2015 Progress Report: Initial Annual CEMALB Progress Report: Human Health Effects of Environmental Pollutants Year 1, period beginning 4/1/15

EPA Grant Number: 83578501
Center: Center for Environmental Medicine, Asthma, lung biology
Center Director: Peden, David B
Title: Initial Annual CEMALB Progress Report: Human Health Effects of Environmental Pollutants Year 1, period beginning 4/1/15
Investigators: Peden, David B , Jaspers, Ilona , Hernandez, Michelle L
Current Investigators: Peden, David B , Jaspers, Ilona , Hernandez, Michelle L , Alexis, Neil , Smith, Judith , Noah, Terry , Bennett, William D , Robinette, Carole
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Schmitt, Michael
Project Period: April 1, 2015 through March 31, 2022
Project Period Covered by this Report: April 1, 2015 through March 31,2016
Project Amount: $9,800,000
RFA: Human Health Effects of Environmental Pollutants (2014) RFA Text
Research Category: Human Health

Objective:

Discussion of the research performed during the reporting period and results (outputs/outcomes) that have been generated.

As originally proposed, this center is organized to be responsive to the research areas outlined in the funding announcement, which included: a) Multi-pollutant Interactions, b) Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, c) Susceptibility to Air Pollutants, d) Social Determinants of Health, e) Intervention Studies, and f) Biological Mechanisms.

At the beginning of year 1 (start 4/1/2015) the center was initially composed of three projects, two support cores and an administrative core. Project 1 is led by David Peden and was originally entitled Biological Determinants of Inflammatory Response to Pollutants. Project 2 is led by Ilona Jaspers and is entitled Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources. Project 3 is led by Michelle Hernandez was originally entitled IL-1β and Anakinra in Modulation of O3-induced inflammation in Asthma. These three projects respond to the areas Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Intervention Studies.

Additionally, the funding announcement outlines the potential for additional program specific supplements to base funding to targeted program needs. During this initial year, two above base projects were proposed and agreed upon by the steering committee, both led by Dr. Jaspers (UNC) and Dr. Diaz-Sanchez (EPA). One was Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects led by and the second was Environmental Health Education. &Listed below are project summaries from year one. Detailed descriptions of each project are provided in the detailed project reports which are provided with this overall report. As Item 5 calls for a detailed discussion of the Products (outputs/outcomes) obtained during this project period, Products will be addressed in that item.

Project Discussions:

Project 1: Biological Determinants of Inflammatory Response to Pollutants (revised to Development of Interventions to mitigate Inflammatory Response to Pollutants): The primary activity of this project in the first year was to develop the protocols required to allow volunteers to undergo inhalation challenge ozone, endotoxin and woodsmoke particles. The scientific premise for this is to determine if inpiduals have a general biological predisposition to be responsive to pollutants, or if response is pollutant specific. To determine this, the responses of volunteers to these pro-inflammatory pollutants will be compared. At present, protocols for woodsmoke and low level ozone challenge have been approved, and a protocol for endotoxin challenge is being reviewed by the FDA (due to its IND requirement). At present volunteers are undergoing woodsmoke challenge and are set to undergo low level ozone challenge in the next 4-8 weeks (protocol is under EPA review, having completed IRB review). We have also used data from our biorepository to assess if response to LPS is reproducible, within inpiduals. We have found that it is reproducible, and that IL-8, in addition to PMNs, is a reliable biomarker for induced inflammatory response. This is important, as there are technical advantages for using IL-8 (vs. PMNs) in assessing sputum inflammation, which will be useful in these planned analyses as well as in field studies. Further, in reviewing data and samples in the biorepository, we have samples from 123 volunteers, in which 76 were LPS responders (>10% increase in PMNs) and 45 were non-responders with regard to increased sputum PMNs. Of this sample, there are 49 in whom baseline and post challenge mRNA and miRNA samples in sputum cells are available. Thus, we will compare baseline markers of inflammation and gene expression and mi-RNA features in responders vs. non-responders, to determine if there are biological features which define response to LPS (similar to studies we have undertaken with ozone).

As will be outlined under Item 2, the scope of project 1 was modified to include intervention studies, focusing on examination of the actions of nutriceuticals on environmentally-induced disease. These focus on the effect of gamma tocopherol (gT) on response to pollutant-induced airway inflammation (inhaled endotoxin, ozone and ultimately woodsmoke particles, led by Dr. Peden), as well as studies of the effect of omega-3 fatty acids and olive oil on response to ozone (led by Drs. Samet and Tong of the EPA). At present, subject recruitment for gT is well underway (anticipated n=15 will be completed by 9/2016), and study of the action of gT on ozone induced inflammation is scheduled to commence in July of 2016. Additionally, to determine if shorter courses on gT might be used for anti-inflammatory action, an open label dosing study has been competed, and indicates that 3 doses of gT given over 24 hours provides levels of gT and its active metabolite that should protect against inflammation. The study of omega-3 fatty acids and olive oil on inflammatory response is currently being revised to address an IRB requirement than an IND be obtained.

Project 1 also now entails development of other modalities than may be employed to protect against environmentally-induced inflammation. This includes using the facilities at the HSF to test environmental and physiological sensors being developed through a collaboration with the NSF Nanosystems Engineering Research Center (NERC) for Advanced Self-Powered Systems of Integrated Sensors and Technologies (ASSIST) based at NCSU (with partners at UVa). ASSIST engineers are developing nano-enabled energy harvesting, energy storage, nanodevices and sensors to create innovative battery-free, body-powered, and wearable health monitoring systems.

Finally, UNC convened an Environmental Task Force to begin to leverage groups on campus and in the region to develop multidisciplinary approaches to environmental health. One project has been initiated, leveraging the Task Force and efforts on campus focused on the Precision Medicine Initiative. This is an Environmental Data effort, in which environmental and weather modeling capabilities (Institute for the Environment), computational efforts (RENCI, the NC TraCS Institute) and collaboration with the UNC Health Care System and the US EPA are being developed to determine how environmental, weather and local environmental factors (SES, greenspace, proximity to arterial roads) impact health events. This workgroup is being led by Drs. Peden (UNC), Cascio (EPA) and Band (UNC Institute for the Environment). Initial efforts will focus on achieved health care and environmental data in persons with diseases known to be impacted by pollutants (asthma, congestive heart disease and diabetes). This workgroup is continuing to develop the initial project and with a goal of submitting an IRB application in August, 2016. These data will then be used to undertake prospective studies in environmental forecasting to prevent health adverse health outcomes in at risk populations served by the UNC Health Care System.

