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SAFETY/TOXICITY ASSESSMENT OF CERIA (A MODEL ENGINEERED NP) TO THE BRAIN
Impact/Purpose:
The long-term objectives are to determine the physico-chemical properties of engineered nanomaterials (ENM) that influence their distribution into the cells comprising the blood-brain barrier and the brain and to characterize their beneficial and/or hazardous effects on the brain. The work will be conducted with cerium oxide (CeO2) as a model insoluble, stable metal oxide tracer. Initial studies will utilize systemic ENM administration in the rat for hazard identification to define the NOAEL and LOAEL and a dose-response assessment. The Specific Aims will test the following 4 null hypotheses. 1) That the size (~ 10, 30 and 100 nm diameter spherical CeO2 ENMs) and shape (~ 30 nm spherical, disk and rod) CeO2 ENMs do not influence their distribution into, or effects on, the rat brain. 2) That the surface properties (hydrophilicity/hydrophobicity, surface charge, and steric inhibition) do not influence ENM distribution into, or effects on, the rat brain. The functionalized CeO2 ENMs to be given to rats will be based on an extensive in vitro comparison of the physico-chemical properties of silanes and polymers bound to the surface of CeO2 ENMs. 3) That the surface properties of ENMs do not affect their protein opsonization and that the opsonizing protein nature does not influence ENM distribution into, or effects on, the rat brain. 4) That, over time, there are no changes in the physico-chemical properties of ENMs after they enter the brain and that there is unaltered biopersistence. Additionally, this work will 5) determine the rate and mechanism(s) of brain uptake of ENMs that have the greatest potential for toxicity to the BBB and the brain and the target cells of the BBB and brain for ENM-induced toxicity and 6) the mechanism(s) mediating the toxicity.
The long-term objectives are to determine the physico-chemical properties of engineered nanomaterials (ENM) that influence their distribution into the cells comprising the blood-brain barrier and the brain and to characterize their beneficial and/or hazardous effects on the brain. The work will be conducted with cerium oxide (CeO2) as a model insoluble, stable metal oxide tracer. Initial studies will utilize systemic ENM administration in the rat for hazard identification to define the NOAEL and LOAEL and a dose-response assessment. The Specific Aims will test the following 4 null hypotheses. 1) That the size (~ 10, 30 and 100 nm diameter spherical CeO2 ENMs) and shape (~ 30 nm spherical, disk and rod) CeO2 ENMs do not influence their distribution into, or effects on, the rat brain. 2) That the surface properties (hydrophilicity/hydrophobicity, surface charge, and steric inhibition) do not influence ENM distribution into, or effects on, the rat brain. The functionalized CeO2 ENMs to be given to rats will be based on an extensive in vitro comparison of the physico-chemical properties of silanes and polymers bound to the surface of CeO2 ENMs. 3) That the surface properties of ENMs do not affect their protein opsonization and that the opsonizing protein nature does not influence ENM distribution into, or effects on, the rat brain. 4) That, over time, there are no changes in the physico-chemical properties of ENMs after they enter the brain and that there is unaltered biopersistence. Additionally, this work will 5) determine the rate and mechanism(s) of brain uptake of ENMs that have the greatest potential for toxicity to the BBB and the brain and the target cells of the BBB and brain for ENM-induced toxicity and 6) the mechanism(s) mediating the toxicity.
Description:
The results will indicate the influence of the size, shape and various surface chemistry properties of ENMs on their entrance into BBB cells and the brain, compared to selected peripheral organs, the effects they produce in the brain, their biopersistence and biotransformation in the brain. The results should also define the rate of brain entry of those ENMs that most rapidly enter the brain and the cells most susceptible to adverse effects of ENMs. These studies address the following suggested research foci of the solicitation: systemic distribution of nanoscale materials, identification of critical physic-chemical parameters of nanomaterials that correlate with biological responses, biotransformation and bioaccumulation of nanomaterials, toxicological responses following nanoscale material exposure, and the determination of the influence of physico-chemical properties of nanoscale materials on biological compatibility or toxicity. The studies will be designed to maximize the application of the results to risk-assessment.