Roles of CYP1 & 19 in Fundulus Steroids & PAH Metabolism

CYP1 的作用

• 批准号: 6819825
• 负责人: KRISTINE L WILLETT
• 金额: $ 25.69万
• 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/6819825
• 关键词: DNA damage; alternatives to animals in research; aromatase; biological models; carbopolycyclic compound; cytochrome P450; egg /ovum; embryo /fetus toxicology; environmental toxicology; enzyme activity; estrogens; gene environment interaction; gene expression; growth /development; killifish; larva; mature animal; oxidative stress; reproduction; steroid metabolism; toxin metabolism; water pollution

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（PAHS）是无处不在的污染物，是人类健康的关注，因为它们与人类癌症和内分泌干扰有关。 FISH的杂质将用作模型生物体，以研究CYP1B和/或CYP19参与苯并（A）pyrene介导的毒性的分子机制的中心假设。具体目的是： 1）通过体外重组系统，评估CYP1B和CYP19在BAP，雌激素代谢和雌激素合成中的各自作用， 2）确定BAP诱导的CYP1 B介导的代谢在遗传毒性中很重要的程度。 AIM 2.1：在BAP暴露后成年鱼类中，将定量组织特异性CYP1B表达，有毒代谢产物形成，DNA加合物和氧化应激之间的关系。 AIM 2.2：确定卵或幼虫BAP暴露如何影响CYP1B表达和相关的毒理学终点。 AIM 2.3：确定裸露鱼类肿瘤组织中CYP1B和CYP19的上调。 3）测量BAP诱导的芳香酶变化与生殖或发育成功之间的关联。 AIM 3.1：确定母体BAP暴露是否会降低生殖成功。 AIM 3.2：确定卵和幼虫BAP暴露是否以及如何改变芳香化酶表达，以及这是否与发育不足有关。这些目标的成功完成将为这些重要的P450基因及其在PAH的作用机理中的作用提供更深入的分子理解。这项研究将进一步定义地白主义作为研究PAH相关毒性的模型生物以及人类CYP19或CYP1 B相关疗法的发展。