Project 2: Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources: This project focused on the effect of oxidant pollutants derived from the incomplete combustion of organic matter, such as burning of biomass or woodsmoke. These are of increased global public health concern and associated with increased susceptibility to respiratory infections, including viral infections in children. More than two billion people in the world use biomass (including indoor wood burning) as their main source of energy for domestic heating and cooking. For this project, investigators from UNC and EPA developed a human in vivo exposure and viral challenge study to directly assess the effect of a model biomass component (woodsmoke) in human volunteers. These studies used the human in vivo experimental protocol developed by investigators at UNC using the FDA-approved live attenuated influenza virus (LAIV) vaccine as a model for viral infections in human volunteers. Inoculation with LAIV causes a self-limiting replicative infection, which induces similar cytokine and antiviral host defense responses as community-acquired infections. This human LAIV inoculation model was previously used to assess interactions between exposure to diesel exhaust and viral infections, which demonstrated that underlying allergy rhinitis enhances the interaction between DE and viral infection, leading to increased viral replication and markers of allergic inflammation. These approaches are now being applied to woodsmoke. Clinical protocol development, IRB approval, recruitment of subjects, and proper maintenance of databases were done in collaboration with the Medical, Physiology and Study Coordination Core (led by Drs. Noah and Jaspers). All samples collected as part of these protocols will be used to analyze the endpoints identified above in collaboration with the Biorepository and Cell Biology Core (led by Drs. Alexis and Jaspers).

To date, 40 subjects were randomized for exposure to either air (n=20) or 500 ug/m3 WSP (n=20) and inoculated with LAIV shortly after completion of the exposure. Baseline and post-inoculation nasal lavages, nasal biopsies, collection of epithelial lining fluid (ELF), and collection of peripheral blood have been performed by CEMALB personnel. The following sample analyses have been completed: 1) Gene expression of NLF cells, 2) cytokines/chemokines (27 analytes) of ELF, 3) mediators in cell-free NLF, 4) gene expression profiles nasal biopsies for inflammation genes. These data are currently being analyzed in collaboration with the CEMALB Biostatistics Core (Dr. Haibo Zhou), as well as the Genomics Core at UNC-CH. Our initial findings indicate a very mild effect of WSP on subsequent LAIV infection, indicative of enhanced innate immune responses resulting in decreased viral replication.

In our studies which examined the effect of diesel exhaust on LAIV responses, we observed that persons with allergic airway disease were more susceptible to the effect the pollutant on LAIV than healthy volunteers, primarily by causing an increase in allergic type inflammation. In continued studies, we propose to assess the effect of effect of woodsmoke (with and without LAIV) on allergic inflammation, as well as on real-life viral infections. These are logical additions to the original plan, which focused on examining the effects of woodsmoke on live-attenuated influenza virus (LAIV)-induced responses in healthy non-allergic volunteers. To do so, we will activate an existing IND protocol approved to use LAIV in allergic asthmatics. We will initially examine the effect of LAIV on nasal mucosal inflammatory responses in allergic asthma, then extend these studies to comparison of woodsmoke-induced alterations of virus-induced host responses in normal and allergic inpiduals.

We also undertook in vitro studies, using our well-established model of differentiated human nasal epithelial cells (hNECs). Superficial scrape biopsies obtained from healthy human volunteers and were expanded and differentiated in vitro, similar to our previous studies. For the woodsmoke exposure, we used an in vitro deposition system (the Quantaire; formerly described as the electrostatic aerosol in vitro exposure system = EAVES), which was designed in collaboration with investigators from the UNC Gillings School of Global Public Health. We planed to expose differentiated NECs to woodsmoke generated as described above for SA1 for 2 hrs prior to infection with influenza virus and assessed for 1) viral replication, 2) markers of host defense responses (i.e. interferon, TLR, and RIG-I networks using NanoString technology), 3) markers of inflammation (i.e. IL-6, IL-8, TNF, IL-1, etc. using multiplex ELISA), 4) cytotoxicity (i.e. markers of necrosis and apoptosis using fluorescent probes), and 5) markers of oxidative stress. However, we had technical difficulties with the exposure systems facilitating direct exposure of hNECs with woodsmoke. We are now exploring alternative strategies to achieve this aim. These include utilizing in vitro particulate air pollution exposure systems currently being developed by EPA investigators.

We also examined the interaction of epithelial cells with immune cells, which we hypothesize is an essential aspect of the biological response to pollutants. Differentiated NECs or other models of human lung epithelial cells are being cultured alone or in co-culture with immune cells (e.g. macrophages, NK cells, or dendritic cells) and exposed to woodsmoke prior to infection with influenza virus. Co-cultures are separated and each cell type will be inpidually analyzed for changes in 1) viral replication, 2) markers of host defense responses (i.e. interferon, TLR, and RIG-I networks using NanoString technology), 3) markers of inflammation (i.e. IL-6, IL-8, TNF, IL-1, etc. using multiplex ELISA), 4) cytotoxicity (i.e. markers of necrosis and apoptosis using fluorescent probes), and 5) markers of oxidative stress. In addition to our existing model of infecting epithelial cells in vitro with influenza virus, we will also develop an in vitro hRV infection protocol. We have recently demonstrated that exposure to particulate air pollution mixtures affect the ability of NK cell to induce apoptosis of eosinophils, thus potentially prolonging the survival of these cells in the nasal mucosa and causing more persistent allergic inflammation. Therefore, we anticipate shifting our focus to interrogating how exposure to WSP may affect the ability of innate immune cells, such as macrophages or NK cells affect the ability to resolve inflammation through the process of efferocytosis.

Project 3: IL-1β and Anakinra in Modulation of O3-induced inflammation in Asthma (now revised to Establish whether LPS inhalation induces Systemic inflammation and CV inflammation): The original focus for this project was examine the effect of anakinra (IL-1 receptor antagonist) on ozone induced inflammation. However, (as will be described in Item 2), there was concern that anakinra, because of its expense, might prove to be impractical as an intervention to use from a public health perspective. Additionally, recent studies suggest that biological components of PM account for changes in blood pressure in a study of volunteers who were experimentally exposed to PM. Given that Dr. Hernandez has direct experience in performing inhalation challenge with endotoxin, the Steering Committee decided that Project 3 would redirect efforts to examination of the role of biological components of PM on cardiovascular outcomes.

To assess the impact of bioaerosol inhalation on CV endpoints, we will undertake a double-blinded, placebo-controlled crossover study of the effect of an inhaled 20,000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE that we obtain from the NIH Endotoxin Biorepository) vs. saline inhalation in 20 human volunteers with a 2 week wash-out period between each arm. This study requires us to obtain an Investigational New Drug application from the FDA. After project 3 was approved on 2/2/2016, the PI applied for an amendment to the existing CCRE IND: Protocol 15, Amendment #55 of IND BB-9998 Airway response to clinical center reference endotoxin in healthy adults. On 5/5/2016, we received notification from the FDA review coordinator no clinical hold on proceeding with this study, though minor revisions were requested to the document. We submitted the revised protocol on 5/23/16 to FDA, and an IRB application was submitted to UNC on 5/26/16. In the interim, we have prepared the IRB document, and will submit the IRB application. We anticipate IRB approval by early August of 2016.

