DETECTION OF ENDOG AND EXOGEN DERIVED ETHYLENE OXIDE DNA ADDUCTS BY 3H & 14C AM

3H 检测内源和外源衍生的环氧乙烷 DNA 加合物

• 批准号: 7977076
• 负责人: Karen A Brown
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977076
• 关键词: Acute; Biological; Biological Markers; Carcinogens; Chemical Industry; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Conflict (Psychology); Coupled; DNA; DNA Adduction; DNA Adducts; Deoxyguanosine; Dose; Epidemiologic Studies; Ethylene Oxide; Ethylenes; Exposure to; Fatty Acids; Funding; Goals; Grant; Human; Institution; Isotopes; Label; Lead; Malignant Neoplasms; Metabolic; Methionine; Methods; Occupational; Occupational Exposure; Oral Administration; Pathway interactions; Physiological Processes; Rattus; Relative (related person); Research; Research Personnel; Resource Development; Resources; Risk; Role; Route; Source; Tissues; United States National Institutes of Health; Unsaturated Fatty Acids; Work; accelerator mass spectrometry; adduct; cancer risk; chemical carcinogen; in vivo; oxidation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ethylene oxide is a widely used intermediate in the chemical industry and is also formed endogenously from the metabolic oxidation of ethylene, which is generated during normal physiological processes. Although ethylene oxide is classed as a human carcinogen, epidemiological studies provide conflicting evidence regarding its ability to induce human cancers. Consequently, there is a need to assess the risks associated with low dose occupational exposures to this chemical. Ethylene oxide reacts with DNA, primarily forming N7-(2-hydroxyethyl)-2¿-deoxyguanosine adducts (7HEG), which can be used as a biomarker of exposure and potential cancer risk. The ultimate goal of this project is to identify sources of endogenous adduct formation and determine the relative contribution of low dose ethylene oxide exposures to the overall level of 7HEG adducts formed in vivo. This will be achieved through the administration of [3H]-labeled biological precursors of ethylene (unsaturated fatty acids and methionine) and [14C]-ethylene oxide, coupled with accelerator mass spectrometry analysis. Specifically, this project will involve first establishing the sources and level of endogenous 7HEG adducts formed in rat tissues through oral administration of [3H]-labeled unsaturated fatty acids or methionine. The level of exogenously derived 7HEG adducts formed in rat tissues following acute administration of [14C]-ethylene oxide over a range of doses, including occupational exposure levels will also be determined in parallel studies. In order to determine the relative contribution of adducts from endogenous and exogenous sources, a [3H]-labeled fatty acid or [3H]-methionine will be co-administered with [14C]-ethylene oxide. Analysis of the DNA adducts formed using dual-isotope AMS will demonstrate whether adduct formation by different routes is additive and whether ethylene oxide is able to influence endogenous adduct levels. Through this work we will identify sources of endogenous 7HEG adduct formation and quantify the effect of occupational levels of ethylene oxide on adduct formation, which will aid in assessing the risk to humans exposed to this chemical. Furthermore, the methods developed could be applied to the study of other chemical carcinogens capable of generating DNA adducts also formed endogenously. This will lead to a better appreciation of the relative roles of endogenous and exogenous pathways of DNA adduct formation and the risks associated with exposure to industrial chemicals.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 环氧乙烷是一种广泛应用于化学工业的中间体，也是在正常生理过程中产生的乙烯代谢氧化的内源产物。尽管环氧乙烷被归类为人类致癌物质，但流行病学研究对其诱发人类癌症的能力提供了相互矛盾的证据。因此，有必要评估与低剂量职业接触这种化学品有关的风险。环氧乙烷与DNA反应，主要生成N7-(2-羟乙基)-2-脱氧鸟苷加合物(7HEG)，可作为接触和潜在癌症风险的生物标志物。该项目的最终目标是确定内源性加合物的形成来源，并确定低剂量环氧乙烷暴露对体内形成的7HEG加合物总体水平的相对贡献。这将通过给予[~3H]标记的乙烯(不饱和脂肪酸和蛋氨酸)和[14C]-环氧乙烷的生物前体，结合加速器质谱分析来实现。 具体地说，该项目将首先通过口服[~3H]标记的不饱和脂肪酸或蛋氨酸，确定在大鼠组织中形成的内源性7HEG加合物的来源和水平。在包括职业暴露水平在内的一系列剂量范围内急性给予[14C]-环氧乙烷后，大鼠组织中形成的外源性7HEG加合物水平也将在平行研究中确定。为了确定内源和外源加合物的相对贡献，将[~3H]标记的脂肪酸或[~3H]-蛋氨酸与[~(14)C]-环氧乙烷共同给药。使用双同位素AMS分析形成的DNA加合物将证明不同途径形成的加合物是否具有相加性，以及环氧乙烷是否能够影响内源加合物水平。 通过这项工作，我们将确定内源性7HEG加合物的形成来源，并量化职业水平的环氧乙烷对加合物形成的影响，这将有助于评估人类接触这种化学物质的风险。此外，所开发的方法也可以应用于其他化学致癌物的研究，这些致癌物能够产生也是内源性形成的DNA加合物。这将使人们更好地了解DNA加合物形成的内源和外源途径的相对作用，以及与接触工业化学品有关的风险。