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: 7724086
• 负责人: Karen A Brown
• 金额: $ 6.06万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7724086
• 关键词: Acute; Biological; Biological Markers; Carcinogens; Chemical Industry; Chemicals; Class; Computer Retrieval of Information on Scientific Projects Database; Conflict (Psychology); Coupled; DNA; DNA Adduction; DNA Adducts; Deoxyguanosine; Detection; Dose; Epidemiologic Studies; Ethylene; 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; Range; Rattus; Relative (related person); Research; Research Personnel; 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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 氧化乙烯是化学工业中广泛使用的中间体，也是由乙烯代谢氧化物内源形成的，乙烯是在正常物理过程中产生的。尽管氧化乙烷被归类为人类致癌，但流行病学研究提供了相互矛盾的证据，证明其诱导人类癌症的能力。因此，有必要评估与低剂量占据这种化学物质相关的风险。氧化乙烷与DNA，主要形成N7-（2-羟基乙基）-2�-羟基鸟苷加合物（7HEG）反应，可以用作暴露和潜在癌症风险的生物标志物。该项目的最终目标是识别内源性加合物形成的来源，并确定低剂量乙烷氧化物暴露于体内形成的7heg加合物的总体水平的相对贡献。这将通过施用[3H]标记的乙烯（不饱和脂肪酸和甲基氨酸）和[14C] - 氧化物的[3H]标记的生物学前体，并与加速器质谱分析相结合。 具体而言，该项目将首先建立通过口服[3H]标记的未饱和脂肪酸或甲硫氨酸在大鼠组织中形成的内源性7HEG加合物的来源和水平。急性施用[14C] - 乙烯氧化物在一系列剂量上，包括职业暴露水平在内的大鼠组织中形成的外源衍生的7heg加合物水平也将在平行研究中确定。为了确定内源性和外源性来源的添加剂的相对贡献，[3H]标记的脂肪酸或[3H] - 甲宁氨酸将与[14C] - 乙烯氧化物共同使用。对使用双异位素AM形成的DNA添加剂的分析将证明不同途径的添加剂形成是否是加性的，并且氧化乙烷是否能够影响内源性添加剂水平。 通过这项工作，我们将确定内源性7heg加合物形成的来源，并量化氧化乙烷水平对添加剂形成的影响，这将有助于评估对这种化学物质暴露的人类的风险。此外，开发的方法可用于研究能够产生DNA加合物的其他化学致癌物的研究。这将导致对DNA加合物形成的内源性和外源性途径的相对作用以及与工业化学物质接触相关的风险的相对作用。