While proceeding with this approval process, we have also queried our Biorepository and Data Base and have identified data from 48 healthy volunteers and 13 allergic asthmatics who have participated in one of our endotoxin studies using 20,000 EU CCRE within the past 10 years. Each of these studies involved a CCRE, but no saline control challenge. Physiological data which are available include blood pressure and heart rate data across a number of timepoints after the LPS inhalation, including immediately after and 30 minutes after exposure. Biological data include neutrophil counts and cytokine levels in the blood and sputum at baseline and 6 hours after challenge. Twenty-one subjects underwent cross-over studies where they received treatment with one of two therapeutics and a placebo control treatment: 1200 mg gamma Tocopherol (n=13) or 100 mg anakinra (n=18). Thus, by using biorepository data, we can undertake initial investigation of the relationship between change in systemic or airway LPS responsiveness (defined by increase in blood neutrophil count) and changes in blood pressure and heart rate. We can also extend this to determine if agents we have found inhibit airway inflammation due to CCRE also modify cardiovascular effects. We anticipate that a publication will be submitted by Fall of 2016.

Additionally, Dr. Hernandez continued work on two protocols which began during the prior funding period and were continued during this agreement, remain consistent with the themes to be examined within this project. One of these projects was Teen AIRE: Does baseline asthma control influence susceptibility to pollutant-induced cardiopulmonary health effects in African-American adolescents with persistent asthma?. This is an observational panel study of African American adolescents, ages 12-17, with persistent asthma living in a defined geographical area of Wake County. Asthma status was assessed using NHLBI guideline criteria, with 14 volunteers having poorly controlled asthma and 11 having well controlled asthma. These volunteers were followed over a course of 6-8 weeks through 6 visits. Endpoints included weekly measurements of pulmonary function, assessment of asthma control through the Asthma Control Questionnaire, autonomic control of heart rhythm and vascular markers of inflammation, and clotting/coagulation and exposure. Health effects markers will be compared to ambient fine particle (PM2.5), coarse particle (PM­10) and ozone concentrations in the 5 days preceding each participants clinic visits in their residential locations. These data are being analyzed to test the hypothesis that poorly controlled asthma is a risk factor for CV effects of ambient air pollution.

Dr. Hernandez also completed data collection for the protocol Broccoz: A randomized clinical trial of the NRF2 activator Sulforaphane against ozone-induced injury. This project follows on prior work by both EPA and UNC scientists that indicates that oral supplementation with Sulforaphane (SFN), an antioxidant compound derived from broccosprouts, upregulates expression of NRF2-regulated antioxidant enzymes in nasal cells which should protect against oxidant stress related responses induced by pollutants. We tested in vivo if SFN can suppress O3-induced decrements in lung function and inflammation in human volunteers. Sixteen healthy volunteers completed a double-blinded, placebo controlled crossover study in which they were treated with a SFN-rich broccosprout homogenate (BSH) vs. alfalfa sprout homogenate (placebo). After 3 days of daily supplementation, they underwent a 2-hour 0.4 part per million O3 exposure. Spirometry was performed immediately before and after the O3 exposures. Sputum induction was performed four hours after the O3 exposure. We observed that while three days of supplementation with BSH significantly increased plasma levels of SFN and its metabolites (p=0.001) compared to placebo, BSH did not significantly blunt O3-induced decrements in spirometry or increases in post-O3 sputum neutrophilia, sputum inflammatory cytokines, or nasal epithelial cell NRF2-regulated gene expression. Thus, three days of BSH supplementation successfully increased systemic SFN levels and its major metabolites in healthy volunteers, but did not confer protection against O3 -induced changes in lung function or airway inflammation in vivo. This manuscript was submitted to Respiratory Research on 5/27/16 and is currently in review.

Above Base Project: Environmental Health Education: Both the EPA and CEMALB have a long and distinguished track record in support of activities that promote environmental public health education. Environmental Health is a fast moving field that encompasses toxicology, environmental medicine, microbiome, epidemiology, genomics, epigenetics, and many other fields. In addition, community engagement in public health research and in the dissemination of scientific facts is of increasing interest. Currently, CEMALB and UNC-CH at large has several initiatives to train students/postdocs by familiarizing them in the latest developments in these areas so as to enable them to understand better current and future environmental challenges. Linking state-of-the-art biomedical training with opportunities to actively engage in community-based public health research will better prepare our trainees for careers in Environmental Health.

In order to foster these initiatives, following goals are proposed:

To attract potential trainees to the field of Environmental Public Health.

To provide the opportunity for trainees to travel to meetings to further their education in Environmental Public Health

To provide the opportunity for trainees to interact with experts in Environmental Public Health

To enhance community-based research skills by supporting additional training opportunities

In pursuing these goals, we solicited applications from 3 trainees and awarded 2 travel awards. All three applications were reviewed by a committee composed of the members of the Curriculum in Toxicology executive committee (which includes UNC and EPA Scientists) and ranked based on their merit. The two awarded trainees traveled to the 2016 Society of Toxicology meeting to present their research and interact with other environmental health scientists. Additionally, a committee composed of current Curriculum in Toxicology predoctoral and postdoctoral trainees identified 5-6 experts in environmental public health (usually 5-6) and ranks them based on interest of their research focus and reputation for mentoring young scientists. The top candidate is invited for a seminar at UNC-CH and discussions with local scientists. The committee organizes the invitation, the seminar, as well as the overall itinerary for the invited speaker. The attendance of the seminar usually exceeds 50 attendees, including many investigators from CEMALB and EPA. During the current reporting period, Dr. Debra Laskin, PhD, Distinguished Professor and Roy A. Bowers Endowed Chair of the Department of Pharmacology & Toxicology at Rutgers University (speaking on Macrophages and Ozone-induced Lung Injury: A Battle of Forces) and Dr. Dana Barr, PhD, Research Professor from the Department of Environmental Health of the Rollins School of Public Health at Emory University (speaking on Exposure Science: A Tool for Giving Perspective to Toxicology ) were selected.

Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects: Large datasets generated through emerging omics technology (epigenomics, metagenomics, genomics, proteomics, microbiomics and metabolomics) are increasingly being used to provide unbiased assessment of pollutant-induced adverse health effects, including identification of biomarkers of exposure, biomarkers of health effects, prediction of susceptibility and understanding biological mechanisms. Investigators in CEMALB have used these technologies to understand responsiveness to pollutants, such as ozone, investigate epigenetic markers of susceptibility, and identify novel biological pathways. In addition, utilizing metagenomic analyses of human samples, studies are proposed assessing the interplay between mucosal microbiota and inhaled pollutants in the mediating adverse health effects. This project provided additional support for trainees to extend findings of projects they are undertaking using dataset analyses of omics data. Toxicology graduate students Dana Walsh, Emma Bowers, and a post-doctoral fellow, Dr. Jaime Mirowsky have been supported this year in this fashion. The specifics of these projects are described in the specific project summaries, and have yielded 7 publications and 1 submission to date.

