The effects of depleted uranium shrapnel on mitochondrial cellular function.

工程摘要 现代战争的一个后果是，通过使用含铀弹药， 军火了解环境或职业接触贫铀的影响很重要 保护人类健康。铀化学毒理学领域的研究结果好坏参半， 这增加了贫铀接触风险和作用机制的不确定性。研究 这里提出的建议将讨论贫铀在体内的化学毒性和紫外线辐射可能发挥的作用 增强（或协同）铀的作用机制。核心问题是， 通过弹片或伤口污染内化的贫铀， 损伤包括线粒体功能障碍和DNA损伤，这两者都在癌症状态中观察到。 除了该项目所涵盖的关键生物医学科学外，R15奖项的总体目标 是让学生参与拟议研究活动的各个方面，以吸引下一代STEM investigators.学生们将使用斑马鱼（胚胎，幼虫和成虫）进行实验，以测试 假设内部贫化铀的数量与职业和环境有关， 破坏线粒体功能和基因组稳定性。我们还将测试紫外线B射线（UV- B）辐射与DU相互作用，导致协同增加遗传毒性。值得注意的是， 贫铀弹，特别是弹片造成的贫铀弹，可能将金属负荷带入或靠近其皮肤 其中可能发生与阳光照射（包括UV-B）的相互作用。 我们的研究利用了一种无色素的斑马鱼，可以纵向跟踪铀植入物， 因为这种动物的皮肤在幼虫时是透明的，在成虫时是半透明的。我们独特的学习系统是易于处理的 正如我们的初步数据所证明的那样，大部分数据是由学生产生的。 PI实验室的研究人员。此外，斑马鱼的成本低于啮齿动物模型， 相对容易维护，使纵向研究在我们的能力范围内。 从这些研究中得出的结果将提供支持或反对铀化学毒理学的证据， 急性或持续暴露于多种内化途径。我们认为这是一个全面的办法 评估贫铀对人类构成的风险，同时处理潜在的风险修正因素。

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.