RESEARCH PLAN A.
SPECIFIC AIMS. The intent of project 2 is to generate physiologically and pathobiologically relevant data via the exposure of a model organism, specifically the mouse, to nanomaterials containing silver, gold, or silicate. This basic information is fundamental to the development of risk analyses for these nanomaterials, as will be developed in Project 3. Additionally, it will provide raw materials and benchmarks of physiologic relevance for the materials science and in vitro mechanistic data generated in Project 1 and the Scientific Core. Variations in nanomaterial mass ratios and dose as well as host and environmental factors, specifically sex and gut microbial status, will be evaluated. The Scientific Aims and Functions will be achieved using polydisperse nanoAg and nanoAu with a mean diameter <100 nm obtained from commercial ('real world) sources and well characterized amorphous SiO{2} spheres from Project 1 (15, 80 and 100 nm mean diameter) mixed to give a simulated normal distribution with respect to particle number. A subset of mice will be administered the antibiotic cefoperazone (0.5 mg/ml) in drinking water for a portion of the experiment as it has been demonstrated to alter the number and composition of intestinal microbiota in humans [1, 2] and mice [3,4]. This experimental approach will be used to test the hypothesis that engineered nanomaterials alter the composition of enteric microflora and compromise the 'tone' of the epithelial barrier in the gut (collaboration between Projects 1&2). It is further hypothesized that antibiotic-induced alterations in microfloral composition and number will increase absorption of engineered nanomaterials and induce a pro-inflammatory state in the gut epithelium associated lymphoid tissues, liver and spleen. These hypotheses will be addressed by the following specific aims:
Specific aim 1 : Determine pharmacokinetic profiles as a function of dose and time for all three materials in a normal and a microbiotically altered (antibiotic treated) state (coordinated with Project 1) using well-characterized polydisperse preparations (Scientific Core) Specific aim 2: Determine tissue distributions as a function of dose and time for all three materials detailed in Aim 1 in a normal and a microbially altered state Specific aim 3: Determine the toxicologic pathology profile for all three materials in a normal and a microbiotically altered state Specific aim 4: Determine the immunologic profile for all three materials in the gut, blood and major lymphoid organs in the normal and microbiotically altered state
