2011 Progress Report: Cardiometabolic Effects of Exposure to Differing Mixtures and Concentrations of PM2.5 in Obese and Lean AdultsEPA 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: January 1, 2011 through July 31,2011
RFA: Clean Air Research Centers (2009) RFA Text | Recipients Lists
Research Category: Health Effects , Air
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 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. Although 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 are 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 two dissimilar multipollutant 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 locales comprised of dissimilar PM2.5 mixtures (industrial/urban versus a nearroadway/ 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.
There have been no changes in study investigators or personnel. The project timeline and study protocol have been modified from the original design in order to better overlap with the aims of Projects 2-3 of GLACIER and to accord with the theme of investigating the health effects of air pollution mixtures in a multipollutant context. During years 1-2 (study #1), we now will perform human coarse CAP exposures at a rural site (Dexter, MI) and urban site (Dearborn, MI). This will allow for comparisons of acute responses in humans to those following coarse CAP exposures in animal models as planned in Project 2. We will enroll 25 obese and 25 lean subjects who will each receive exposures to filtered air (FA), rural and urban coarse CAP (target levels 150-300 μg/m3) in a randomized blinded crossover fashion. All study outcomes (human health cardio-metabolic endpoints) have remained the same from the original study design. During the 7 months of activity of Year 1 for Project 1 (December 2010 - July 2011), we have successfully started the project. We completed assembling as well as rural site set up of the coarse CAP exposure facility (AIRCARE-2) at the Dexter, MI location. The concentrator was tested demonstrating an approximate 25-30 fold enrichment of ambient coarse PM levels. All PM characterization supplies and equipment were installed into the facility as required and then tested/validated (per exposure core protocols) including filter-based measurements (quartz and teflon filters; endotoxin filters) and real-time monitoring devices (nepholometer, APS system, CO2 and temperature monitors). The exposure facility was subsequently tested on 3 human subjects during April 2011 without incident or adverse event. All cardiovascular outcome equipment and devices (previously validated) were brought to the exposure facility and tested (per protocols). All aspects of CAP exposures, PM monitoring and obtaining CV outcomes now have been tested, validated, and shown to occur as expected per designs. Randomized human subject exposures (official study subjects) began in May 2011. As of July 22, 2011, we have completed 8 subjects at the rural Dexter site (2 exposures each, coarse CAP and filtered air) for a total of 16 exposures. There have been no adverse events.
All aspects of the study protocol now are proceeding per the modified study design. Subject recruitment actively continues. We anticipate completing study #1 within 2 years (rural coarse CAP exposures by the summer of 2012 and urban coarse CAP exposures in Dearborn, MI by spring 2013). Thereafter, we will begin study #2 – which will precede along the designs of the original project 1 protocol. This encompasses the randomized crossover exposure of 25 healthy and 25 obese adults to 4 randomized scenarios at Dearborn, MI, including urban/industrial fine CAP (PM2.5) at both high and low concentrations (35 versus >100 μg/m3) versus filtered air. The high concentration CAP exposures will be performed twice (after pre-treatments with placebo versus α+β adrenergic blockade).
Journal Articles:No journal articles submitted with this report: View all 17 publications for this subproject
Supplemental Keywords: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
Progress and Final Reports:Original Abstract
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