The effects of depleted uranium shrapnel on mitochondrial cellular function.

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Project Abstract A consequence of modern combat is exposure to depleted uranium through the use of uranium-containing munitions. Understanding the effects of environmental or occupational exposure to depleted uranium is important for protecting human health. Research in the area of uranium chemical toxicology has yielded mixed results, raising uncertainty as to the risks of depleted uranium exposure and mechanisms of action. The research proposed here will address depleted uranium chemical toxicity in vivo and the role ultraviolet radiation may play in potentiating (or synergizing) uranium’s mechanisms of action. The central question being addressed is if depleted uranium internalized through shrapnel or wound contamination causes persistent cellular and genetic damage including mitochondrial dysfunction and DNA damage, both of which are observed in cancer states. In addition to the critical biomedical science encompassed by this project, an overarching goal of R15 awards is to involve students with all aspects of the proposed research activities to engage the next generation of STEM investigators. Students will carry out experiments using zebrafish (embryos, larvae and adults), to test the hypothesis that internalized depleted uranium, in amounts that are occupationally and environmentally-relevant, disrupts mitochondrial function and genomic stability. We will also test the hypothesis that ultraviolet B-ray (UV- B) radiation interact with DU leading to synergistically increased genotoxicity. Notably, humans exposed to depleted uranium, particularly as a consequence of shrapnel, may carry the metal burden in or near their skin where interaction with sun exposure (including UV-B) may occur. Our studies leverage a pigment-free strain of zebrafish that enables longitudinal tracking of uranium implants, as the animal’s skin is transparent as a larva and translucent as an adult. Our unique study system is tractable for students as demonstrated by our preliminary data in which the great majority of data was produced by student researchers in the PI’s laboratory group. Furthermore, the zebrafish is less costly than rodent models and relatively easy to maintain, making longitudinal studies well within our capabilities. Outcomes derived from these studies will provide evidence for or against uranium chemical toxicology from acute or persistent exposure from multiple routes of internalization. We assert this is a comprehensive approach to assess the risk depleted uranium poses to humans while addressing potential risk modifiers.