Iron Oxide Nanoparticle-Induced Oxidative Stress and InflammationEPA Grant Number: R831722
Title: Iron Oxide Nanoparticle-Induced Oxidative Stress and Inflammation
Investigators: Elder, Alison C.P. , Yang, Hong
Current Investigators: Elder, Alison C.P. , Finkelstein, Jack , Oberdörster, Günter , Yang, Hong
Institution: University of Rochester
EPA Project Officer: Carleton, James N
Project Period: September 1, 2004 through February 28, 2008
Project Amount: $335,000
RFA: Exploratory Research to Anticipate Future Environmental Issues: Impacts of Manufactured Nanomaterials on Human Health and the Environment (2003) RFA Text | Recipients Lists
Research Category: Exploratory Research - Nanotechnology , Health , Safer Chemicals , Nanotechnology , Health Effects
The manufacture of nanoparticles (<100 nm diameter) of varying shapes and compositions has exploded over the last several years with applications ranging from diagnostic imaging to nanoscale molecular construction. Given the vast potential use of these materials, both intentional and unintentional human exposures are likely. Although much has recently been learned about their synthesis, very little is known about cellular or organ responses upon contact with nanoparticles. A defining feature of nanoparticles is their large specific surface area; thus, it is possible that current concepts of dose expressed as mass concentration, which is very low for nanoparticles, may fail in predicting exposure outcomes if this feature is not taken into account. We hypothesize that the small size of nanoparticles contributes to their evasion of normal particle clearance mechanisms, increases the likelihood of contact with cells of many types, particularly epithelial cells, and allows their translocation to sites distant from the original exposure. We hypothesize further that this contact results in inflammation and oxidant stress and that the large surface area of the nanoparticles potentiates their effects. We will address these hypotheses with the following objectives to determine if nanoparticles: 1) induce oxidative stress and toxicity in cultured epithelial and endothelial cells; 2) cause lung inflammation or extrapulmonary effects after in vivo exposure; and 3) are translocated to extrapulmonary sites.
This project, through the Principle and Co-Investigators, will be conducted in a multidisciplinary manner, combining expertise in the fields of toxicology and materials science. We will primarily use nanoparticles composed of iron oxide (Fe2O3, 3-25 nm), but for specific experiments, bulk composition and surface coatings will be varied. Nanoparticles may gain access to tissues in humans through inhalation or via the blood (i.e. oral, intravenous, or inhalation exposure). Thus, for in vitro studies, we will use human alveolar epithelial and umbilical vein endothelial cells and monitor their uptake of nanoparticles as well as inflammation- and oxidative stress-related responses using a range of doses. For in vivo studies, we will use F-344 rats for intratracheal instillation and intravenous injection exposures. Endpoints related to lung inflammation, inflammatory cell activation, and oxidative stress as well as those indicating vascular endothelial injury and acute phase responses will be assessed. Comparisons will be made with ultrafine (20 nm) TiO2 particles. Tissues from exposed rats (lung, liver, and olfactory bulb) will also be examined for the presence of the particles following intratracheal and intranasal instillations and intravenous injection exposures.
This project will provide dose-, size- and composition-related toxicological information about nanoparticles and will also explore their translocation to extrapulmonary tissues. The insight gained regarding mechanisms of response to nanoparticles and their disposition after exposure can be used to predict outcomes of human exposures in environmental, occupational, and therapeutic settings.