PBC ESTROGENICITY IN HUMAN BREAST CANCER CELLS

莫霍克族的美国土著居民居住在 圣瑞吉斯印第安人保留区的Akwesasne面临着 多氯联苯（PCB）暴露于邻近的高度 污染的马塞纳，纽约超级基金网站。 研究已经证明 多氯联苯的混合物（Aroclors）或特定的多氯联苯同系物表现出雌激素性 在非人类系统中的影响，连同已知的潜在的 雌激素改变神经化学功能 一个假定的机制，多氯联苯增强的变化，神经化学功能。 我们假设PCB介导的改变是雌激素性的， 雌激素依赖于PCB的具体结构及其 P450催化代谢为羟基化代谢物。 雌激素活性 多氯联苯只在动物系统中建立， 细节有限 建立机制支持拟议的 广泛的流行病学研究，以确定环境的作用， 在Akwesasne的超级基金站点的神经化学功能障碍的污染物 将需要进一步广泛的评价雌激素的潜力， 人体衍生系统中的多氯联苯及其代谢物。 的具体目标 主要内容有：1. 评价其体外雌激素样活性， 多氯联苯同系物及其羟基化代谢产物的抗雌激素活性 雌激素诱导人乳腺癌细胞MCF-7 依赖和点。 这将发展结构-功能关系 并确定多氯联苯的代谢是否是一个必要的先决条件 因为它们的雌激素作用。 2. 研究人体代谢 在微粒体中使用人类P450的选定PCB同系物系统， 诱导或对照MCF-7细胞、人肝细胞和人P450 在哺乳动物细胞中表达。 3. 描述多氯联苯代谢的特征 在从组织（肝、脑、肾和 神经毒性研究产生的多氯联苯暴露大鼠的子宫）。 4. 为了确定雌激素和/或抗雌激素活性与 从生物降解研究中提取的沉积物样品。

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.