The effects of depleted uranium shrapnel on mitochondrial cellular function.

项目摘要 现代战斗的一个后果是通过使用含铀的武器暴露在贫铀中。 军需品。了解环境或职业暴露于贫铀的影响很重要。 为了保护人类健康。铀化学毒理学领域的研究结果喜忧参半， 增加了贫铀暴露的风险和行动机制的不确定性。这项研究 本文将讨论体内贫铀的化学毒性和紫外线辐射可能起到的作用。 在增强(或协同)铀的作用机制方面。正在解决的中心问题是 通过弹片或伤口污染内化的贫铀导致持久的细胞和遗传 损伤包括线粒体功能障碍和DNA损伤，这两种损伤都在癌症状态下观察到。 除了该项目包含的关键生物医学科学外，R15奖项的首要目标 是让学生参与拟议的研究活动的所有方面，以参与下一代STEM 调查人员。学生们将用斑马鱼(胚胎、幼虫和成鱼)进行实验，以测试 假设将贫化铀内在化，其数量与职业和环境相关， 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，协同增加遗传毒性。值得注意的是，暴露于 贫铀，特别是作为弹片的后果，可能会在他们的皮肤内或附近携带金属负担。 可能与阳光照射(包括紫外线-B)发生相互作用的地方。 我们的研究利用了一种不含色素的斑马鱼，这种斑马鱼可以纵向追踪铀植入物， 因为这种动物的皮肤像幼虫一样透明，像成虫一样半透明。我们独特的学习系统是易于处理的 对于学生来说，正如我们的初步数据所表明的那样，其中大部分数据是由学生产生的 国际和平研究所实验室小组的研究人员。此外，斑马鱼比啮齿动物模型更便宜，而且 相对容易维护，使纵向研究完全在我们的能力范围内。 这些研究的结果将提供支持或反对铀化学毒理学的证据 来自多种内化途径的急性或持续性暴露。我们坚称这是一种全面的方法 评估贫化铀对人类构成的风险，同时解决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.