susceptible populations, acute cardiovascualr effects, human exposure, physiology, cardiopulmonary, cardiotoxicity, acute exposure

    Relevant Websites:

    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