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。暴露于天然铀与铀矿工中的肺和肾脏疾病有关，暴露于枯竭的铀与士兵中的肺癌无关。人类流行病学几乎完全关注铀的放射学毒性，而不是其化学毒性。此外，紫外线对铀的光活化是一种良好的实验室工具，尚未被视为皮肤中铀毒性的一种作用方式。该试验项目的总体目标是评估以下假设：如果UVB光将铀光激活以形成铀（V）和活性氧，则通过与单独的药物不同的动作方式，对UVB光和铀的共侵蚀可能是协同刺激性的。该假设将通过测量铀和UVB光的能力在人角质形成细胞的HPRT基因座上引起突变。铀在暴露细胞核中的定位还将通过电子显微镜与能量分散X射线光谱探测。该项目将提供可能挑战铀主要是放射线诱变的当前范式的数据。这项工作的结果可能提供了化学作用模式的证据，特别是，铀（VI）的光激活可能引起与仅铀或UVB光引起的突变。拟议的工作还可以提供数据，以扩大从肺和肾脏的铀毒性的重点，以将皮肤作为致癌作用的靶心器官，并可能推动生成新的假设，以供未来的流行病学研究。 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。我们将测量铀通过紫外光激活的能力，并将测量此过程中发生的DNA突变。数据可能支持铀参与皮肤癌的机制。