Cardiopulmonary disease pilot projects
- Chemical Mechanism of Ozone-Induced DNA Damage
- Mapping Global Surface Ozone Concentrations for Use in Global Burden of Disease Assessments
- Using CRISPR/Cas9 Technology to Establish the Role of NRF2 as a Driver of Isoprene SOA-Induced Genomic Stress Response
- Understanding the health effects of isoprene-derived particulate matter
- Photochemically aged atmospheric engineered nanoparticles and respiratory toxicity
- Ozone-induced responses in human volunteers: linking genomic profiles in airway cells with biological responses
- Free to Breathe, Free to Teach: indoor air quality in schools and respiratory health of teachers
- Analysis of bias due to model resolution in assessments of global premature human mortalities from exposure to outdoor air pollutants
- Changes in toenail concentration of trace elements in relation to cardiovascular disease risk factors
- Effects of diesel exhaust particles on influenza-induced nasal inflammation in allergic rhinitics
- Purines in exhaled breath condensate as biomarkers of inflammation
- Pilot feasibility study of farm endotoxin, asthma, and gene-environment interaction
- Environmental determinants of physical activity and obesity
- Oxidative stress in the obese/diabetic heart
- Determination of endogenous apurinic/apyrimidinic sites in genomic DNA and 8-oxo-7,8-dihydro-2′-deoxyguanosine in brain and nasal respiratory and olfactory tissues of healthy canines exposed to air pollutants
Ozone is a unique environmental challenge due to its relatively high toxicity and large exposed human population. Ozone is thought to be incapable of penetrating past epithelia cell membrane. However, recently sensors highly specific for ozone were reported to have detected ozone inside cells after ozone exposure. The overarching hypothesis of this proposal is that ozone-induced DNA damage may as well result from the direct reaction of ozone itself with DNA intracellularly. To test the hypothesis, direct ozonolysis of nucleoside in the basis of product identification and characterization is proposed to establish the product profile. Furthermore for comparison, the ozonolysis of DNA will then be analyzed for the products profile of ozone- induced DNA damage. Eventually extracted DNA from cultured cell or biological sample exposed with ozone will be analyzed. Once new adducts are validated, either increased by or unique to ozone exposure, they could be used as quantifiable biomarkers of ozone injury and toxicity.
Mapping Global Surface Ozone Concentrations for Use in Global Burden of Disease Assessments
Principal Investigator: J. Jason West, Associate Professor, Environmental Sciences & Engineering.
Ambient ozone air pollution is likely related to hundreds of thousands of premature deaths globally each year. Previous Global Burden of Disease (GBD) assessments for ambient ozone, however, have only used a single global atmospheric model, and no ozone observations, to estimates ambient concentrations. Here we will take advantage of an unprecedented global database of ozone observations currently being compiled for the Tropospheric Ozone Assessment Report, and multiple global model simulations from the HTAP-2, ACCMIP, and AerChemMIP multi-model inter-comparisons. We will perform a statistical fusion of global surface observations and global multi-model ensembles to estimate global surface ozone concentrations. Two methods of statistical data fusion will be used in succession based on their complexity, using observations to correct for model biases – a constant linear correction method, and the non-parametric Regionalized Air quality Model Performance (RAMP) approach. This pilot project will provide a global ozone dataset to the GBD team for their use in ongoing GBD assessments, and will provide a basis for us to apply for continued funding to pursue improved data fusion methods in the future.
Using CRISPR/Cas9 Technology to Establish the Role of NRF2 as a Driver of Isoprene SOA-Induced Genomic Stress Response
Principal Investigator: Rebecca Fry and Co-PIs: Jason D. Surratt and William Vizuete, Department Environmental Sciences & Engineering.
