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ResearchTopic: Environmental & Occupational Exposures
/ Depleted Uranium & Other Heavy Metals
Completed Research Projects
Title: Preconceptional Paternal Exposure to Embedded Depleted Uranium Fragments: Transmission of Genetic Damage to Offspring
Synopsis: This animal study investigated if male mice with embedded fragments of depleted uranium transmitted genetic damage to their offspring.
Overall Summary: The Persian Gulf War resulted in a number of friendly fire casualties among U.S. personnel injured by fragments of depleted uranium (DU) munitions. The demonstrated effectiveness of such weapons makes it likely that they may be used against U.S. forces in future conflicts. Uncertainty about how aggressively to remove fragments of the radioactive, chemically toxic DU has stimulated research into the long-term health consequences of embedded DU fragments. There has been no previous research to determine whether long-term exposure to embedded DU can affect the health of offspring of personnel wounded by DU.
Overall Project Objective: This study investigates whether male mice carrying embedded fragments of DU transmit genetic damage to their offspring. Other studies have demonstrated that paternal preconceptional exposure to radiation or metal can induce cancer in unexposed offspring. The transgenic mouse model proposed for this study allows us to estimate overall mutation frequency in tissues from progeny of exposed males by following mutations in lacI gene. We hypothesize that long-term chronic exposure to embedded DU results in paternal transmission of genetic damage to unexposed F1 generation offspring, characterized by increased frequency of in vivo mutations in tissues. Transgenerational transmission of genetic damage may occur because of an induction of germ-line genomic instability and/or direct sperm mutations.
Results to Date: Complete.
Project: DOD-158
Agency: Department Of Defense
Location: Armed Forces Radiobiology Research Institute (AFRRI)
P.I. Name: A C Miller
Status: Complete
Study Start Date: March 01, 2002
Estimated Completion Date: January 31, 2006
Specific Aims: (1) Determine whether chronic preconceptional paternal exposure to DU results in transmission of genetic damage to F1 progeny. (2) Measure the mutagenic frequency in reproductive organs of implanted male mice chronically exposed to DU and correlate with tissue uranium content. (3) Assess direct damage to paternal spermatozoa DNA.
Methodology: Male mice will be implanted with DU pellets and mated to unimplanted female mice 1, 4, or 7 months after implantation surgery. We will use an in vivo mutation assay to examine tissue mutation frequency in both chronically exposed male mice and their Fl generation offspring. This mutation system employs a [lambda]lacI shuttle vector carried by cells of the ?Big Blue? transgenic mouse (strain C57BL/6, a hemizygous mouse containing 40 copies/cell of a [lambda]lacI shuttle vector). To assess mutagenesis, DNA ([lambda]lacI shuttle vector) will be recovered from specific organs. The packaged [lambda]lacI shuttle vector will then be assayed in vitro for mutations. Responses in F1 generation mice will be compared to progeny from mice implanted with the inert metal tantalum (negative control), mice implanted with a heavy metal tungsten alloy (a proposed DU surrogate), and mice receiving whole-body, low-dose neutron (high LET) radiation (DU radiation control). At selected times after implantation, we will assess in vivo mutagenesis in several uranium target organs, including kidney, bone marrow, and muscle, in both implanted male parents and their F1 offspring. We will correlate all results with tissue metal content. We will also determine DNA damage in the spermatozoa of metal-implanted mice using the single-cell gel electrophoresis comet assay. All mice will be characterized histologically.
Publications:
No Publications at this time...
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