Roles of CYP1 & 19 in Fundulus Steroids & PAH Metabolism

CYP1 的作用

• 批准号: 7226210
• 负责人: KRISTINE L WILLETT
• 金额: $ 22.47万
• 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/7226210
• 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）是普遍存在的污染物，是人类健康问题，因为它们与人类癌症和内分泌干扰有关。将以鱼类底栖动物作为模式生物，研究CYP 1B和/或CYP 19参与苯并（a）芘介导毒性的分子机制这一中心假设。具体目标是： 1)使用体外重组系统评估CYP 1B和CYP 19在BaP和雌激素代谢以及雌激素合成中的各自作用， 2)确定BaP诱导的CYP 1 B介导的代谢在遗传毒性中的重要程度。目标2.1：在BaP暴露后的成鱼中，将定量组织特异性CYP 1B表达、毒性代谢物形成、DNA加合物和氧化应激之间的关系。目的2.2：确定卵或幼虫BaP暴露如何影响CYP 1B表达和相关毒理学终点。目的2.3：确定CYP 1B和CYP 19如何在暴露鱼的肿瘤组织中上调。 3)测量苯并（a）芘诱导的芳香化酶变化与基底生殖或发育成功之间的关联。 目标3.1：确定母体苯并（a）芘暴露是否会降低生殖成功率。 目的3.2：确定卵和幼虫苯并（a）芘暴露是否以及如何改变芳香化酶表达，以及这是否与发育缺陷相关。这些目标的成功完成将为这些重要的P450基因及其在多环芳烃作用机制中的作用提供更深入的分子理解。本研究将进一步确定底作为研究PAH相关毒性和开发人CYP 19或CYP 1 B相关治疗药物的模式生物的效用。