Our research team has shown that isoprene, the most abundantly emitted non-methane hydrocarbon, has the potential to induce toxic effects in human lung cells. This increased toxicity is a result of atmospheric oxidation of isoprene in the presence of acidic sulfate aerosol that leads to secondary organic aerosol (SOA). We have already shown SOA exposures have equal, or even higher oxidative stress potentials than diesel exhaust PM. Further, our team has also demonstrated that SOA exposures result in expression of oxidative stress and inflammation response-related genes in human lung cells. From this in vitro work we showed enrichment for altered expression of gene expression that is transcriptionally controlled by the Nuclear factor (erythroid-derived 2)-like 2 (NRF2). This pathway represents a target pathway influencing population susceptibility to SOA exposure. We propose a truly transdisciplinary study that integrates toxicogenomics, synthetic organic chemistry, and atmospheric analytical chemistry to test the novel hypothesis that NRF2 is a mediator of the genomic response to isoprene-derived SOA on key inflammatory-associated pathways in lung cells. Results from this study have relevance to population-based susceptibility to SOA.
Understanding the health effects of isoprene-derived particulate matter
Principal Investigator: Dr. Jason Douglas Surratt, Assistant Professor of Environmental Sciences and Engineering, GSGPH.
Fine particulate matter (PM2.5) is associated with damaging effects on the human respiratory and cardiovascular systems. Our recent work has clearly shown that anthropogenic pollutants significantly enhance isoprene (2-methyl-1,3-butadiene) oxidation as a source of PM2.5. Since isoprene has only recently been recognized as the single largest source of global PM2.5, its inhalation induced health effects are largely unknown. We propose to test the hypothesis that isoprene-derived PM induces toxicity and biological effects in lung cells. Our specific aims are to: (1) Examine toxicity and biological effects of PM2.5 derived from the photochemical oxidation of isoprene representative of urban and downwind-urban atmospheres (2) Examine toxicity and biological effects of PM derived directly from the downstream oxidation products (critical intermediates) of isoprene that are representative of urban and downwind-urban atmospheres. Results from in vitro assays will provide preliminary data for an extramural grant application and will serve as the basis for translating the findings into future clinical studies with collaborators at the EPA Human Studies Facility. CEHS facilities that will be used include the Biostatistics and Bioinformatics and Systems Biology Cores.
Photochemically aged atmospheric engineered nanoparticles and respiratory toxicity
Principal Investigator: Dr. William Vizuete, Assistant Professor of Environmental Sciences and Engineering, GSGPH.
The global market for nanomaterials is projected to reach $6.2 billion by 2015 with their prevalence in the environment increasing. It is likely that atmospheric oxidation will alter these materials. We have shown that oxidation of air toxics is associated with increased toxicity to lung cells. We hypothesize that when metal oxide engineered nanoparticles (ENP) undergo photochemical oxidation that an increase in particle toxicity will result. To test this we propose to leverage NSF-funded smog chamber experiments in which ENP undergo photochemical oxidation. We will assess for the first time the inflammatory responses of lung cells in these experiments using gene expression as biomarkers. We propose to use a novel in vitro exposure device to conduct direct exposures without re-suspension. The device exposes epithelial lung cells at an air-liquid interface, just as they would in a normal lung environment without agglomeration of ENP or loss of oxidation products. Results showing increased toxicity of ENP will provide data needed to pursue larger NIH-funded projects with an ultimate goal of identifying compounds produced in photochemical oxidation and their effects on living tissues.
Pilot study on mechanisms of soot inhalation injury to large airways in humans
Principal Investigator: Terry L. Noah, MD, Professor, Pediatric Pulmonology, and Samuel Jones, MD (Co-PI), Assistant Professor, Surgery; Department of Pediatrics and Center for Environmental Medicine, Asthma and Lung Biology, School of Medicine.
Acute lung injury (ALI) after burn/inhalational injuries is caused by environmental factors including smoke, thermal, or chemical injury. Few studies have investigated factors leading to ALI after these exposures. We propose to test the hypothesis that injury responses (inflammatory, antioxidant, antimicrobial) in large airways epithelium, induced by toxins in inhaled soot, contribute to progression to ALI. Our specific aims are to (1) characterize the chemical composition of inhaled soot particles taken directly from the airways of inhalation injury victims; (2) measure the impact of soot particles on cultured human airway epithelial injury response pathways in vitro; and (3) compare levels of injury response factors in bronchial washings between patients who do vs. do not progress to ALI. This project will expand the Pulmonary Disease/CEMALB FIRG to include investigators from the UNC School of Public Health and the NC Jaycee Burn Center, and will provide preliminary data for an extramural grant application aimed at discovering key pathophysiologic pathways and novel therapeutic targets in acute severe environmental toxin inhalation injuries. The project will utilize the CEHS Biostatistics and Bioinformatics, Integrative Health Sciences, and Career Development Cores.