(2) Discussion of difficulties the Center has encountered in carrying out its mission, and remedial actions taken. If the goals/hypotheses of any project funded under this Center have been modified from the original application, provide the revised goals and discuss the reason for the change. A discussion of any problems, delays, or adverse conditions which may materially impair the ability to meet the results (outputs/outcomes) specified in the application should also be provided.

 

Revised goals for any projects and 3 and discussion of the reason for the change: As noted in the funding announcement, the projects originally described in the application should be illustrative in nature rather than an attempt to describe every potential study that may be initiated. A final description of projects will benefit from discussions between the awardee and the HSD. Upon funding in 4/1/2015, there was substantial and frequent review of priorities during discussions of the Steering Committee. It was noted that there had been a significant shift in EPA programmatic focus from a primary emphasis on NAAQS standard setting towards increased attention on Environmental Public Health. It was also noted that environmental impacts on cardiovascular disease as well as a continued focus on asthma and identification of risk populations was important. These discussions led to a change in emphasis in Projects 1 and 3.

Revised Goals for Project 1: The original goal of project 1, led by Dr. Peden, was to: 1.) identify gene expression patterns in volunteers exposed to O3 to uncover potential mechanisms of response, 2.) compare airway inflammatory response of volunteers exposed to ozone and LPS on separate occasions, and 3.) determine if in vitro responses of cells to ozone and LPS reflected the degree of response seen in airway samples and blood samples of volunteers. However, with increased attention focused on development of public health interventions, it was mutually decided to modify the goals of Project 1, which was renamed Development of Interventions to mitigate Inflammatory Response to Pollutants.

 

Revised Specific Aim 1 retains much of the original intent of the project, and focuses on undertaking straightforward, open label inhalation challenges with ozone, LPS and wood smoke and recruiting volunteers into each protocol separately. We hypothesize that persons with increased response to ozone will also have increased inflammatory response to other pollutants. If this is true, then it suggests that there are risk factors which generally increase risk for adverse response for pollutants. In addition to assessing the response phenotype (airway neutrophilia) we will also assess a number of other endpoints (airway and circulating cytokines, gene expression profiles, serum lipid, CRP and fibrinogen samples). Over the course of the next 6 years, we hope to build on our database of people exposed to pollutants and use various omics techniques to identify biomarkers of exposure and risk for adverse response, and uncover mechanisms that may become the basis for regulation or potential intervention. This revised aim addresses the subject areas Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants and Biological Mechanisms listed in the funding announcement.

Revised Specific Aim 2 focuses on the development of interventions for adverse response to air pollutants. This focus takes advantage of >20 years of experience by Dr. Peden with research development of potential interventions, who also received new support from NIEHS and EPA to assess the effect of gamma tocopherol on adverse response to pollutants, including wood smoke. This new support did not materialize until after submission and awarding of this EPA assistance agreement. Coincident with this development, EPA scientists (Drs. Samet, Tong, Diaz-Sanchez) were confronted with new regulatory requirements in their long standing interest in the effect of omega-3-fatty acids and olive oil on lung function, cardiovascular and inflammatory effects of ozone and particulate matter. Dr. Peden has extensive experience with the FDA, being a sponsor-investigator for 7 Investigational New Drug (IND) applications and currently serving on the Allergenic Products Advisory Committee of the FDA. He also has contacts with a vendor who can provide GMP-grade test agent (omega-3-fatty acids and olive oil) which can be approved by the FDA. The proposed study will be conducted as an amendment to the ozone IND currently held by Dr. Peden. This revised aim is very responsive to EPA mission and falls under the category of Intervention Studies noted in the funding announcement.

Revised Specific Aim 3 builds on activities supported by the CEMALB and EPA which were included in the original application as a proposed above based project entitled Above Base Pilot Project 3: Development of Personalized Environmental and Physiologic Sensors. Despite not receiving additional EPA funding, this project is being supported by EPA through access to HSF exposure facilities and has proven to be a very promising area of study. Progress is being made in developing and testing sensors being produced by engineers of the NSF funded ASSIST center, of which Dr. Peden is Medical Director and Dr. Cascio of the EPA has served as a consultant. Additionally, the Environmental Data Project described in the progress report for Project 1 developed after the current assistance agreement was submitted, reviewed and funded. It was felt by both UNC and EPA investigators that these efforts more immediately addressed the environmental public health mission of both organizations. This revised aim addresses these funding announcement research Areas: Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Intervention Studies and Biological Mechanisms.

Approval of modification of Project 1: As documented in minutes from the Steering Committee meetings on 9/1/2015 and 11/3/2015, EPA priorities have evolved from the time this cooperative agreement was submitted and approved. This led to proposed changes in Project 1, with the primary revision reviewed on 11/3/2015. The minutes of the meeting of the Steering Committee from 5/6 confirm that this project revision was accepted.

Revised Goals for Project 3: Project 3 underwent revisions from the original proposal (focused on studying the effect of IL-1 blockade with anakinra on inhaled LPS challenge), to focus on the impact of bioaerosols on cardiovascular responses. This project will examine the effect of LPS, a component of particulate matter, on systemic and cardiovascular (CV) inflammatory responses in humans. This is based on literature supporting that short term exposure to LPS, a biological constituent of particulate matter, is associated with increased blood pressure in controlled human exposures (Zhong et al, Endotoxin and β-1,3-D-Glucan in concentrated ambient particles induce rapid increase in blood pressure in controlled human exposures, Hypertension 2015). There is a growing body of literature that supports IL-1β, a byproduct of LPS-induced inflammation, as a central mediator of systemic and CV responses. Short-term changes in air pollution are also associated with changes in stiffness of the conduit arteries and with exacerbations of heart failure. Moreover, inhibition of IL-1β activity with anakinra improves vascular endothelial function and left ventricular contractile function in patients with chronic inflammatory diseases. Thus, it is plausible that through IL-1β release, LPS adversely affects CV outcomes by modifying heart rate variability through autonomic control of heart rate, impairing endothelial function, increasing vascular stiffness, and depressing myocardial contractility.

Approval of modification of Project 3: As documented in the minutes of the Steering Committee meetings on 9/1/2015, 11/3/2015, and 2/2/2016, this change in focus was extensively discussed and felt to better match immediate EPA public health. The final iteration of project 3 was unanimously approved by EPA investigators and the CEMALB on 2/2/2016.

Difficulties the Center has encountered in carrying out its mission, and remedial actions taken: Protocol Activation: The changes in emphasis outlined above over the first year led to a number of changes (or additions to) human exposure protocols. As these projects were being developed, there was significant discussion between members of the steering committee regarding specific elements of each protocol. Reaching scientific consensus on many projects, including the LPS challenge protocol for revised Project 3, the low level ozone study and reactivated 0.4 ppm ozone study for project 1, required often several weeks of discussion and protocol review. Once these changes were agreed upon, each protocol required protocol development and regulatory approval from the UNC IRB, the EPA and occasionally the FDA (if an IND is involved, as is the case with endotoxin). It is not uncommon for each of these steps to require submission, initial review, resubmission and subsequent re-review, with each step taking 1-3 months. Further, these regulatory steps occur sequentially, not simultaneously. In the current regulatory environment, it is common for protocols to take up to 6-12 months from conception to study launch. To date, many of these regulatory steps across Projects 1 and 3 have been achieved and by August, we anticipate most of these protocols to be actively recruiting. Furthermore, we have simultaneously been completing projects which began in the prior EPA agreement, and are able to use data and samples from the Database and Biorepository to address many of the goals of this project. Overall, this program is on track for completion of the goals outlined in project revisions.

