Mechanisms of Xenoestrogen Action - Predoctoral Minority

异雌激素作用机制 - 博士前少数

• 批准号: 7097284
• 负责人: MINERVA MERCADO-FELICIANO
• 金额: $ 2.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-19 至 2007-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097284
• 关键词: biological signal transduction; biotransformation; cell growth regulation; cytochrome P450; environment related neoplasm /cancer; environmental contamination; environmental exposure; enzyme activity; estrogen analog; estrogen receptors; guanine nucleotide binding protein; hormone regulation /control mechanism; immunoprecipitation; laboratory mouse; laboratory rat; ligands; mitogen activated protein kinase; oncoprotein p21; phosphatidylinositol 3 kinase; predoctoral investigator; protein kinase A; protein tyrosine kinase; receptor binding; western blottings

DESCRIPTION (provided by applicant): The objective of the proposed research is to determine the role of non-classical molecular pathways mediating estrogenic effects, i.e. pathways that do not rely on direct, ligand-induced activation of the nuclear estrogen receptors (ER) as transcription factors. Specific Aims: (1) Determine the molecular mechanism(s) by which relevant concentrations of xenobiotics act as estrogens; (2) Determine the role of metabolic activation in the non-classical activity of estrogenic compounds. Approach: The ability of test compounds to activate classical and non-classical estrogen signaling pathways will be examined. Pathways to be studied include steroid receptor-mediated transcription, tyrosine kinase/p21ras/MAPK, PI3K/AKT and GPCR30/PKA. The role of metabolic conversion in order to activate these pathways will be assessed. The cytochrome P450 isozymes are suspected of mediating such bioactivation. The impact of different persistent environmental pollutants will be assessed in each molecular pathway and in downstream effects, such as gene expression, apoptosis and cell proliferation.

描述（由申请人提供）：拟议研究的目的是确定介导雌激素作用的非经典分子途径的作用，即不依赖配体诱导的核雌激素受体（ER）激活作为转录因子的途径。具体目的：（1）确定相关浓度的异种生物作为雌激素的分子机制； （2）确定代谢激活在雌激素化合物非经典活性中的作用。方法：将检查测试化合物激活经典和非经典雌激素信号通路的能力。要研究的途径包括类固醇受体介导的转录，酪氨酸激酶/p21RAS/MAPK，PI3K/AKT和GPCR30/PKA。将评估代谢转化率在激活这些途径中的作用。细胞色素P450同工酶被怀疑介导这种生物活化。将在每个分子途径和下游效应（例如基因表达，凋亡和细胞增殖）中评估不同持续环境污染物的影响。

项目成果

Measurement of polybrominated diphenyl ethers and metabolites in mouse plasma after exposure to a commercial pentabromodiphenyl ether mixture.

• DOI: 10.1289/ehp.10011
• 发表时间: 2007-07
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Qiu X;Mercado-Feliciano M;Bigsby RM;Hites RA
• 通讯作者: Hites RA

Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-alpha ligands.

• DOI: 10.1289/ehp.11343
• 发表时间: 2008-10
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Mercado-Feliciano M;Bigsby RM
• 通讯作者: Bigsby RM

The polybrominated diphenyl ether mixture DE-71 is mildly estrogenic.

• DOI: 10.1289/ehp.10643
• 发表时间: 2008-05
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Mercado-Feliciano M;Bigsby RM
• 通讯作者: Bigsby RM