Ozone-induced responses in human volunteers: linking genomic profiles in airway cells with biological responses
Principal Investigator: Ilona Jaspers, Ph.D; Associate Professor of Pediatrics and of Environmental Sciences and Engineering
Ozone (O3) continues to be of great public health importance, including in North Carolina, where O3 levels reach dangerous levels every year. O3-exposure results in pro-inflammatory responses in the lung, marked by influx of neutrophils, release of inflammatory mediators, and exacerbation of existing diseases, such as asthma. Analysis of gene expression profiles induced upon O3 exposure in the lung has never been done in humans. The goal of the studies proposed here is to identify biomarkers of exposure to O3 in airway cells collected from human volunteers. Specifically, we will use existing RNA samples and biological data available to us through ongoing studies in which human volunteers are exposed to O3 and airway cells are obtained before and after exposure. Using oligonucleotide arrays we will establish miRNA and mRNA signatures associated with O3 exposure and associate gene expression profiles with biological outcomes, such as neutrophil influx, for each individual. We anticipate uncovering miRNA and mRNA signatures that will yield novel insights into potential mechanisms of O3-induced adverse health effects and identify markers of susceptibility to O3-induced responses in humans.
Recent research suggests that teachers have the highest asthma prevalence of any occupational group in the United States. Asthma is also a leading cause of student absences from school. Due to the high number of occupants and scarce funds for maintenance, school buildings often suffer from poor indoor air quality (IAQ). In many schools, excessive moisture is a recurrent problem which increases exposure to asthma triggers such as mold, dust mites, roaches, and rodents. We will investigate the impact of relative humidity levels on asthma exacerbations among teachers at twelve public schools in North Carolina (NC). Though relative humidity can be cheaply measured and controlled, ours will be the first longitudinal study of humidity and asthma exacerbations in teachers. We will assess structural factors affecting indoor air quality (IAQ) in schools and monitor teachers’ respiratory health over time. Our study will provide locally relevant, scientific evidence of practical methods to reduce asthma triggers in schools. This research will be paired with training on sustainable IAQ practices to reduce the burden of environmental illnesses in schools through multi-agency collaboration.
Analysis of bias due to model resolution in assessments of global premature human mortalities from exposure to outdoor air pollutants
Principal Investigator: J. Jason West, Assistant Professor, Department of Environmental Sciences & Engineering, Gillings School of Global Public Health.
Analysis of the global-scale effects of air quality on human health is increasingly relevant, and the PI has led health impact assessments using global atmospheric chemical transport models. These analyses are limited by coarse grid resolution, and fail to capture the fine-scale distributions of concentration and population, particularly in urban regions. We will analyze the bias in assessments of air pollution-related mortality caused by the coarse resolution of global models, by comparing with a finer-scale regional model over the US. Stage 1 will analyze the total mortality due to exposure to ozone and fine particulate matter over the US, quantify the bias due to the coarse model resolution of the global model, analyze this bias geographically and by season, and quantify the bias in using national baseline mortality rates rather than county-level rates. Stage 2 will quantify these biases for the effect of a change in precursor emissions on ozone-related mortality, which may have a different spatial structure than the total mortality. These analyses will support future proposed applications, such as modeling future air pollution mortality in global energy-economic scenarios.
