CELLULAR GENOTOXICITY OF PHOTOACTIVATED URANIUM

光活化铀的细胞遗传毒性

• 批准号: 8036952
• 负责人: Diane M Stearns
• 金额: $ 44.7万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036952
• 关键词: CELLULAR; GENOTOXICITY; PHOTOACTIVATED; URANIUM

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.

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病和肾病有关，而接触贫铀与士兵患肺癌的关系微弱。人类流行病学几乎完全关注铀的放射毒性而不是化学毒性。此外，紫外线对铀的光活化是一种常用的实验室工具，但尚未被认为是铀对皮肤毒性的作用方式。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，那么同时暴露于 UVB 光和铀可能会通过与单独使用任一试剂不同的作用模式产生协同诱变。这一假设将通过测量铀和 UVB 光引起人类角质形成细胞 HaCat 细胞 hprt 基因座突变的能力来检验。还将通过电子显微镜结合能量色散 X 射线光谱来探测暴露细胞核中铀的定位。该项目将提供的数据可能会挑战当前铀主要是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，以扩大肺和肾铀毒性的焦点，将皮肤作为致癌的靶器官，并可能推动未来流行病学研究新假设的产生。 公共健康相关性：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，并将测量该过程中发生的 DNA 突变。数据可能支持铀与皮肤癌有关的机制。