CELLULAR GENOTOXICITY OF PHOTOACTIVATED URANIUM

描述（由申请人提供）：铀是一种重要的新兴毒物。接触天然铀与铀矿工人的肺部和肾脏疾病有关，接触贫化铀与士兵的肺癌关系不大。人类流行病学几乎只关注铀的放射性毒性，而不是其化学毒性。此外，紫外线对铀的光活化是一种常用的实验室工具，尚未被视为皮肤中铀毒性的作用模式。该试点项目的总体目标是评估以下假设：如果铀被UVB光活化形成铀（V）和活性氧，那么共同暴露于UVB光和铀可能是协同致突变的，通过一种不同于单独使用任何一种试剂的作用模式。将通过测量铀和UVB光在人角质形成细胞HaCat细胞的hprt基因座处引起突变的能力来测试该假设。铀在暴露细胞核中的定位也将通过电子显微镜结合能量色散X射线光谱学来探测。该项目将提供数据，可能挑战目前铀主要是一种放射性诱变剂的范式。这项工作的结果可能为化学作用模式提供证据，特别是铀（VI）的光活化可以引起与单独由铀或UVB光引起的突变不同的突变。拟议的工作还可能提供数据，将铀毒性的重点从肺和肾扩大到包括皮肤作为致癌作用的靶器官，并可能为未来的流行病学研究产生新的假设。 公共卫生相关性： 这项工作的目的是确定重金属铀如何损害DNA。我们将测量铀被紫外线激活的能力，并测量在此过程中发生的DNA突变。数据可能支持铀参与皮肤癌的机制。

DESCRIPTION (provided by applicant): Uranium is an important emerging toxicant. Exposure to natural uranium has been linked to lung and kidney diseases in uranium miners, and exposure to depleted uranium has been weakly linked to lung cancer in soldiers. Human epidemiology has focused almost exclusively on uranium's radiological toxicity rather than its chemical toxicity. Furthermore, the photoactivation of uranium by UV light is a well-used laboratory tool that has not been considered as a mode of action for uranium toxicity in the skin. The overall goal of this pilot project is to evaluate the following hypothesis: If uranium is photoactivated by UVB light to form uranium(V) and reactive oxygen, then co-exposure to UVB light and uranium may be synergistically mutagenic, through a mode of action that is different than either agent alone. This hypothesis will be tested by measuring the ability of uranium and UVB light to cause mutations at the hprt locus of human keratinocyte HaCat cells. The localization of uranium in the nuclei of exposed cells will also be probed by electron microscopy combined with Energy Dispersive X-ray Spectroscopy. This project will provide data that may challenge the current paradigm that uranium is predominantly a radiological mutagen. Results from this work may provide evidence for chemical modes of action, specifically, that the photoactivation of uranium(VI) can cause mutations that are different than those caused by either uranium or UVB light alone. The proposed work may also provide data to expand the focus of uranium toxicity from lung and kidney to include skin as a target organ for carcinogenesis, and may drive the generation of new hypotheses for future epidemiological studies. PUBLIC HEALTH RELEVANCE: The purpose of this work is to determine how the heavy metal uranium damages DNA. We will measure the ability of uranium to be activated by UV light, and will measure the DNA mutations that occur from this process. Data may support a mechanism for uranium to be involved in skin cancer.