Description: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17 percent of US adults. SDB and air pollution have each been linked to increased risk of autonomic dysfunction, pulmonary and systemic inflammation, elevated blood pressure, paroxysmal atrial fibrillation, ventricular arrhythmias, myocardial infarction, and cardiovascular mortality, but the influence of pollution on SDB is poorly understood. Many of the adverse cardiac effects of SDB are thought to be due in part to clinically significant apnea/hypopnea- induced hypoxemia and respiratory acidosis. However, there is only limited evidence that treatment of SDB with continuous positive airway pressure (CPAP) improves airway inflammation, blood pressure and other adverse cardiac outcomes. Although CPAP stabilizes airway patency and improves oxygenation, patients on CPAP are still exposed to pro-inflammatory allergens and air pollutants. We have demonstrated that current CPAP systems are not designed to efficiently filter either allergens or smaller respirable particles present in room air. We propose to pilot a randomized cross-over clinical trial of effective filtration of allergens and respirable particles during CPAP use, with the ultimate purpose to evaluate whether effective particle filtration improves airway inflammation, systemic inflammation, autonomic function, and blood pressure.
Pilot Grant Awardee: Korrick, S
Project Title: Conception with Assisted Reproductive Technology (ART), prenatal phthalate and bisphenol A (BPA) exposure and infant neurodevelopment
Award Amount: $15,500
Description: The long-term impact of Assisted Reproductive Technology (ART)-related exposure of gametes/embryos to physical and hormonal factors, including alterations in gonadal steroid exposures in early development, is largely unstudied. Early life exposure to phthalates and bisphenol A (BPA) has been associated with adverse development, especially that related to gonadal hormones. Prenatal exposure to gonadal steroids, in turn, is responsible for important aspects of brain development with impacts on cognition and behavior. The goal of this pilot is to assess the associations of ART, prenatal phthalate and BPA exposure, and (secondarily) their interaction, with infant neurocognitive development. Participants will be 30 infants (15 spontaneous, 15 ART conceptions) from a study of the relation of phthalates and BPA with infertility and pregnancy outcomes. Infants (age 12 months) will be assessed with standardized measures of cognition, behavior, and language. The relation of these tests with ART and phthalate/BPA exposure measures will be modeled. There is a notable paucity of information on the relation of phthalates, BPA and ART with childhood neurobehavioral development despite prevalent exposures and evidence suggestive of risk. The goal of this pilot is to begin to address this critical knowledge gap and to thereby develop the basis for a future more comprehensive study.
Pilot Grant Awardee: Tejera-Alvarez, P
Project Title: A Functional Study of Polymorphisms in the PI3 Gene, an inhibitor of Neutrophil Elastase in Inflammatory Lung Diseases
Award Amount: $22,650
Description: The inhalation of toxic gases (air pollution, cigarette smoke, noxious gases) as well as particles and microorganisms contribute to lung injury. Such insults exacerbate the pulmonary inflammatory response by increasing the concentration of pro-inflammatory mediators and target cells. Augmentation of neutrophils in the airways causes increased proteolytic enzymes, and results in the initiation and propagation of pulmonary damage. PI3 (pre-elafin) is a specific neutrophil elastase inhibitor. Our recent findings revealed that PI3 gene expression is down-regulated during the acute respiratory distress syndrome (ARDS) development. Recently, the polymorphism (SNP) rs2664581, located in exon 2 of pre-elafin, has been associated with increased ARDS risk and with PI3 circulating levels. However, because SNP rs2664581 is in high linkage disequilibrium (LD) with the remaining SNPs in the PI3 gene, it is difficult to distinguish between the casual SNP and those that are markers in LD with the functional SNP. This study is aimed at the functional characterization of the SNPs in PI3 gene. Our findings could contribute to a better understanding of the role PI3 as a neutrophil proteases inhibitor in the pathogenesis of inflammatory lung diseases. Morevover, the study brings together a multidisciplinary team, incorporating several experienced pulmonary researchers new to the field of environmental lung disease research.
Presentations of this work include: Tejera et al., 2010, Am. J. Respir. Crit. Care Med., 181: A6466. Tejera et al., 2011, Am. J. Respir. Crit. Care Med., 183: A5233
Pilot Grant Awardee: Wang, Z
Project Title: Application of Satellite Aerosol Remote Sensing Technology to Estimate the Health Impacts of Airborne Particles
Amount of Award: $25,000
Description: Numerous epidemiological studies have indicated that exposure to ambient-level fine particulate matter (PM2.5) is associated with increased morbidity and mortality from cardiopulmonary diseases and lung cancer. Exposure assessments are usually dependent on ground monitoring networks, which lack spatially complete coverage, especially in rural areas. With the rapid technological progress, satellite-based remote sensing provides a unique opportunity to monitor air quality from space at global, continental, national and regional scales. Studies have shown that satellite-derived aerosol optical depth (AOD) is correlated with ground-level PM2.5. Initial satellite-based environmental health studies revealed that the standardized county-level biennial mortality rates (2003-2004) of chronic heart diseases in the United States were associated with two-year average AOD raster data. Our preliminary study found that AOD is significantly associated with daily unscheduled hospital outpatient visits in Beijing, China for cardiovascular diseases, cerebrovascular diseases, and respiratory diseases, but not associated with cancer, injury, and skin diseases. We propose to expand our satellite-based study using newly acquired hospital admission data with much larger population coverage, which collected from all major hospitals in Beijing over a longer observational period (5 years, 2004 – 2008).
