PI: Joanne M. Jordan, M.D., MPH, Herman & Louise Smith Distinguished Professor of Medicine; Professor, Orthopaedics; Adjunct Professor, Epidemiology; Director, Thurston Arthritis Research Center; Chief, Division of Rheumatology, Allergy, & Immunology.
Project 2: Prenatal DDE Exposure, Child Obesity and Cardio-metabolic Markers.
Project 3: Understanding the Health Effects of Isoprene-Derived Particulate Matter.
Project 4: Photochemically Aged Atmospheric Engineered Nanoparticles and Respiratory Toxicity.
Project: Identifying genes that influence lead-induced OA.
Millions of people worldwide, are exposed to lead (Pb) at levels that are detrimental to human health. Such exposure is associated with various inflammatory diseases including osteoarthritis (OA). An understudied mechanism that may contribute to Pb-induced disease is cellular dysregulation associated with epigenetic alterations to DNA. Such epigenetic alterations can influence the regulatory mechanisms controlling gene expression. In this application, the team has come together to test a common hypothesis related to Pb exposure. Specifically, we hypothesize that epigenomic alterations, namely dysregulation of DNA methylation, contribute in a significant way to Pb-induced OA. The research will establish the links between Pb exposure, epigenetic alterations and OA. The proposed research crosses disciplines, is highly synergistic, and brings a novel area of metals research to the UNC-CEHS. The identified epigenetic marks may serve as biomarkers of both Pb exposure and disease. This research is directly in line with the mission of the CEHS.
Project: Prenatal DDE Exposure, Child Obesity and Cardio-metabolic Markers.
Animal models strongly suggest prenatal exposure to endocrine-disrupting chemicals (EDCs) may increase risk of obesity and related disorders by “re-programming” metabolism, but human data are limited and mixed. Recent studies point especially to the organochlorine compound DDE as a candidate obesogen. The proposed project will use a birth cohort in which fetal exposure to DDE was associated with rapid infant weight gain to address critical questions. We will conduct analyses to examine whether associations persist with overweight at age 5y, exploring complex issues such non-linear dose response, and whether associations may be attributable to chemical mixtures or postnatal exposure, rather than prenatal DDE exposure alone. We also aim to explore associations with early cardiometabolic markers, which have not been previously studied. This innovation will deepen understanding of whether EDCs may directly affect metabolism, vs. secondary to prolonged obesity. Results will inform critical design issues for an R01 application, by identifying: (i) cardiometabolic markers for study in a larger sample; (ii) candidate locus-specific epigenetic markers for study based on cardiometabolic markers affected; and (iii) approaches for studying effects involving exposure mixtures.
Project: Understanding the Health Effects of Isoprene-Derived Particulate Matter.
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.
Project: Photochemically Aged Atmospheric Engineered Nanoparticles and Respiratory Toxicity.
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.
|Funded by NIEHS Grant # P30 ES010126|