Cancer induction in the ovary by an environmental pollutant, dibenzo[a,l]pyrene

环境污染物二苯并[a,l]芘诱发卵巢癌

• 批准号: 8445857
• 负责人: Kun-Ming Chen
• 金额: $ 22.95万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445857
• 关键词: 8-Oxo-2' -Deoxyguanosine; 8-hydroxy-2' -deoxyguanosine; Accounting; Animal Model; Aromatic Polycyclic Hydrocarbons; Binding; Biochemical; Biological; Biological Markers; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Cells; Cessation of life; Chronic; Classification; Cytochrome P450; DNA; DNA Adducts; DNA Binding; DNA Damage; DNA Repair Enzymes; DNA lesion; Data Reporting; Detection; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; ERBB2 gene; Early Diagnosis; Environment; Environmental Carcinogens; Environmental Pollutants; Epithelial ovarian cancer; Epoxy Compounds; Etiology; Excision; Experimental Animal Model; Exposure to; Genetic; Glycols; Histologic; Human; Intervention; Lead; Lesion; Literature; Lung; Luteal Cells; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary gland; Mediating; Messenger RNA; Metabolism; Methods; Molecular; Molecular Conformation; Mucinous; Mucinous Neoplasm; Mus; Organ; Ovarian; Ovary; Oxidation-Reduction; PTGS2 gene; Prevention; Process; Proteins; Protocols documentation; Pyrenes; Quinones; Reactive Oxygen Species; Reporting; Risk; Rodent; Role; Skin; Smoker; Staging; Survival Rate; Symptoms; Testing; Time; Tissues; Tobacco smoke; Tobacco smoking; Woman; absorption; adduct; animal model development; base; benzo(a)pyrene-DNA adduct; c-myc Genes; cancer diagnosis; carcinogenesis; carcinogenicity; chemical carcinogen; cigarette smoking; design; disease characteristic; female reproductive system; genotoxicity; granulose; human disease; in vivo; malignant phenotype; molecular marker; novel strategies; ovarian neoplasm; prevent; public health relevance; response; tumor

DESCRIPTION (provided by applicant): There are usually no obvious symptoms of early stage ovarian cancer; therefore, the five-year survival rate for ovarian cancer patients is 44%. The etiology of ovarian cancer is multifactorial and remains largely undefined; therefore, the mechanisms by which this disease progresses to more malignant phenotype are poorly understood. Recent studies have shown that tobacco smoking is associated with cancer of the ovary. The mechanisms that can account for the role of tobacco smoking on this disease remain unknown. In this project we seek to uncover the mechanisms that can account for ovarian carcinogenesis in mice treated with dibenzo[a,l]pyrene (DB[a,l]P); an environmental pollutant and a tobacco smoke constituent. Presence of DNA adducts in tissues exposed to environmental carcinogens is crucial to the initiation of the carcinogenic process, and therefore the detection of DNA adducts derived from cigarette smoke constituents in ovaries may indicate increasing the risk of ovarian cancer. Diol-epoxides derived from polycyclic aromatic hydrocarbons (PAH) can covalently bind to DNA of ovarian cells from human exposed to cigarette smoke. There is ample evidence in the literature that DB[a,l]P, an environmental pollutant and a tobacco smoke component, is the most powerful PAH carcinogen (skin, mammary, lung, and ovary) known to date; its remarkable genotoxicity has been attributed to the sterically hindered fjord region diol epoxides (+)-anti- DB[a,l]PDE. In addition, reactive oxygen species (ROS) derived from redox cycling of o-quinone derived from dihydrodiol metabolite of DB[a,l]P can lead to the formation of the mutagenic lesion, 8-hydroxy-2'- deoxyguanosine (8-oxo-dG). Literature reports and our preliminary results, have shown the induction of ovarian cancer by DB[a,l]P. We also detected DB[a,l]PDE-DNA adducts for the first time in the ovaries of mice treated with DB[a,l]P using our newly developed LC-MS/MS method. However, it remains unknown that whether DB[a,l]P is metabolically activated in ovary of mouse and which DB[a,l]P-induced DNA adducts or damage is/are responsible for its carcinogenicity. We hypothesize that the levels and conformations of the DNA adducts formed, and their removal by mammalian DNA repair enzymes are critical factors involved in the initiation stage of carcinogenesis of DB[a,l]P in ovaries of mice (both covalent adducts and those induced by ROS). We further hypothesize that DB[a,l]P-induced DNA adducts will influence the expression of certain proteins that may be critical in the development of ovarian cancer. In this project, we aim to determine 1. the pharmacokinetic parameters and the tissues distribution of DB[a,l]P, and 2. a. the formation and disappearance of various DNA lesions in the ovary of mice treated with DB[a,l]P (covalent adducts and 8-oxo- dG) as a function of time, b. the optimal dose for DB[a,l]P to induce ovarian cancer more specifically, and c. the effect of DB[a,l]P on molecular markers which are important in human ovarian cancer development.

