Project 1 Cellular uptake, clearance, and effects of C60 and MWCNTs in epithelial

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Abstract The overall aim of Project 1 is to develop data, through the use of rat, mouse and human epithelial and endothelial cells isolated from the pulmonary, cardiovascular, and reproductive system, for use in Project 3 to construct and validate a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to extrapolate human health risks associated with exposure to nanomaterials. Human exposure to nanomaterials may occur through occupational exposure, environmental exposure, or intentional use as a delivery vehicle for therapeutic agents. To date, the majority of animal studies on the toxicity associated with nanomaterials have focused on male or non-pregnant rodents. As discussed in the overall theme of this proposal, we are utilizing the pregnant rodent to model potentially susceptible populations at greater risk for adverse health effects associated with nanomaterial exposure. In Specific Aim 1 of Project 1, we will generate, characterize, and radiolabel the two carbon-based nanomaterials in the graphene class¿ the fullerene C60 and forms of multiwalled carbon nanotube (MWCNT), that will be used in each project. Specifically, Project 1 will utilize unlabeled C60 and three forms of MWCNTs: end-capped MWCNTs, oxidation-damaged MWCNTs (MWCNT(COOH)n), and iron-containing oxidation-damaged MWCNTs (FemMWCNT(COOH)n). We will use the terms "forms of MWCNTs" to refer to these three forms of MWCNTs. Project 1 will also utilize the carbon-14 uniformly labeled analogs f C(U)]C60, rC(U)]MWCNTs, r''C(U)]MWCNT(COOH)n, and r^C(U)]FemMWCNT(COOH)n. To begin providing data on the cellular fate of these nanomaterials for use in establishing a PBPK/PD model in Project 3, we will utilize three cell types to represent potential target organs: lung (alveolar type 1 & 11 epithelial cells), the cardiovascular system (aortic endothelial cells), and the reproductive system (placental endothelial cells). In the first 2 years of Project 1, the distribution and effect ofthe nanoparticles will be evaluated in vitro using rat cells to complement the in vivo data obtained from Project 2. During Years 3-4, we will begin to validate the rat model by testing the in vitro effects of C60 and forms of MWCNTs on the same population of cells isolated from mice. Lastly, in Year 5 of Project 1, we will examine the effects of C60 and forms of MWCNTs on human epithelial and endothelial cells to extrapolate to human risk assessment. Project 1 co-Leaders will work closely with the Center Management Team and the National Institute of Environmental Health Sciences (NIEHS) Project Officer to determine any necessary changes in direction as data is developed. Project 1 co-Leaders will provide the in vitro results to Projects 2 and 3 co-Leaders as they become available to permit refinement of the scope of research in Projects 2 and 3. The effects of C60 and forms of MWCNTs at the cellular and sub-cellular level will be tested with the three Specific Aims outlined below.