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ADDUCTS AS QUANTITATIVE MARKERS OF BUTADIENE MUTAGENESIS

加合物作为丁二烯诱变的定量标记

基本信息

批准号：
7900708
负责人：
JAMES A SWENBERG
金额：
$ 33.78万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-03 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900708
关键词：
1,3-Butadiene 8-(2,3,4-trihydroxybutyl)guanine Accounting Address Adenine Animals Biological Assay Biological Markers Blood specimen Butadiene Butane Butanes Butylene Glycols Carcinogens Characteristics Chronic Cloning Complementary DNA Coupling DNA DNA Adduction DNA Adducts DNA Damage DNA Repair DNA Repair Disorder DNA Repair Pathway Data Deamination Dependence Dependency Dose Drug Metabolic Detoxication Environmental Exposure Epoxy Compounds Exposure to Female Frequencies Future Gene Expression Gene Mutation Genes Genetic Genomics Glutathione Glycols Goals Grant Guanine Hemoglobin Human In Vitro Inbred F344 Rats Induced Mutation Inosine Ketones Knowledge Lead Lesion Link Measures Metabolic Metabolic Pathway Metabolism Methods Molecular Molecular Epidemiology Molecular Profiling Mus Mutagenesis Mutation Mutation Spectra N-terminal Nature Nucleotide Excision Repair Pathway interactions Procedures Proto-Oncogenes RAS genes Rattus Relative (related person)Reporter Genes Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Rodent Role Sampling Source T-Lymphocyte Testing Time Tissues Toxic effect Valine Wild Type Mouse Xenobiotics adduct base carcinogenesis carcinogenicity crosslink design epidemiology study erythritol anhydride improved in vivo interest mutant programs repaired research study response sex tumor urinary

项目摘要

DESCRIPTION (provided by applicant): 1,3-butadiene (BD) is a known carcinogen. However, the DNA adducts responsible for mutations remain unknown. The overall goals of the proposed research are to examine the molecular dose of previously unexplored DNA adducts in rodents exposed to BD and 3-butene-1, 2-diol (BD-diol), comparing the data with mutation frequencies and mutational spectra to determine if a particular adduct could be used as a quantitative indicator of mutagenesis, and to evaluate effects of exposure on gene expression. The first hypothesis to be tested is that hydroxymethylvinyl ketone (HMVK) is formed in vivo during exposure to BD and BD-diol in a sex, species, and exposure concentration dependent manner resulting in important differences in mutagenicity. The second hypothesis is that promutagenic N1 adenine adducts convert to the more stable inosine adducts which are poorly repaired and accumulate during chronic exposure to BD. Several specific aims will be accomplished while addressing these hypotheses. Specific Aim 1 is to examine the formation of potentially mutagenic DNA adducts (specifically 1, N2-propanodeoxyguanosine) by HMVK in vivo. The second aim is to determine the utility of the N-terminal valine adduct of HMVK (HMVK-Val) as a biomarker of HMVK formation by BD and BD-diol. Specific Aim 3 is to develop methods for detecting N1- inosine, N1 - and N6 adenine adducts derived from BD metabolites in vivo. Specific Aim 4 is to determine the mutagenic responses induced by BD exposures and characterize the impact of BD-diol derived metabolites on the spectra of mutations induced by BD exposure in the B6C3F1 mouse and F344 rat to identify which adducts studied in Aims 1 and 3 are quantitative indicators of mutagenesis. Specific Aim 5 will examine the effects of exposure to BD and BD-diol on gene expression and DNA repair pathways. Collectively, these experiments have been designed to look at adduct formation, DNA repair, mutagenicity, and genomic alterations in rodents exposed BD and BD-diol, as well as the impact of glutathione depletion and DNA repair deficiency. Finally, HMVK-Val adducts will be measured in samples from BD exposed humans. Our research will identify critical metabolites and adducts that are responsible for BD mutagenicity, as well as develop biomarkers suitable for future molecular epidemiology studies. Ultimately these data will improve our understanding of critical mechanisms of toxicity and ability to accurately assess the risk of BD to humans.

性状（由申请人提供）：1，3-丁二烯（BD）是一种已知致癌物。然而，导致突变的DNA加合物仍然未知。拟议研究的总体目标是检查暴露于BD和3-丁烯-1，2-二醇（BD-二醇）的啮齿动物中先前未探索的DNA加合物的分子剂量，将数据与突变频率和突变谱进行比较，以确定特定加合物是否可用作诱变的定量指标，并评估暴露对基因表达的影响。待检验的第一个假设是，在暴露于BD和BD-二醇期间，以性别、种属和暴露浓度依赖性方式在体内形成羟甲基乙烯基酮（HMVK），导致致突变性的重要差异。第二个假设是，promutagenic N1腺嘌呤加合物转化为更稳定的肌苷加合物，这是修复不良，积累在慢性暴露于BD。在处理这些假设时，将实现几个具体目标。具体目的1是检查HMVK在体内形成的潜在致突变DNA加合物（特别是1，N2-丙脱氧鸟苷）。第二个目的是确定HMVK的N-末端缬氨酸加合物（HMVK-Val）作为BD和BD-二醇形成HMVK的生物标志物的效用。具体目标3是开发用于检测体内来自BD代谢物的N1-肌苷、N1 -和N6腺嘌呤加合物的方法。具体目的4是确定BD暴露诱导的致突变反应，并表征BD-二醇衍生代谢物对BD暴露诱导的B6 C3 F1小鼠和F344大鼠突变谱的影响，以确定目的1和3中研究的加合物是致突变的定量指标。具体目标5将检查暴露于BD和BD-二醇对基因表达和DNA修复途径的影响。总的来说，这些实验旨在研究暴露于BD和BD-二醇的啮齿动物中的加合物形成、DNA修复、致突变性和基因组改变，以及谷胱甘肽耗竭和DNA修复缺陷的影响。最后，将在BD暴露人体样本中测量HMVK-Val加合物。我们的研究将确定负责BD致突变性的关键代谢物和加合物，以及开发适合未来分子流行病学研究的生物标志物。最终，这些数据将提高我们对关键毒性机制的理解，并能够准确评估BD对人类的风险。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Age-, gender-, and species-dependent mutagenicity in T cells of mice and rats exposed by inhalation to 1,3-butadiene.

吸入 1,3-丁二烯的小鼠和大鼠的 T 细胞具有年龄、性别和物种依赖性致突变性。

DOI：
10.1016/j.cbi.2006.07.005
发表时间：
2007
期刊：
Chemico-biological interactions
影响因子：
5.1
作者：
Meng,Quanxin;Walker,DaleM;McDonald,JakeD;Henderson,RogeneF;Carter,MeghanM;CookJr,DennisL;McCash,ConsueloL;Torres,SalinaM;Bauer,MichaelJ;Seilkop,StevenK;Upton,PatriciaB;Georgieva,NadiaI;Boysen,Gunnar;Swenberg,JamesA;
通讯作者：

Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol.

暴露于 3-丁烯-1,2-二醇的啮齿类动物中 3,4-环氧-1,2-丁二醇的 DNA 和血红蛋白加合物的定量。