Maximizing Sputum Analyses: Relevant to Projects 1 and 3, we have been assessing ways to improve subject eligibility for controlled exposure studies. One of these is to determine if biomarkers besides sputum PMNs might be used as a reflection of inflammation. As noted by the report by Kobernick et al (see publications), we have found that cytokines, and most notably IL-8, are reliable markers for inflammation. This is important, as the cellularity of the sample is not as crucial and we can be more liberal in recruiting studies with regard to volunteers being able to provide adequate sputum samples.

PM exposure system for in vitro studies in Project 2: Due to technical difficulties with the exposure systems facilitating direct exposure of hNECs with woodsmoke, we are exploring alternative strategies to achieve this aim. These include utilizing in vitro particulate air pollution exposure systems currently being developed by EPA investigators. If this system is successful, then it will be possible to fully achieve Aim 2 of Project 2 of this program.

(3) Discussion of any absence or changes of key personnel involved in the inpidual projects or Center management.

There have been no changes in key personnel involved in any of the projects. Dr. Hernandez has taken on the role of Chief Medical Officer of the CEMALB, and in this role is co-directing the Medical, Physiology and Study Coordination Core with Dr. Noah, though he remains engaged in this role. This de facto co-directorship has developed coincident with Dr. Noah being appointed to Senior Vice Chair of the Department of Pediatrics. In December of 2015, Cherisa Williams resigned as Administrative Director of the CEMALB. Judy Smith has now joined the CEMALB as Administrative Director. She brings substantial experience from the UNC Office of Sponsored Research, and continues to work effectively with the Department of Pediatrics fiscal accounting group, with whom the CEMALB contracts for accounting services.

(4) Discussion of expenditures to date and an explanation of any costs which are significantly higher or lower than originally estimated.

A detailed financial report will accompany this annual report. Overall, actual expenditures are matching up appropriately with how these were budgeted. For the base projects, the total cost expenditures (direct and indirect) were anticipated to be $800,000, with actual expenditures listed as $806,589.32 (a 0.8% variance). Slight over-spending in general and specifically in personnel categories is due to fact that pre-award spending was allowed effective 2/1/15 and therefore initial year of funding covered a fourteen month period.

It should be noted that when the agreement was originally funded, the UNC OSR only established the account for the administrative core, which results in some accounts appearing underspent and others overspent. This is being addressed, and has not had a notable effect on overall fiscal management.

(5) Discussion of how the quality assurance requirements of the following are being met in accordance with 40 C.F.R. Part 30, Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations.

The quality assurance requirements of the CEMALB are being met in the following manner: The CEMALB is part of the University of North Carolina, School of Medicine. Consequently, the CEMALB administrative structure and policies are typical of academic institutions in that it gives its investigators substantial independence in carrying out their research activities. Support staff working on a project are usually under the supervision of the investigator who leads the project. Therefore, Quality Assurance Program (QAP) for CEMALB research has traditionally been a responsibility delegated to inpidual investigators. Investigator control and responsibility for quality assurance (QA) have been maintained as central features of the CEMALB QAP. The QA/QC officer for CEMALB is Dr. Neil Alexis (neil_alexis@med.unc.edu) and access to the QAP can be arranged through contacting his office.

The CEMALB QAP exists to provide guidelines to its staff and assist investigators in dealing with issues that affect the quality of the data produced by CEMALB research activities, particularly, data accuracy and validity. In this regard, the QAP is in itself the implementation of a QA policy by the CEMALB. The QAP serves to prevent, detect and correct any deviations in data integrity and quality. In addition, the QAP acts to facilitate compliance with outside granting agency requirements for research grant proposals or potential audits. The main areas covered by the CEMALB QAP and therefore meeting the requirements of 40 C.F.R. Part 30, Grants and Agreements with Institutions of higher Education, Hospitals, and Other Non-Profit include: Organization and management; Quality Systems; Project or Component Specific QA; Documentation and Records. In addition to the CEMALB QAP, CEMALB investigators and staff preparing projects supported by US EPA follow relevant Quality Assurance Documents prepared by the US EPA Quality Staff. The complete list of US EPA QA documents can be accessed at the following website: https://www.epa.gov/quality/qa. Below are the most applicable documents that are accessible to CEMALB investigators.

1. EPA Requirements for Quality Management Plans (QA/R-2), EPA/240/B-01/002, March 2001. Provides specifications for Quality Management Plans (QMPs) for organizations that receive funding from EPA. These specifications are equivalent to chapter 3 of EPA Manual 5360.

https://www.epa.gov/quality/qs-docs/r2-final.pdf

2. EPA Requirement for Quality Assurance Project Plans (QA/R-5), EPA/240/B-01/003, March 2001. Provides specifications for QA Project Plans prepared for activities conducted by or funded by EPA. These specifications are equivalent to chapter 5 of EPA Manual 5360.

https://www.epa.gov/quality/qs-docs/r5-final.pdf

3. Data Quality Assessment: A Reviewers Guide (QA/G-9R), EPA/240/B-06/002, February 2006. General guidance to organizations on assessing data quality criteria and performance specifications for decision making. G-9R is non-technical document and shows a reviewer what constitutes an appropriate Data Quality Assessment (DQA).

https://www.epa.gov/quality/qs-docs/g9r-final

4. Guidance for Quality Assurance Project Plans (QA/G-5), EPA/240/R-02/009, December 2002. Guidance on developing Quality Assurance Project Plans that meet EPA specifications.

https://www.epa.gov/quality/qs-docs/g5g-final.pdf

5. Guidance for Preparing Standard Operating Procedures (QA/G-6), EPA/240/B-07/001, April 2007. Guidance on the development and documentation of Standard Operating Procedures.

https://www.epa.gov/quality/qs-docs/g6-final.pdf

The G:\\Shared\CEMALB\QA\SOP directory also contains the following files that may help the investigators to develop the QA and SOP/ROP for specific projects:

QMP for the EPHD US EPA National Health and Environmental Effects Research Laboratory-Health pisions (NHEERL-H) Guidelines for Laboratory Record Keeping (NHEERL-H/QA-RK-95/00). QA_BALT.wpd is Quality Assurance Project Plan for 1998 Baltimore epi study, as an example of QMA. Furthermore, in addition to the CEMALB QAP the investigators and staff preparing a project sponsored by other granting agencies and funding entities follow QAPs issued by those institutions as appropriate. For example, each NIH Institute, FDA or HEI has its own QA guidelines with more specific guidelines for each research category or even specific studies. Documents listed below are used to develop a study-specific QAP.