Pilot Grant Awardee: Deloid, G
Project Title: Novel screening assay for NLRP3 inflammasome activation by engineered nanoparticles
Award Amount: $10,000
Description: Engineered nanomaterials (ENMs) are widely and increasingly used in consumer products and industrial processes. It is therefore important to rigorously investigate potential effects of ENMs on health, including effects on the immune system. The multiprotein inflammasome complex is a central mediator of innate and adaptive immune responses. Inflammasomes have been implicated in the pathogenesis of a wide range of acute and chronic inflammatory disorders, including silicosis and asbestosis, and play a critical role in host defense against bacterial and viral pathogens, including Mycobacterium tuberculosis and Influenza.
Inflammasomes form in response to diverse pathogen and danger associated molecular patterns, and consist of NOD-like receptors (e.g. NLRP3), adaptor proteins (e.g. ASC), and inactive pro-caspase 1, which is cleaved within the inflammasome to active caspase 1, whose proteolytic activities mediate multiple inflammatory processes.
We will develop novel high-throughput fluorescence microscopy-based assays for detection of the NLRP3 inflammasome formation (association of NLRP3 and ASC, and ASC and caspase 1), and utilize these assays to assess the effects of a panel of ENMs on inflammasome activity in macrophages.
Pilot Grant Awardee: Godleski, J
Project Title: Exposure to Traffic Particles and DNA Methylation
Award Amount: $20,000
Description: The aim of this research is to define the role of epigenetic mechanisms specifically in vasoconstriction of blood vessels of the lung and heart after exposure to traffic-related ambient particles. Measuring the level of DNA methylation of three gene promoters involved in vascular processes (eNOS, NOTCH4 and endothelin-1) in rat heart and lung tissue will allow for comparison of PM exposed versus unexposed tissues. Differences in methylation could implicate changes in expression levels of these genes providing a mechanism by which particulate matter induces vasoconstriction. To date, sequencing has been conducted on a number of animal tissues in analyzing the eNOS promoter of rat heart and lung tissues and indications point to this being a very promising avenue of research. We hope to be able to expand this area of research on the NOTCH4 and endothelin-1 gene promoters.
Pilot Grant Awardee; McNeely, E
Project Title: Flight attendant exposures to flame retardants in airplanes
Award Amount: $20,000
Description: The evidence for flame retardants, such as polybrominated diphenyl ethers (PBDEs), to be chemicals toxicants has led to a ban on their manufacture in new products both in the U.S. and in the European Union (EU).Still, airplanes are a significant source of these compounds because of safety regulations that required their use. Recent studies have confirmed moderate levels of PBDE compounds in planes and one small study has noted higher passenger body burdens of these compounds after flight. Cabin crew continuously work in these environments, yet no study of their exposure has been done. This pilot proposes to evaluate exposure to these compounds after flight in a sample of flight attendants using two measures of exposure; serum levels of PBDEs and dust samples for PBDEs (via a newly developed hand-wipe method). This is the first study of these exposures in flight attendants, a workforce expected to grow to 106,000 workers by 2018. Aircraft exposures are particularly concerning for the majority of the U.S. flight crew who are female, many in their prime childbearing years, because new evidence shows PBDE exposures to be associated with decreases in thyroid hormones and that lower maternal circulating thyroid hormones have been associated with life-long adverse consequences on the nervous system, including cognitive function, in the offspring.
Pilot Grant Awardee: Mittleman, M
Project Title: Atrial fibrillation, ambient exposures and epigenetic mechanisms
Award Amount: $20,000
Project Description: Atrial fibrillation (AF) is a common arrhythmia responsible for a high mortality burden, but the etiology and risk factors are not well understood. Studies of familial aggregation have shown a complex pattern of inheritance, suggesting a potential role for polygenetic pathways, epigenetics and gene-environment interactions. However, these associations have not been explored. We propose to examine the relationship between DNA methylation in peripheral white cells and tissue from the right atrial appendage in a population of patients undergoing coronary artery bypass graft (CABG) surgery at Beth Israel Deaconess Medical Center. We will also look at the relationship between short and long term air pollution exposure and extent of methylation of the heart tissue and white cells. This pilot study will provide data that will allow for population-based case-control and cohort studies of the interaction between ambient air pollution exposure and DNA methylation on AF incidence outside of the post-CABG setting.
Atrial fibrillation (AF) is a common arrhythmia responsible for a high morbidity burden, but established risk factors account for only a portion of incident AF. Epigenetic mechanisms such as methylation of CpG islands in the DNA alter gene expression or phenotypic profile without modification to the DNA sequence and may influence atrial function, but this association has not been explored. Recent studies have demonstrated that environmental exposures to air pollution are associated with changes in the methylation of leukocytes. DNA-methylation can easily be assessed in peripheral white blood cells, but the relationship of leukocyte methylation to the methylation patterns in target tissue of the atrium is unknown.
We propose the following aims to be investigated in this pilot study of patients who undergo coronary artery bypass graft (CABG) surgery at Beth Israel Deaconess Medical Center. Subjects included in the study will be free of AF and other known atrial arrhythmias at the time of the procedure. We plan to collect preoperative clinical information and AF incidence in the postoperative period during the index hospitalization.
- To investigate the association between methylation in atrial target tissue and peripheral white cell methylation as measured by both global and genome-wide methylation analyses.
- To develop pilot data on the association between methylation at the site of the right atrial appendage and short and long-term exposures to ambient air pollutants.
If we find that peripheral leukocytes provide relevant information about methylation in atrial tissue, this will allow for population-based case-control and cohort studies of the role of air pollution on epigenetic changes leading to atrial fibrillation outside of the post-CABG setting.