DISRUPTION OF ESTROGENIC RESPONSES BY PCB-PAH MIXTURES

PCB-PAH 混合物对雌激素反应的干扰

• 批准号: 6498281
• 负责人: Kathleen Frances Arcaro
• 金额: $ 16.48万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498281
• 关键词: breast neoplasms; carbopolycyclic compound; environment related neoplasm /cancer; estradiol; estrogen receptors; estrogens; halobiphenyl /halotriphenyl compound; hormone metabolism; hormone regulation /control mechanism; liver metabolism; receptor binding; soil sampling; tissue /cell culture; toxicant interaction; toxin metabolism; water pollution

There is widespread concern that exposure to chemicals in the environment may be related to the observed increase in the incidence of breast cancer. Among the chemicals of concern are polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), which have the potential to disrupt estrogenic responses. It is difficult to predict the health effects of exposure to complex mixtures of these chemicals because individual congeners of PCBs and PAHs can be either estrogenic or anti-estrogenic and act through a variety of mechanisms potentially leading to additive, antagonistic or synergistic effects. Furthermore, the microbial reductive dechlorination of PCBs and the metabolic transformation of both PCBs and PAHs within the body, may substantially alter the activity of these mixtures. It is hypothesized that reductive dechlorination of PCBs increases the estrogenic activity of the resulting mixture, and that metabolism of PCBs and PAHs further alters the estrogenic and anti-estrogenic activity of these mixtures. Thus, the objective of this proposal is to determine how mixtures of PCBs and PAHs may interact and modulate estrogenic activity in human cells. Specifically we will: 1) Determine the estrogenic and anti-estrogenic activity of relevant complex mixtures of PCBs and PAHs. Extracts from sediment samples and mixtures reflecting the composition of PCBs and PAHs detected in human tissue, food and water will be tested in human breast cancer cells for their estrogenic and anti-estrogenic activity. 2) Determine how mixtures of PCBs and PAHs alter estrogenic activity and assess whether knowledge of the activity of the individual components is sufficient to predict the activity of the mixture. Mechanisms to be investigated include, estrogen receptor (ER) binding, regulation of ER level, metabolism of 17-estradiol metabolism of PCBs and PAHs in breast cancer cells. The nature of the interactions will be explored using full dose-response curves and probit analysis. 3) Determine the extent to which the estrogenic and anti-estrogenic activity of a mixture is altered by metabolism in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes will be tested for their estrogenic and anti-estrogenic activity in human breast cancer cells. Knowledge gained from these studies will provide insight into the relationship between exposure to environmental estrogens and health risk.

人们普遍担心，接触环境中的化学物质可能与观察到的乳腺癌发病率增加有关。 值得关注的化学物质包括多氯联苯 (PCB) 和多环芳烃 (PAH)，它们有可能破坏雌激素反应。很难预测接触这些化学物质的复杂混合物对健康的影响，因为 PCB 和 PAH 的单个同系物可能具有雌激素作用，也可能具有抗雌激素作用，并通过多种机制发挥作用，可能导致相加、拮抗或协同效应。此外，PCB 的微生物还原脱氯以及 PCB 和 PAH 在体内的代谢转化可能会显着改变这些混合物的活性。据推测，PCB 的还原脱氯增加了所得混合物的雌激素活性，并且 PCB 和 PAH 的代谢进一步改变了这些混合物的雌激素和抗雌激素活性。因此，该提案的目的是确定 PCB 和 PAH 的混合物如何相互作用并调节人体细胞中的雌激素活性。具体来说，我们将： 1) 确定 PCB 和 PAH 的相关复杂混合物的雌激素和抗雌激素活性。沉积物样品和混合物的提取物反映了人体组织、食物和水中检测到的多氯联苯和多环芳烃的成分，将在人类乳腺癌细胞中测试其雌激素和抗雌激素活性。 2) 确定 PCB 和 PAH 的混合物如何改变雌激素活性，并评估对各个成分活性的了解是否足以预测混合物的活性。待研究的机制包括乳腺癌细胞中雌激素受体（ER）结合、ER水平调节、17-雌二醇代谢、PCBs和PAHs代谢。将使用完整的剂量反应曲线和概率分析来探索相互作用的本质。 3) 确定混合物的雌激素和抗雌激素活性因人肝微粒体代谢而改变的程度，并确定主要活性代谢物。在人肝微粒体中孵育产生的代谢物，并鉴定主要活性代谢物。在人肝微粒体中孵育产生的代谢物将在人乳腺癌细胞中测试其雌激素和抗雌激素活性。从这些研究中获得的知识将有助于深入了解环境雌激素暴露与健康风险之间的关系。

项目成果

PLD1 is overexpressed in an ER-negative MCF-7 cell line variant and a subset of phospho-Akt-negative breast carcinomas.

• DOI: 10.1038/sj.bjc.6603926
• 发表时间: 2007-09-17
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Gozgit, J. M.;Pentecost, B. T.;Marconi, S. A.;Ricketts-Loriaux, R. S. J.;Otis, C. N.;Arcaro, K. F.
• 通讯作者: Arcaro, K. F.

Beta-galactosidase and alpha-mannosidase inhibit formation of multicellular nodules in breast cancer cell cultures.

• 发表时间: 2004
• 期刊: Anticancer research
• 影响因子: 2
• 作者: K. Arcaro;Jo C. Wang;C. Otis;B. Zuckerman