The following NIH documents related to human research will be helpful in preparation, and conduct of a NIH sponsored studies, namely:

(a) Guidelines for the Conduct of Research Involving Human Subjects,

(b) Guidelines for Writing Research Protocols, and

(c) Assurance of Compliance with DHHS Regulations for the Protection of Human Subjects (45 CFR 46), published by the NIH Office of Human Subjects Research.

Progress Summary:

  1. Results (outputs/outcomes) to date, emphasizing findings and their significance to the field, their relationship to the general goals of the award, their relevance to the Agency’s mission, and their potential practical applications.

Project 1:

This report demonstrates that response to endotoxin for a given individual is reproducible across 2 or more challenges, that is high responders are always high responders and non-responders are always non-responders. This is consistent with the hypothesis that specific, stable biological factors account for risk of response to environmental pollutants, and pragmatically provides confidence that a single challenge with endotoxin can be considered reflective of that person’s response to endotoxin, allowing for comparison of this data point with that recovered after ozone and wood smoke challenge. This study also demonstrated that IL-8 and other cytokines in sputum correlated well with PMNs, making then excellent biomarkers to assess inflammation in the airway. This is of importance for investigators undertaking translational research for environmental or pulmonary research. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement:

Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Biological Mechanisms.

  1. Dieffenderfer J, Goodell H, Mills S, McKnight M, Yao S, Lin F, Beppler E, Bent B, Misra V, Zhu Y, Oralkan O, Strohmaier J, Muth J, Peden D, and Bozkurt A. Low Power Wearable Systems for Continuous Monitoring of Environment and Health for Chronic Respiratory Disease. In Press, available on line, Journal of Biomedical and Health Informatics, 2016

    This report outlined technical advances made in developing low power sensor arrays to assess environmental exposures and physiological response to such exposures. This is an important step in developing deployable prototypes for use in environmental research and ultimately in environmental health applications. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement:

Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Intervention Studies.

  1. Cascio WE, Gilmour MI, Peden DB. Ambient Air Pollution and Increases in Blood Pressure: Role for Biological Constituents of Particulate Matter. Hypertension. 2015 Jun 29. pii: HYPERTENSION AHA.115.05563. Invited Commentary

This editorial on a study demonstrating that biological factors in PM account for change in blood pressure has influenced the priorities of the CEMALB research undertaken under this assistance agreement, and provides insight into potential mechanisms by which biological components of PM exert this effect. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement:

Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Biological Mechanisms.

Publications:

  1. Pawlak, E, Noah, N, Zhou, H, Diaz-Sanchez, D, Chehrazi, C, Robinette, C, Müller, L, Jaspers, I. Diesel Exposure Suppresses Natural Killer Cell Function And Resolution Of Eosinophil Inflammation: A Randomized Controlled Trial Of Exposure In Allergic Rhinitics. Particle and Fibre Toxicol. 6;13(1):24.

In this study, demonstrated that exposure to Diesel Exhaust prolongs viral-induced eosinophil activation in allergic persons, which was accompanied by decreased markers of NK cell recruitment and activation. Separate in vitro studies showed that exposure to DE particles decreases the ability of NK cells to kill eosinophils. Taken together, these follow-up studies suggest that DE-induced exacerbation of allergic inflammation in the context of viral infections may be mediated by decreased activity of NK cells and their ability to clear eosinophils. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement:

Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Biological Mechanisms.

Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects:

 

  1. Mirowsky JE, Dailey LA, Devlin RB. 2016. Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells. Inhalation Toxicology. 28: 374-382.

 

This study examined differences in gene expression in epithelial cells, suggesting both common and unique mechanisms for response to these pollutants. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement: Susceptibility to Air Pollutants, and Biological Mechanisms.

  1. Zhou S, Pan G, Behrooz L, Vilcassim R, Mirowsky JE, Breysee P, Rule A, Huang JS, Weitzman M, Gordon T. 2016. Secondhand hookah smoke: an occupational hazard for hookah bar employees. Tobacco Control. 0:1-6.

This study examined the effect of hookah smoke to bar workers. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement: Susceptibility to Air Pollutants.

  1. Mirowsky JE, Peltier RE, Lippmann M, Thurston G, Neas L, Diaz-Sanchez D, Carter J, Laumbach R, Gordon T. 2015. Repeated measures of inflammation, blood pressure, and heart rate variability associated with traffic exposures in healthy adults. Environmental Health. 14:66-77.

The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement: Susceptibility to Air Pollutants.

  1. Mirowsky JE, Gordon T. 2015. Non-invasive effects measurements for air pollution human studies: methods, analysis, and implications.

    Journal of Exposure Science and Environmental Epidemiology. 25:354-380.

The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement: Susceptibility to Air Pollutants.

  1. McCullough SD, Bowers EC, On DM, Morgan DS, Dailey LA, Hines RN, Devlin RB, Diaz-Sanchez D. Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression. Toxicol Sci. 2016 Mar;150(1):216-24. doi: 10.1093/toxsci/kfv324. Epub 2015 Dec 29. PubMed PMID: 26719369; PubMed Central PMCID: PMC4838038.

This study examined differences in gene expression in airway cells, suggesting mechanisms for response to these pollutants. The results of this study are relevant for the following subject themes for the EPA mission noted in the funding announcement: Susceptibility to Air Pollutants, and Biological Mechanisms.

  1. Assurance that research misconduct has not occurred during the reporting period. EPA defines research misconduct as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results [65 FR 76262. I], or ordering, advising or suggesting that subordinates engage in research misconduct.

There has been no research misconduct during this reporting period. This is assured in part by adherence to editorial policy of journals to which papers are submitted. Additionally, according to University Policy, any UNC faculty or employee having reason to believe that someone has engaged in research misconduct related to University research has an obligation to report his/her concerns to his/her own department chair (or equivalent unit head) or directly to the Research Integrity Officer (who is, or is appointed by, the Vice Chancellor for Research). The Department Chair (or equivalent) shall immediately notify the RIO, who will inform the Deciding Official (Dean of the School of Medicine). If the circumstances described do not meet the definition of research misconduct, the RIO may refer the individual or allegation to other offices or officials with responsibility for resolving the issue.

Future Activities:

These have been covered extensively in the individual project reports, but overall, it is anticipated that recruitment into the clinical research protocols of Projects 1 and 3, and initiating the influenza vaccine studies in asthmatics for project 2 will continue into year 2. A great number of protocols have recently secured approval, so a significant amount of regulatory burden has been met. It is anticipated that the majority of the clinical projects will require 1 to 2 years to complete. Additionally, analyses of biorepository data will continue to augment productivity of each of the projects.