The importance of trace elements from both dietary and environmental sources in relation to human health has been increasingly recognized. Some trace elements have nutritional benefits and others can be toxic to human health. Growing evidence suggests that certain trace elements (Hg, Cd, As, Pb, Se, and Cr) may be associated with cardiovascular disease (CVD) risk factors including metabolic syndrome, markers of inflammation, hypertension, and sub-clinical atherosclerosis. However, the longitudinal associations of trace elements in early life with the evolution of CVD risk factors are largely unknown. The overall objective is to examine changes in selected trace element concentrations in toenails in relation to the development of CVD risk factors and sub-clinical atherosclerosis among young adults in the ongoing longitudinal study of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The purposes of this pilot study are: to demonstrate the feasibility of the second toenail collection in a randomly selected sub-cohort of CARDIA; to determine the distributions of changes in selected trace element among gender and ethnic groups; and to generate preliminary data for future grant application.
Effects of diesel exhaust particles on influenza-induced nasal inflammation in allergic rhinitics
Principal Investigator: Terry L. Noah, MD; Associate Professor and Division Chief, UNC Pediatric Pulmonology
Asthma is exacerbated commonly by viruses and pollutants, but little is currently known about the effects of interaction of these factors on allergic or asthmatic inflammation. Our preliminary data suggest that exposure of human respiratory epithelium to DEP causes increased infectivity for influenza virus and increased expression of inflammatory factors in vitro and in mice in vivo. We propose a clinical/translational study testing the hypothesis that allergic rhinitics (AR) have enhanced inflammatory responses to live attenuated influenza virus (LAIV) following diesel DEP exposures, through a randomized, prospective comparison study between cohorts of AR subjects receiving DEP/placebo, followed by LAIV. Primary outcomes will be production of IL-13 and ECP, two markers of allergic inflammation, at the mucosal surface. A large number of secondary outcomes will be assessed including inflammatory cells, other cytokines and mediators, expression profiles for Phase II network genes in biopsied nasal epithelium, and the effect of genotype for the antioxidant gene GTSM1. The relevance of this work to public health is the possibility of identifying novel antioxidant strategies for reducing the impact of inhaled oxidant pollutants on virus-induced asthma exacerbations. This project would generate preliminary data for an NIH application extending our initial findings and testing potential therapeutic interventions.
Purines in exhaled breath condensate as biomarkers of inflammation
Principal Investigator: Charles R. Esther Jr., MD, PhD, assistant professor, Division of Pediatric Pulmonology, Department of Pediatric
Inhaled environmental insults trigger an inflammatory response in the airway and are involved in the pathogenesis of lung disease such as asthma. Extracellular purines, which act as regulatory molecules in the airway, can serve as biomarkers of this inflammation. The goal of this proposal is to develop a non-invasive method to measure airway purines as a biomarker of inflammation. Exhaled breath condensate (EBC) collection provides the non-invasive means to obtain airway samples, but EBC contains very small amounts of airway fluid. We will therefore develop sensitive methods to identify and quantify purines in EBC using the mass spectrometers in the Biomarkers Facility Core. Methods will be validated by comparing the results from EBC to the more established (though more invasive) technique of bronchoalveolar lavage, and by measuring EBC purines from subjects with the inflammatory lung disease cystic fibrosis. Once methods have been optimized and validated, we will analyze samples collected from asthmatics exposed to ozone to demonstrate that measurement of purines in EBC can be used to investigate the physiological response to environmental insults.
Asthma is the most common chronic childhood disease. What causes asthma is still not clearly understood. The current paradigm is the “hygiene hypothesis,” which postulates that high exposure to microbial products found on farms, such as endotoxin, stimulates the young immune system to develop Th1 response pathways instead of Th2 pathways and thereby protects against the development of asthma. Recent discoveries indicate the protective mechanisms involve a gene-environment interaction between farm endotoxin exposure and toll receptors (microbial pattern recognition receptors). The RO1 has the goals to 1) evaluate the role of gene-environment interaction in the development of asthma, 2) examine cytokine response profiles (representing either a TH1 or TH2 polarization) associated with high levels of exposure to farm endotoxin. The purpose of the proposed pilot study is to demonstrate our ability to collect and analyze 1) buccal cells for haplotype analyses of toll 2 receptors, 2) nasal lavage samples for Th1 and TH2-like cytokine profiles, and 3) and home endotoxin samples. Understanding the protective immune response mechanisms in asthma is critical to the development of preventative strategies for childhood asthma.
