Project Details for

ResearchTopic: Environmental & Occupational Exposures / Depleted Uranium & Other Heavy Metals
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Title: Inhalation of Uranium Oxide Aerosol: CNS Deposition, Neurotoxicity, and Role in Gulf War Illness
Synopsis: This animal study evaluated the potential for inhaled uranium oxide (from combustion of depleted uranium) to enter the brain through the nose and cause nervous system damage.
Overall Summary: See project objective.
Overall Project Objective: Investigate the potential for inhaled uranium oxide (UO) aerosols to penetrate the nose-brain barrier, directly enter the central nervous system (CNS), diffusely distribute within the CNS, and result in a slowly developing neurotoxic response.
Results to Date: Our main focus of 2006 has been analysis of tissue from the "Clean-Up Scenario". Full analysis of brain uranium confirms the finding from previous exposure scenarios that only a fraction (about 15%) of the rats exposed to the metal have detectable uranium in the brain. Metal uptake was only seen in brain regions within 2 synapses from the nasal cavity (olfactory glomeruli and mitral cells), and not in deeper brain structures such as the basal ganglia. As Gulf War Illness and the symptom profiles are not consistent across all individuals active in the war, a finding in a small percentage of exposed animals may still have relevance for understanding of at least a component of Gulf War Illness. Immunohistochemical evaluation of olfactory bulbs from the same exposure revealed an upregulation of tyrosine hydroxylase (a marker for dopaminergic neurons) and glial fibrillary acidic protein (a marker for astrogliosis) at 180 days after but not immediately after exposure. The reason for this delayed inflammatory response is still unclear but we are currently evaluating more markers for neuronal degeneration and inflammation to more clearly understand neurochemical changes in the brain after uranium exposure. Large motor neurons in cervical and lumbar spinal cord (neuronal populations that degenerate in ALS) were quantified 180 days post-exposure. Preliminary data do not suggest a loss of large motor neurons in our uranium-exposed rats. Kidney pathology did not appear to be associated consistently with either the re-exposures or the naove exposures in the "Clean-Up Scenario", but alveolar macrophage hyperplasia with inclusion of visible particles in the macrophages was a consistent finding in groups exposed to uranium. This hyperplasia and particle inclusion was apparent even at 180 days post exposure. Preliminary analysis of blood U from "Clean-Up Scenario" revealed elevated U levels up to 30 days post-exposure, with the most pronounced effect immediately post-exposure. Endotoxin instillation did not appear to influence blood U levels. Re-exposed rats exhibited similar increase in blood U as for single-exposed animals. Statistical analysis has yet to be completed but there is a trend for higher blood U contents in rats inhaling U both at the first and second exposure as compared to air the first and U the second exposure only. Progress this year has been significantly slowed down by severe illness and pregnancy in two key personnel, change of research technician and move of the laboratory twice in one year. Therefore we have requested a no-cost extension through May 27 2007- pending approval.
Project: DOD-129
Agency: Department Of Defense
Location: New Mexico, University Health Science Center (MI)
P.I. Name: Johnnye Lewis
Status: Complete
Study Start Date: September 15, 2001
Estimated Completion Date: October 15, 2006
Specific Aims: Test the hypotheses: I.) Inhalation of uranium aerosols from combustion of DU results in CNS deposition and subsequent neurodegeneration in a subset of those exposed; II.) Transient conditions such as inflammation compromise the olfactory epithelium and enhance the entry of uranium and the subsequent development of neurodegeneration; III.) Markers of neurodegeneration are correlated with the concentration and deposition of U within the CNS following inhalation exposure; and IV). The degree of and time-course of neurodegeneration are dose and exposure-duration dependent. These hypotheses will be tested for both short- and long-term exposure scenarios as differences related to exposure rate and dose may be critical to uptake, clearance, and ultimate neurotoxicity.
Methodology: Male and female rats were exposed via nose-only inhalation to uranium oxide aerosols of varying dose and duration to simulate different exposure scenarios: a) "Tank Impact scenario" (Year 1): 15 min exposure to 300-500 mg/m3 UO2; UO3; DUOx (depleted uranium oxide); UO2+ UO3 in a 1:1 mixture by weight; or TaO2 (a negative control) b) "Clean-up scenario" (Year 2): 6h exposure to 1 mg/m3 UO2 + UO3; c) "March-Through scenario" (Year 3-4): 30 days (6h/day, 5 days/week for 6 weeks) exposure to 1 mg/m3 UO2 + UO3. Separate groups were co-exposed to endotoxin to induce nasal inflammation. Clean, filtered air controls were included in all scenarios. In a final exposure, d) "Re-exposure scenario" (Year 3-4), rats were exposed for 30 days (6h/day, 5 days/week for 6 weeks) to 1 mg/m3 UO2 + UO3 + endotoxin 11 months after initial exposure to 1 day or 30 days exposure to 1 mg/m3 UO2 + UO3. Animals were sacrificed at intervals up to a year after exposure. Brains were analyzed for uranium content and markers of inflammation. Measures of oxidative stress and DNA damage are included, as is evaluation of markers of Amyotrophic Lateral Sclerosis (ALS). Blood, kidney and lung tissues were evaluated for cellular pathology and U content.
Publications:
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