Journal Articles: 47 Displayed | Download in RIS Format

Other center views: All 80 publications 47 publications in selected types All 47 journal articles
Type Citation Sub Project Document Sources
Journal Article Bowers EC, McCullough SD. Linking the epigenome with exposure effects and susceptibility:The epigenetic seed and soil model. Toxicological Sciences 2016;155(2):302-14
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  • Journal Article Kobernick AK, Peden DB, Zhou H, Zhou Q, Dillon MA, Alexis NE. Reproducibility of the inflammatory response to inhaled endotoxin in healthy volunteers. Journal of Allergy and Clinical Immunology. 2016;138(4):1205-7
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  • Journal Article Martin WK, Tennant AH, Conolly RB, Prince K, Stevens JS, DeMarini DM, Martin BL, Thompson LC, Gilmour MI, Cascio WE, Hays MD. High-throughput video processing of heart rate responses in multiple wild-type embryonic Zebrafish per imaging field. Scientific reports 2019;9(1):1-4.
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  • Journal Article McCullough SD, Bowers EC, On DM, Morgan DS, Dailey LA, Hines RN, Devlin RB, Diaz-Sanchez D. Baseline chromatin modification levels may predict interindividual variability in ozone-induced gene expression. Toxicological Sciences. 2015;150(1):216-24
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  • Journal Article McCullough SD, On DM, Bowers EC. Using Chromatin Immunoprecipitation in Toxicology:A Step‐by‐Step Guide to Increasing Efficiency, Reducing Variability, and Expanding Applications. Current protocols in toxicology 2017;72(1):3-14 83578501 (2016)
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  • Journal Article Miller DB, Snow SJ, Henriquez A, Schladweiler MC, Ledbetter AD, Richards JE, Andrews DL, Kodavanti UP. Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats. Toxicology and applied pharmacology 2016;306:47-57
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  • Journal Article Mirowsky JE, Peltier RE, Lippmann M, Thurston G, Chen LC, Neas L, Diaz-Sanchez D, Laumbach R, Carter JD, Gordon T. Repeated measures of inflammation, blood pressure, and heart rate variability associated with traffic exposures in healthy adults. Environmental Health. 2015;14(1):66
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  • Journal Article Mirowsky JE, Devlin RB, Diaz-Sanchez D, Cascio W, Grabich SC, Haynes C, Blach C, Hauser ER, Shah S, Kraus W, Olden K. A novel approach for measuring residential socioeconomic factors associated with cardiovascular and metabolic health. Journal of Exposure Science and Environmental Epidemiology 2017;27(3):281
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  • Journal Article Walsh DM, McCullough SD, Yourstone S, Jones SW, Cairns BA, Jones CD, Jaspers I, Diaz-Sanchez D. Alterations in airway microbiota in patients with PaO2/FiO2 ratio≤ 300 after burn and inhalation injury. PloS one 2017;12(3):e0173848
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  • Journal Article Thurston GD, Balmes JR, Garcia E, Gilliland FD, Rice MB, Schikowski T, Van Winkle LS, Annesi-Maesano I, Burchard EG, Carlsten C, Harkema JR. Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society 2020;17(4):387-98.
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  • Journal Article Bass V. San Antonio Oleic acid induces acute pulmonary injury and inflammation in vivo. Society of Toxicology, 2017;10(1):34
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  • Journal Article Miller DB, Karoly ED, Jones JC, Ward WO, Vallanat BD, Andrews DL, Schladweiler MC, Snow SJ, Bass VL, Richards JE, Ghio AJ. Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats. Toxicology and applied pharmacology 2015;286(2):65-79.
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  • Journal Article Pawlak EA, Noah TL, Zhou H, Chehrazi C, Robinette C, Diaz-Sanchez D, Müller L, Jaspers I. Diesel exposure suppresses natural killer cell function and resolution of eosinophil inflammation:a randomized controlled trial of exposure in allergic rhinitics. Particle and fibre toxicology. 2015;13(1):24
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  • Journal Article Cascio WE, Gilmour MI, Peden DB. Ambient air pollution and increases in blood pressure:role for biological constituents of particulate matter. Hypertension. 2015;66(3):469-71.
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  • Journal Article Mirowsky J, Gordon T. Noninvasive effects measurements for air pollution human studies:methods, analysis, and implications. Journal of Exposure Science and Environmental Epidemiology. 2015;25(4):354
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  • Journal Article Rebuli ME, Speen AM, Clapp PW, Jaspers I. Novel applications for a noninvasive sampling method of the nasal mucosa. American Journal of Physiology-Lung Cellular and Molecular Physiology 2016;312(2):L288-96
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  • Journal Article Duran CG, Burbank AJ, Mills KH, Duckworth HR, Aleman MM, Kesic MJ, Peden DB, Pan Y, Zhou H, Hernandez ML. A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respiratory Research 2016;17(1):89.
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  • Journal Article Mirowsky JE, Dailey LA, Devlin RB. Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells. Inhalation toxicology. 2016;28(8):374-82
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  • Journal Article Snow SJ, Gordon CJ, Bass VL, Schladweiler MC, Ledbetter AD, Jarema KA, Phillips PM, Johnstone AF, Kodavanti UP. Age-related differences in pulmonary effects of acute and subchronic episodic ozone exposures in Brown Norway rats. Inhalation toxicology 2016;28(7):313-23.
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  • Journal Article Dieffenderfer J, Goodell H, Mills S, McKnight M, Yao S, Lin F, Beppler E, Bent B, Lee B, Misra V, Zhu Y. Low-power wearable systems for continuous monitoring of environment and health for chronic respiratory disease. IEEE journal of biomedical and health informatics. 2016;20(5):1251-64.
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  • Journal Article Henriquez A, House J, Miller DB, Snow SJ, Fisher A, Ren H, Schladweiler MC, Ledbetter AD, Wright F, Kodavanti UP. Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation. Toxicology and applied pharmacology 2017;329:249-58
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  • Journal Article Snow SJ, McGee MA, Henriquez A, Richards JE, Schladweiler MC, Ledbetter AD, Kodavanti UP. Respiratory effects and systemic stress response following acute acrolein inhalation in rats. Toxicological Sciences 2017;158(2):454-64
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  • Journal Article Miller CN, Dye JA, Ledbetter AD, Schladweiler MC, Richards JH, Snow SJ, Wood CE, Henriquez AR, Thompson LC, Farraj AK, Hazari MS. Uterine artery flow and offspring growth in long-evans rats following maternal exposure to ozone during implantation. Environmental health perspectives 2017;125(12):127005
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  • Journal Article Mirowsky JE, Carraway MS, Dhingra R, Tong H, Neas L, Diaz-Sanchez D, Cascio W, Case M, Crooks J, Hauser ER, Dowdy ZE. Ozone exposure is associated with acute changes in inflammation, fibrinolysis, and endothelial cell function in coronary artery disease patients. Environmental Health 2017;16(1):126