描述（申请人提供）：早期卵巢癌通常没有明显症状；因此，卵巢癌患者的五年生存率为44%。卵巢癌的病因是多因素的，并且在很大程度上仍不明确。因此，人们对这种疾病进展为恶性表型的机制知之甚少。最近的研究表明，吸烟与卵巢癌有关。吸烟对这种疾病的作用机制仍不清楚。在这个项目中，我们试图揭示用二苯并[a,l]芘（DB[a,l]P）治疗的小鼠卵巢癌发生的机制；环境污染物和烟草烟雾成分。 暴露于环境致癌物的组织中DNA加合物的存在对于致癌过程的启动至关重要，因此在卵巢中检测到源自香烟烟雾成分的DNA加合物可能表明卵巢癌的风险增加。源自多环芳烃 (PAH) 的二醇环氧化物可以与暴露于香烟烟雾的人类卵巢细胞的 DNA 共价结合。文献中有充分证据表明，DB[a,l]P（一种环境污染物和烟草烟雾成分）是迄今为止已知的最强的 PAH 致癌物（皮肤、乳腺、肺和卵巢）；其显着的遗传毒性归因于空间位阻峡湾地区二醇环氧化物 (+)-抗 DB[a,l]PDE。此外，DB[a,l]P 的二氢二醇代谢物衍生的邻醌的氧化还原循环产生的活性氧 (ROS) 可导致诱变病变 8-羟基-2'-脱氧鸟苷 (8-氧代-dG)。文献报道和我们的初步结果表明，DB[a,l]P 可诱导卵巢癌。我们还使用我们新开发的 LC-MS/MS 方法首次在接受 DB[a,l]P 处理的小鼠卵巢中检测到 DB[a,l]PDE-DNA 加合物。然而，DB[a,l]P 是否在小鼠卵巢中代谢激活以及哪些 DB[a,l]P 诱导的 DNA 加合物或损伤是其致癌性仍不清楚。我们假设形成的 DNA 加合物的水平和构象以及它们被哺乳动物 DNA 修复酶去除是参与小鼠卵巢中 DB[a,l]P 致癌起始阶段的关键因素（共价加合物和诱导的加合物）。由ROS）。我们进一步假设 DB[a,l]P 诱导的 DNA 加合物将影响某些蛋白质的表达，这些蛋白质可能对卵巢癌的发展至关重要。在这个项目中，我们的目标是确定 1. DB[a,l]P 的药代动力学参数和组织分布，以及 2. a. DB[a,l]P 的药代动力学参数和组织分布。用 DB[a,l]P（共价加合物和 8-oxo-dG）处理的小鼠卵巢中各种 DNA 损伤的形成和消失随时间的变化，b． DB[a,l]P 更特异地诱导卵巢癌的最佳剂量，以及 c． DB[a,l]P 对人类卵巢癌发展中重要的分子标记物的影响。