PBC ESTROGENICITY IN HUMAN BREAST CANCER CELLS

人乳腺癌细胞中的 PBC 雌激素

• 批准号: 6504072
• 负责人: JOHN F GIERTHY
• 金额: $ 23.08万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504072
• 关键词: MCF7 cell; cell growth regulation; chemical structure function; cytochrome P450; estrogen analog; estrogen inhibitor; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; laboratory rat; liver metabolism; mass spectrometry; microsomes; neurochemistry; plasminogen activator; toxin metabolism

The Native American population of the Mohawk national who inhabit the Akwesasne in the St. Regis Indian Reservation is at high risk of polychlorinated biphenyl (PCB) exposures from the adjacent highly contaminated Massena, NY Superfund site. Studies have demonstrated that mixtures of PCBs (Aroclors) or specific PCB congeners exhibit estrogenic effects in non-human systems which, together with the known potential of estrogens to alter neurochemical function alteration of estrogens, provide a putative mechanism for PCB-potentiated changes in neurochemical function. We hypothesize that PCB mediated alterations are estrogenic and that this estrogenicity is dependent on the specific structure of the PCB and on its P450-catalyzed metabolism to a hydroxylated metabolite. The estrogenicity of PCBs has only been established in animal systems and then only in very limited detail. The establishment of mechanisms in support of proposed extensive epidemiologic studies to establish a role for environmental pollutants in neurochemical disfunction at the Superfund Site at Akwesasne will require further extensive evaluations of the estrogenic potential of PCBs and their metabolites in human derived systems. The specific aims of the project are: 1. To evaluate the in vitro estrogenicity and antiestrogenicity of PCB congeners and their hydroxylated metabolites in a human breast cancer cell line, MCF-7, using the induction of estrogen dependent and points. This will develop structure-function relationships and establish whether metabolism of the PCBs is an essential prerequisite for their estrogenic action. 2. To investigate the metabolism in human systems of selected PCB congeners using human P450s in microsomes from induced or control MCF-7 cells, human hepatocytes, and human P450s expressed in mammalian cells. 3. To characterize the PCB metabolism potentiated in microsomes prepared from tissue (liver, brain, kidney, and uterus) from PCB exposed rats generated by the neurotoxicity studies. 4. To determine the estrogenic and/or antiestrogenic activity associated with extracts of sediment samples from biodegradation studies.

居住在莫霍克族国民的美国原住民 圣瑞吉印第安人保留地的Akwesasne有高风险 来自相邻的多氯联苯双苯基（PCB）暴露 纽约超级基金网站受污染的Massena。 研究表明 PCBS（AROCLOR）或特定PCB同类物的混合物表现出雌激素 非人类系统的影响，以及已知的潜力 雌激素改变雌激素的神经化学功能改变，提供 PCB训练化神经化学功能变化的推定机制。 我们假设PCB介导的改变具有雌激素，这是 雌激素性取决于PCB的特异性结构 P450催化的代谢为羟化代谢产物。 雌激素 PCB仅在动物系统中建立 有限的细节。 建立支持拟议的机制 广泛的流行病学研究以确立环境的作用 Akwesasne的超级基金站点的神经化学失调中的污染物 将需要对雌激素潜力的进一步评估 PCB及其在人类衍生系统中的代谢产物。 具体目的 该项目是：1。评估体外雌激素和 PCB同类物及其羟基化代谢产物的抗雌激素 人类乳腺癌细胞系MCF-7，使用雌激素的诱导 依赖和点。 这将发展结构功能关系 并确定PCB的代谢是否是必不可少的先决条件 为了他们的雌激素作用。 2。调查人类的新陈代谢 使用人类P450在微粒体中使用人类P450的系统系统 诱导或控制MCF-7细胞，人肝细胞和人P450 在哺乳动物细胞中表达。 3。表征PCB代谢 从组织（肝脏，脑，肾脏和 子宫）来自PCB暴露于神经毒性研究产生的大鼠。 4。 确定与 来自生物降解研究的沉积物样品提取物。