DNA Adducts of Styrene and Other Vinyl Monomers

苯乙烯和其他乙烯基单体的 DNA 加合物

• 批准号: 7794908
• 负责人: Michael P Stone
• 金额: $ 36.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7794908
• 关键词: 3,4-epoxy-1-butene; Alkylation; Amino Acids; Base Pairing; Binding; Biochemical; Biological; Biological Process; Breathing; Butadiene; Bypass; Cancer Etiology; Carcinogens; Chemistry; Chronic; Complex; Crystallization; Crystallography; DNA; DNA Adducts; DNA Alkylation; DNA Crosslinking; DNA Damage; DNA Sequence; DNA Structure; Deamination; Deoxyadenosines; Deoxyuridine; Divalent Cations; Enzymes; Epoxy Compounds; Etiology; Exposure to; FAPy; Face; Family; Glycols; Human; Hydrogen Bonding; Induced Mutation; Investigation; Kinetics; Lesion; Major Groove; Malignant Neoplasms; Mediating; Modeling; Molecular Conformation; Monitor; Mono-S; Mutagenesis; Mutation; Nature; Nucleotides; Occupational Exposure; Outcome; Plastics; Polymerase; Production; Residual state; Risk; Role; Rotation; Rubber; Sampling; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Sulfolobus solfataricus; Synchrotrons; adduct; base; crosslink; deoxyinosine; erythritol anhydride; genotoxicity; hydroxyl group; insight; leukemia; medical schools; monomer; next generation; professor; stereochemistry

DESCRIPTION (provided by applicant): Styrene and butadiene, used in the production of rubber and plastics, are implicated in the etiology of human cancer. Butadiene is classified by the USEPA as "carcinogenic to humans by inhalation", by the NTP as a "known human carcinogen". Chronic occupational exposures to mixtures of styrene and butadiene correlate with risk for leukemias. This project will examine the etiology of butadiene-induced mutagenesis, developing structure-activity relationships for DNA adducts arising from butadiene epoxides and associated with human genotoxicity. The first aim will combine NMR, crystallography, and biochemical approaches to examine N1- deoxyinosine adducts arising from deamination of N1-deoxyadenosine alkylation products. We propose a role for Y-family Pol i utilizing the Hoogsteen face of dl for templating, allowing incorporation of protonated dCTP or dATP. The second aim will employ NMR and crystallographic approaches to examine stereoisomeric N3-dU adducts of butadiene monoepoxide, which arise from deamination of N3-dC adducts. We propose that they do not undergo rotation about the glycosyl bond, into the syn conformation, thus leading to fundamentally different biological and mutagenic outcomes. The third aim will use NMR, biochemical, and site-specific mutagenesis to examine N7-dG adducts arising from exposures to butadiene epoxides. Emphasis will be placed on relationships of N7-dG adduction to the formation of interstrand and intrastrand crosslinks by butadiene diepoxide; this depends upon DNA sequence and diepoxide stereochemistry. Interstrand crosslinks form in 5'-GNC-3' sequences. We propose that the orientations of N7-dG butadiene diol epoxide mono-adducts depend upon stereochemistry, differentially orienting the diol epoxides for interstrand vs. intrastrand crosslinking. The chemistry, mutational spectra, and replication bypass of N7-dG FAPy re-arrangement products will be examined. Overall, we will delineate mechanism(s) by which N1-dl and N3-dU butadiene adducts induce mutations, and why specific polymerase(s) mediate lesion bypass. Insight will be gained into DNA crosslinking chemistry of butadiene diepoxides. Insight will be gained into the chemistry of butadiene N7-dG FAPy lesions, their biological processing, and their structures. This is essential to understanding how occupational exposures to mixtures of styrene and butadiene contribute to human genotoxicity and cancer etiology.

描述（由申请人提供）：苯乙烯和丁二烯，用于橡胶和塑料的生产，与人类癌症的病因有关。丁二烯被美国环保署列为“经吸入对人类致癌”，被国家毒理学规划列为“已知的人类致癌物”。长期职业性接触苯乙烯和丁二烯的混合物与患白血病的风险有关。该项目将研究丁二烯诱变的病因学，发展由环氧丁二烯产生的DNA加合物的结构-活性关系，并与人类遗传毒性相关。第一个目标将结合核磁共振，晶体学和生化方法来检查N1-脱氧腺苷烷基化产物脱氨产生的N1-脱氧腺苷加合物。我们利用dl的Hoogsteen面为模板提出了y家族Pol i的作用，允许纳入质子化的dCTP或dATP。第二个目标将采用核磁共振和晶体学方法来检查由N3-dC加合物脱氨产生的单环氧丁二烯的立体异构体N3-dU加合物。我们认为它们不会围绕糖基键旋转成syn构象，从而导致根本不同的生物学和诱变结果。第三个目标将使用核磁共振、生化和位点特异性诱变来检查暴露于环氧丁二烯产生的N7-dG加合物。重点将放在N7-dG内合与二氧化丁二烯形成链间和链内交联的关系；这取决于DNA序列和二氧化物立体化学。链间交联形成5‘-GNC-3’序列。我们提出N7-dG丁二烯环氧二醇单加合物的取向取决于立体化学，在链间和链内交联中对环氧二醇进行不同的取向。研究了N7-dG FAPy重排产物的化学性质、突变谱和复制旁路。总的来说，我们将描述N1-dl和N3-dU丁二烯加合物诱导突变的机制，以及为什么特定的聚合酶介导病变旁路。深入了解二氧化丁二烯的DNA交联化学。洞察丁二烯N7-dG FAPy病变的化学，他们的生物过程，和他们的结构。这对于了解职业暴露于苯乙烯和丁二烯混合物如何影响人类遗传毒性和癌症病因学至关重要。