Iron Oxide Nanoparticle-Induced Oxidative Stress and Inflammation

Project Information

Principal Investigator	Alison Elder
Institution	University of Rochester
Project URL	View
Relevance to Implications	High
Class of Nanomaterial	Engineered Nanomaterials
Impact Sector	Human Health
Broad Research Categories	Hazard Risk Assessment
NNI identifier

Funding Information

Country	USA
Anticipated Total Funding	$335,000.00
Annual Funding	$111,666.67
Funding Source	EPA
Funding Mechanism	Extramural
Funding Sector	Government
Start Year	2004
Anticipated End Year	2007

Abstract/Summary

Objective:

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.

Approach:

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.

Expected Results:

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.