2012 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. , Kaplan, Marianna J. , Oral, Elif , Araujo, Jesus
Institution: University of Michigan , University of California - Los Angeles
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
We have elucidated the existence of an important confluence between key facets of the cardio-metabolic 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. 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 also 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 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 above100 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 will also 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 during years 1-2. As detailed in the year 1 report, the timeline and study protocol were modified to better overlap with the aims of projects 2-3. During years 1-2 (Project 1; study #1), the project was modified to perform human coarse CAP exposures at a rural site (Dexter MI) and an urban site (Dearborn MI). From the time period of 6/30/11 to 6/30/12, 32 subjects completed the protocol. Thirty subjects received exposures to both filtered air (FA) and rural coarse CAP at Dexter in a randomized blinded crossover fashion. Two subjects elected to not complete a second exposure due to personal issues unrelated to the study. Thus, we have completed a total of 62 exposures. All study outcomes (human cardio-metabolic endpoints outlined in the study protocol) have remained the same from the original design and have been successfully collected without problems or adverse events. All CAP exposures have been conducted successfully without methodological problems. We reported to our IRB a single patient-related minor adverse event, claustrophobia during an exposure. This was approved by our IRB and the written consent form was modified to reflect this change. The study was originally designed to enroll 50 subjects (100 exposures). In order to complete study 1 within the timeframe that is required given the expectations of the overall GLACIER project goals and moreover due to competing personnel and equipment needs for other projects, we elected to stop rural coarse exposures at the end of June 2012 (after 62 exposures). A new analysis of our estimated statistical power to determine the primary study outcomes based upon this reduced sample size suggested that we will still have ample power to determine biologically meaningful changes in these parameters. All of the biological results, except for the blood biomarkers, have been collected and successfully data-based.
We will begin exposures to urban coarse CAP at Dearborn in September 2012. To accord with the rural exposure study results, we will complete enrollment of a minimum of 32 subjects (receiving both urban CAP and filtered air exposures) during the period of September 2012 to September 2013. We will complete analyses of our study outcomes during this time period as well. We anticipate having at least four manuscripts completed in this period related to specific health outcomes induced by rural and urban coarse CAP (HDL function, insulin sensitivity, endothelial progenitor cell function, and the main study outcomes [blood pressure, vascular function]). We will thereafter begin study #2 in September 2013, 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 four 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 on this Report : 1 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|
|| 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.
Supplemental Keywords:Human exposures, susceptible populations, acute cardiovascular effects, particulate matter, human exposures, cardiometabolic syndrome;, Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, air toxics, Exposure, Health Risk Assessment, 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:http://greatlakesairresearchcenter.org Exit
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