PBC ESTROGENICITY IN HUMAN BREAST CANCER CELLS

居住在莫霍克族的美洲原住民 圣里吉斯印第安人保护区的Akwesasne面临着很高的风险 多氯联苯(多氯联苯)从邻近的高度暴露 受污染的马塞纳，纽约州超级基金网站。研究表明， 多氯联苯(Aroclors)或特定多氯联苯同系物的混合物具有雌激素活性 在非人类系统中的影响，连同已知的潜在的 雌激素改变雌激素的神经化学功能改变，提供 多氯联苯增强神经化学功能变化的可能机制。 我们假设，多氯联苯介导的改变是雌激素样的，这 雌激素活性取决于多氯联苯的特定结构及其 P450催化代谢为羟化代谢物。雌激素样作用 多氯联苯只在动物系统中建立，然后只有在非常 有限的细节。建立机制以支持拟议的 广泛的流行病学研究以确定环境因素的作用 超级基金在Akwesasne的现场，神经化学中的污染物功能失调 将需要进一步广泛地评估其雌激素潜能。 人类衍生系统中的多氯联苯及其代谢物。的具体目标 本研究的主要内容为：1.体外雌激素活性评价 多氯联苯同系物及其羟化代谢产物在小鼠体内的抗雌激素活性 雌激素诱导的人乳腺癌细胞系MCF-7 从属和点。这将发展结构与功能之间的关系 并确定多氯联苯的新陈代谢是否是必要的先决条件 因为它们的雌激素作用。2.研究人体内的代谢 利用人类P450在来自中国的微粒体中选择的多氯联苯同系物系统 诱导或控制MCF-7细胞、人肝细胞和人P450细胞 在哺乳动物细胞中表达。3.表征多氯联苯的代谢 在由组织(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. 确定与以下物质相关的雌激素和/或抗雌激素活性 生物降解研究中的沉积物样品的提取物。

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.