Roles of CYP1 & 19 in Fundulus Steroids & PAH Metabolism

CYP1 的作用

• 批准号: 7417376
• 负责人: KRISTINE L WILLETT
• 金额: $ 0.76万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417376
• 关键词: Adult; Affect; Animal Model; Aromatase; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Biological; Biological Monitoring; CYP19A1 gene; Cancer Model; Chorion; Cytochrome P450; Cytochromes; DNA Adduction; DNA Adducts; Development; End Point; Endocrine disruption; Epoxy Compounds; Estrogen Metabolism; Estrogens; Fishes; Fundulus; Fundulus heteroclitus; Genes; Health; Human; Human Development; In Vitro; Malignant Neoplasms; Mammals; Measures; Mediating; Metabolic; Metabolism; Modeling; Molecular; Oxidation-Reduction; Oxidative Stress; Polycyclic Hydrocarbons; Predisposition; Production; Recombinants; Research; Research Personnel; Role; Specificity; Steroids; System; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Tumor Tissue; Urination; Vertebrates; egg; genotoxicity; in vivo; pollutant; programs; reproductive; reproductive success; steroid metabolism; success; tumor

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are a human health concern because they are implicated in human cancers and endocrine disruption. The fish Fundulus heteroclitus will be used as a model organism to investigate the central hypothesis that CYP1B and/or CYP19 are involved in the molecular mechanisms of benzo(a)pyrene-mediated toxicity. The Specific Aims are to: 1) Assess the respective roles of CYP1B and CYP19s in BaP and estrogen metabolism and estrogen synthesis with in vitro recombinant systems, 2) Determine the extent, to which BaP-induced CYP1 B-mediated metabolism is important in genotoxicity. Aim 2.1: In adult fish following BaP exposure, the relationship between tissue specific CYP1B expression, toxic metabolite formation, DNA adducts and oxidative stress will be quantitated. Aim 2.2: Determine how egg or larval BaP-exposure affects CYP1B expression and associated toxicological endpoints. Aim 2.3: Determine how CYP1B and CYP19 are up-regulated in tumor tissues in exposed fish. 3) Measure the association between BaP-induced changes in aromatase and Fundulus reproductive or developmental success. Aim 3.1: Determine if maternal BaP-exposure decreases reproductive success. Aim 3.2: Determine if and how egg and larval BaP exposures alter aromatase expression and if this is correlated with developmental deficiencies. Successful completion of these Aims will provide a greater molecular understanding of these important P450 genes and their role in the mechanisms of action of PAHs. This research will further define the utility of Fundulus as a model organism for studying PAH-associated toxicities and in the development of human CYP19 or CYP1 B-related therapeutics.

描述（由申请人提供）：多环芳烃 (PAH) 是一种普遍存在的污染物，由于与人类癌症和内分泌干扰有关，因此会引起人类健康问题。鱼眼底异斜鱼将被用作模型生物来研究 CYP1B 和/或 CYP19 参与苯并（a）芘介导的毒性的分子机制的中心假设。具体目标是： 1) 利用体外重组系统评估 CYP1B 和 CYP19s 在 BaP 和雌激素代谢和雌激素合成中各自的作用， 2) 确定 BaP 诱导的 CYP1 B 介导的代谢在遗传毒性中的重要程度。目标 2.1：在暴露于 BaP 后的成鱼中，将定量组织特异性 CYP1B 表达、有毒代谢物形成、DNA 加合物和氧化应激之间的关系。目标 2.2：确定卵或幼虫 BaP 暴露如何影响 CYP1B 表达和相关毒理学终点。目标 2.3：确定 CYP1B 和 CYP19 在暴露鱼的肿瘤组织中如何上调。 3) 测量 BaP 诱导的芳香酶变化与眼底生殖或发育成功之间的关联。 目标 3.1：确定母亲接触 BaP 是否会降低生殖成功率。 目标 3.2：确定卵和幼虫 BaP 暴露是否以及如何改变芳香酶表达，以及这是否与发育缺陷相关。成功完成这些目标将使人们对这些重要的 P450 基因及其在 PAH 作用机制中的作用有更深入的分子了解。这项研究将进一步明确眼底作为模型生物的用途，用于研究 PAH 相关毒性以及开发人类 CYP19 或 CYP1 B 相关疗法。