NORA Manufacturing Sector Strategic Goals
927ZGFZ - Cell-based Assessment for Iron Nanoparticle-induced Health RisksStart Date: 10/1/2008
End Date: 9/30/2009
Principal Investigator (PI)Name: Yong Qian
Funded By: NIOSH
Primary Goal Addressed9.0
Secondary Goal Addressed5.0
Attributed to Manufacturing
This project is to develop an in vitro screening model for assessing the potential vascular toxicity of nanoparticles and to provide a basis for recommendations and guidance on the safe handling of nanoparticles. Specifically, we will identify the molecular mechanisms by which iron nanoparticles induce endothelial cell permeability changes. We will also identify iron nanoparticle-induced production of reactive oxygen species (ROS) in endothelial cells and study the regulatory roles of ROS in iron nanoparticle-induced cell permeability changes. We hypothesize that the production of ROS plays an essential role in iron nanoparticle-induced endothelial cell barrier damage, which can lead to cardiovascular dysfunction. The research strategies applied within this proposal may provide a rapid inexpensive in vitro alternative to the use of animal models to resolve issues in Respiratory Disease and Nanotechnology affecting the Manufacturing Sector.
Nanotechnology is perceived as one of the critical research achievements of this century. Engineered nanoparticles are already being used in many industrial areas. Particularly, iron nanoparticles have being explored for the development of magnetic and electrical applications, catalytic applications, and biomedical applications. However, the unusual physicochemical properties of engineered nanoparticles may also pose adverse effects on biological systems. This proposed research project is to study the potential adverse effects of iron nanoparticles on endothelial cell monolayer at the molecular level to profile their toxicity. The vascular endothelial monolayer forms a semi-selective permeability barrier between blood and the interstitial space to control the movement of blood fluid, proteins, and macromolecules across the vessel wall. Aberrations of permeability barrier integrity play a major role in the pathogenesis of cardiovascular diseases, inflammation, acute lung injury syndromes, and carcinogenesis. Two specific aims are proposed to test the hypothesis that iron nanoparticles may compromise vascular endothelial monolayer integrity through ROS-related signaling pathways. A combination of physical, biochemical and biological approaches will be used. In specific aim 1, we will detect iron nanoparticle-induced actin filament remodeling and microtubule remodeling with confocal microscopic image analysis and Western blot measurements. Since the remodeling of both actin filaments and microtubule is one of essential molecular mechanisms regulating endothelial cell permeability, the identification of their involvements will be important to reveal the molecular mechanisms by which iron nanoparticles induce cell permeability change. In specific aim 2, we will detect iron nanoparticle-induced ROS production with electron spin resonance (ESR) measurements, confocal microscopic image analysis, and flow cytometry quantification. Furthermore, we will determine the regulatory roles of ROS production in iron nanoparticle-induced actin filament remodeling, microtubule remodeling, and cell permeability change using ROS scavengers and gene knockdown approaches. The research strategies applied within this proposal may provide a rapid inexpensive in vitro alternative to the use of animal models to study the cardiovascular health risks of occupational exposure to various nanoparticles. Results will also determine the role of ROS in these adverse health effects: thus, contributing to the development of a predictive algorithm relating physicochemical properties of nanoparticles to their potential bioactivity. The information obtained from this research can be used by NIOSH, OSHA, and EPA in developing protective strategies for nanoparticles in face of little in vivo test data. Workers impacted by this research will be those involved in the synthesis of iron nanoparticles and their use in manufacturing new products.
The new research project will develop an in vitro screening model for assessing the potential vascular toxicity of nanoparticles and to provide a basis for recommendations and guidance on the safe handling of nanoparticles. The information obtained from this research can be used by NIOSH, OSHA, and EPA in developing protective strategies for nanoparticles in face of little in vivo test data. Workers impacted by this research will be those involved in the synthesis of iron nanoparticles and their use in manufacturing new products. Success of the project will be determined by publications in reputable journals in the field, impact on the field as indicated by citations.
Numerous epidemiologic investigations have shown a direct relationship between human ambient particulate exposure and increases in cardiovascular morbidity and mortality. It has been suggested that the ultra fine components of ambient particulate exposure "are potentially the most dangerous" size fraction. However, to date little is known concerning potential adverse cardiovascular effects of engineered nanoparticle exposure in the workplace. Iron nanoparticles are of great interest due to their unique magnetic and catalytic properties. They are being explored for the development of magnetic and electrical applications as well as biomedical applications. Recently, iron nanoparticles have been widely used in coal industry to make clean fuels due to their catalytic activities that facilitate the chemical reactions to form and cleave carbon-carbon bonds. However, a significant knowledge gap currently exists on a complete toxicological profile of iron nanoparticles in contrast to their broad applications in industry.
In 2005, NIOSH formed a Nanotechnology Research Center (NTRC) to identify knowledge gaps/critical issues and develop a strategic plan of goals and objectives to develop information necessary to protect workers involved in the production and use of nanomaterials. Because of potential of metal oxide nanoparticles to be used in magnetic electrical and biomedical applications, the NTRC listed the evaluation of the bioactivity of metal oxide nanoparticles as an important research objective. The NTRC listed the development of rapid, inexpensive, in vitro, screening assays predictive of in vivo bioactivity and toxicity as a critical goal. It also notes the importance of improved mechanistic understanding of physiochemical properties of nanoparticles associated with bioactivity to inform risk assessment efforts.
Accumulating evidence showed that nanoparticle-induced injury is directly related to their high surface area and capability to induce ROS. Therefore, it is highly possible that the induction of ROS upon exposure to engineered nanoparticles plays an important role in generation of adverse biological effects. An objective of this proposed project is to determine whether iron nanoparticles cause ROS-induced damage to endothelial cells which normally form a barrier against the leakage of fluid from the microvasculature. Loss of this barrier function has been associated with the development of cardiovascular disease. Evaluation of whether nanoparticles pose risks of injuries and illnesses for workers in particular risks of cardiovascular disease is directly related to the mission of the NIOSH NTRC. The successes of this project will lead to the creation of an in vitro cell-based predictive model for nanoparticle risk assessments. Information and knowledge gained from this research will form the basis of recommendations and guidance on the safe handling of nanomaterials.
Research results will address the goals of the Manufacturing Sector (100%): Strategic Goal 5 "Reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector." Strategic Goal 9 "Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing.
This project also addresses a goal in Respiratory Disease Cross-Sector (100%): Strategic Goal 5 "Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials. Intermediate Goal 5.1 (09PPRDRIG5.1) "Determine the potential respiratory toxicities of nanomaterials". Activity/Output Goal 5.1.1 (09PPRDRAOG5.1.1) "Perform basic in vitro and in vivo toxicity studies".
Lastly the project addresses a goal in the Nanotechnology Cross Sector (100%): Strategic Goal 1 "Understand and prevent work-related injuries and illnesses possibly caused by nanoparticles/nanomaterials. Intermediate Goal 2 (09PPNANIG2) "Toxicity and internal dose".
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