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  • Journal Article Zhou S, Behrooz L, Weitzman M, Pan G, Vilcassim R, Mirowsky JE, Breysee P, Rule A, Gordon T. Secondhand hookah smoke:an occupational hazard for hookah bar employees. Tobacco control. 2017;26(1):40-5
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  • Journal Article Burbank AJ, Peden DB. Assessing the impact of air pollution on childhood asthma morbidity:how, when, and what to do. Current opinion in allergy and clinical immunology2018;18(2):124-31
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  • Journal Article Henriquez AR, Snow SJ, Schladweiler MC, Miller CN, Dye JA, Ledbetter AD, Richards JE, Mauge-Lewis K, McGee MA, Kodavanti UP. Adrenergic and glucocorticoid receptor antagonists reduce ozone-induced lung injury and inflammation. Toxicology and applied pharmacology 2018;339:161-71
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  • Journal Article Snow SJ, Henriquez AR, Costa DL, Kodavanti UP. Neuroendocrine regulation of air pollution health effects:emerging insights. Toxicological Sciences 2018;164(1):9-20
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  • Journal Article Huang MC, Douillet C, Dover EN, Stýblo M. Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner. Archives of toxicology 2018;92(6):1925-37
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  • Journal Article Hazari MS, Stratford KM, Krantz QT, King C, Krug J, Farraj AK, Gilmour MI. Comparative cardiopulmonary effects of particulate matter-and ozone-enhanced smog atmospheres in mice. Environmental science & technology 2018;52(5):3071-80.
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  • Journal Article Stratford K, Haykal-Coates N, Thompson L, Krantz QT, King C, Krug J, Gilmour MI, Farraj A, Hazari M. Early-life persistent vitamin D deficiency alters cardiopulmonary responses to particulate matter-enhanced atmospheric smog in adult mice. Environmental science & technology 2018;52(5):3054-61.
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  • Journal Article Snow SJ, Cheng WY, Henriquez A, Hodge M, Bass V, Nelson GM, Carswell G, Richards JE, Schladweiler MC, Ledbetter AD, Chorley B. Ozone-induced vascular contractility and pulmonary injury are differentially impacted by diets enriched with coconut oil, fish oil, and olive oil. Toxicological Sciences 2018;163(1):57-69
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  • Journal Article Henriquez AR, Snow SJ, Schladweiler MC, Miller CN, Dye JA, Ledbetter AD, Richards JE, Hargrove MM, Williams WC, Kodavanti UP. Beta-2 adrenergic and glucocorticoid receptor agonists modulate ozone-induced pulmonary protein leakage and inflammation in healthy and adrenalectomized rats. Toxicological Sciences 2018;166(2):288-305.
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  • Journal Article Egorov AI, Converse R, Griffin SM, Styles J, Klein E, Sams E, Hudgens E, Wade TJ. Environmental risk factors for Toxoplasma gondii infections and the impact of latent infections on allostatic load in residents of Central North Carolina. BMC infectious diseases 2018;18(1):421.
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  • Journal Article Lyerly HK, Peden DB. Health and the Environment in North Carolina. North Carolina medical journal2018;79(5):302-5
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  • Journal Article Peden DB. The Unexpected Health Effects of Air Pollution. North Carolina medical journal2018;79(5):309-11
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  • Journal Article Brooks JL, Berry DC, Currin EG, Ledford A, Knafl GJ, Fredrickson BL, Beeber LS, HAPPI Community Partnership Committee, Peden DB, Corbie‐Smith GM. A community‐engaged approach to investigate cardiovascular‐associated inflammation among American Indian women:A research protocol. Research in nursing & health201942(3):165-75
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  • Journal Article Fecho K, Pfaff E, Xu H, Champion J, Cox S, Stillwell L, Peden DB, Bizon C, Krishnamurthy A, Tropsha A, Ahalt SC. A novel approach for exposing and sharing clinical data:the Translator Integrated Clinical and Environmental Exposures Service. Journal of the American Medical Informatics Association 2019;26(10):1064-1073
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  • Journal Article Bass VL, Snow S, Soukup J, Schladweiler M, Ghio A, Kodavanti U, Madden MC. 12-hydroxy oleic acid impairs endothelium-dependent vasorelaxation. Journal of Toxicology and Environmental Health, Part A 2019;82(5):383-6.
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  • Journal Article Cromar KR, Duncan BN, Bartonova A, Benedict K, Brauer M, Habre R, Hagler GS, Haynes JA, Khan S, Kilaru V, Liu Y. Air Pollution Monitoring for Health Research and Patient Care. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society 2019;16(10):1207-14.
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  • Journal Article Miller CN, Kodavanti UP, Stewart EJ, Schaldweiler M, Richards JH, Ledbetter AD, Jarrell LT, Snow SJ, Henriquez AR, Farraj AK, Dye JA. Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats. Reproductive Toxicology 2019;83:63-72.
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  • Journal Article Stevens EL, Rosser F, Forno E, Peden D, Celedón JC. Can the effects of outdoor air pollution on asthma be mitigated?. Journal of Allergy and Clinical Immunology 2019;143(6):2016.
    abstract available  
    83578501 (2019)
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  • Journal Article Corteselli EM, Gibbs-Flournoy E, Simmons SO, Bromberg P, Gold A, Samet JM. Long chain lipid hydroperoxides increase the glutathione redox potential through glutathione peroxidase 4. Biochimica et Biophysica Acta (BBA)-General Subjects 2019;1863(5):950-9.
    abstract available  
    83578501 (2019)
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  • Journal Article Zhang XA, Yates A, Vasilevsky N, Gourdine JP, Callahan TJ, Carmody LC, Danis D, Joachimiak MP, Ravanmehr V, Pfaff ER, Champion J. Semantic integration of clinical laboratory tests from electronic health records for deep phenotyping and biomarker discovery. NPJ digital medicine 2019;2(1):1-9.
    abstract available  
    83578501 (2019)
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  • Journal Article Hargrove MM, Kim YH, King C, Wood CE, Gilmour MI, Dye JA, Gavett SH. Smoldering and flaming biomass wood smoke inhibit respiratory responses in mice. Inhalation Toxicology 2019;31(6):236-47.
    abstract available  
    83578501 (2019)
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  • Journal Article Sood AK, Burbank AJ, Lawson M, Zhou H, Wells HB, Peden DB, Hernandez ML. Systemic inflammatory response to inhaled endotoxin does not correlate with airway response. Respiratory research 2019;20(1):1-4.
    abstract available  
    83578501 (2019)
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  • Journal Article Kim YH, King C, Krantz T, Hargrove MM, George IJ, McGee J, Copeland L, Hays MD, Landis MS, Higuchi M, Gavett SH. The role of fuel type and combustion phase on the toxicity of biomass smoke following inhalation exposure in mice. Archives of toxicology 2019;93(6):1501-13.
    abstract available  
    83578501 (2019)
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  • Progress and Final Reports:

    Original Abstract
  • 2016 Progress Report
  • 2017 Progress Report
  • 2018 Progress Report
  • 2019 Progress Report