Background. With minimal research, particularly longitudinal analysis, there is an increasing call for population-wide environmental/policy interventions to increase physical activity.
Specific Aims. We will link contemporaneous geographic locations of respondents with physical environment variables and data from the Coronary Artery Risk Development in Young Adults Study [CARDIA], a longitudinal study of 5,115 black and white young adults aged 18-30 years at baseline. The specific aim of the pilot is to develop and validate new physical environment measures from existing databases linked to respondents= geographic locations. Future aims include estimating the dynamic effects of patterns and changes in environment variables on activity.
Methods. We will geocode street addresses for respondents from the CARDIA dataset and build an extensive GIS database of activity-related environmental factors (e.g., park and recreation facilities, transport options, accessibility variables, crime, climate, and community design) using a range of federal, commercial, and public databases. We will develop complex longitudinal and spatial analytical models to explore relationships between environmental factors and activity, adjusting for self-selectivity of residential location choice. This will be the first longitudinal study of its kind.
An obesogenic environment exists in the US in which obesity and diabetes flourish. Obesity and subsequent diabetes leads to a concomitant increase in heart disease. Hearts from obese and diabetic rodents exhibit deranged fatty acid (FA) metabolism, with increased rates of mitochondrial and peroxisomal FA oxidation and accumulation of triacylglycerol (TAG). The presence of hydrogen peroxide, elevated catalase, and a diminished ratio of reduced gluatathione (GSH) to oxidized glutathione (GSSG) indicate the presence of oxidative stress. Hyperlipidemia is associated with increased tissue concentrations of lipid peroxides (TBARS); therefore, excess myocardial TAG may contribute to elevated levels of TBARS in the obese/diabetic heart. We hypothesize that altered FA metabolism in the obese/diabetic heart induces oxidative damage which results in the observed heart disease. Mice will be fed either a high fat, high sucrose diet to induce obesity/diabetes or a control diet. We will evaluate the following: a) extent of myocardial TAG accumulation, b) up-regulation of peroxisomal oxidation, c) oxidative state of the heart (GSH/GSSG ratio), d) extent of lipid peroxidation (TBARS/MDA; Nutrient Assessment Facility Core), e) extent of DNA damage (8-OH-dG and M1G; Biomarkers Facility Core), and f) up-regulation of base excision repair (BER) genes. Results from these studies will provide preliminary data for an RO1 proposal investigating obesity/diabetes-induced heart disease.
Determination of endogenous apurinic/apyrimidinic sites in genomic DNA and 8-oxo-7,8-dihydro-2′-deoxyguanosine in brain and nasal respiratory and olfactory tissues of healthy canines exposed to air pollutants
Principal Investigator: Lilian Calderón-Garcidueñas, MD, PhD
Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological DNA damage. The purpose of this study- using a highly sensitive slot blot assay- is to determine the number of endogenous apurinic/apyrimidinic (AP) sites in genomic DNA and to quantitate 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) by HPLC in olfactory and respiratory nasal mucosae, olfactory bulb, entorrhinal, frontal, medial temporal, hippocampal, parietal, and cerebellar tissues from 16 healthy well nourished mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings will be compared to those in 14 age-matched dogs from Tlaxcala, a less polluted control city. We hypothesize that AP sites and 8-oxodG will be increased in animals with a life exposure to air pollutants, particularly in the olfactory-limbic associated structures, and nasal tissues. We will also attempt to demonstrate an association between the DNA damage and the neuropathological findings, specifically the expression of NF-kB and iNOS. Persistent respiratory inflammation and deteriorating olfactory and respiratory barriers, the production of proinflammatory cytokines, the damage to the blood-brain barrier(BBB),and the microcirculation by the iNOS may play a role in the increased DNA damage to the involved structures and the neuropathology observed in the brains of these highly exposed canines. The innovation of this project is not only to study naturally exposed animals and use highly sensitive assays, but also to establish an association between the DNA damage endpoints and the neuropathological and immunohistochemistry findings representing critical information regarding neurodegenerative diseases. Neurodegenerative disorders such as Alzheimer’s may begin early in life with air pollutants playing a crucial role.