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.

人们普遍担心的是，环境中的化学物质暴露可能与观察到的乳腺癌发生率增加有关。 在关注的化学物质中，有氯化的二苯基（PCB）和多环芳烃（PAHS），它们具有破坏雌激素反应的潜力。很难预测暴露于这些化学物质的复杂混合物的健康影响，因为PCB和PAH的个别同类物可能具有雌激素或抗雌激素，并通过各种可能导致添加剂，拮抗或协同作用的机制作用。此外，PCB的微生物还原性脱氯和体内的PCB和PAH的代谢转化可能会大大改变这些混合物的活性。假设PCB的还原性脱氯会增加所得混合物的雌激素活性，并且PCB和PAHS的代谢进一步改变了这些混合物的雌激素和抗源性活性。因此，该建议的目的是确定PCB和PAH的混合物如何相互作用并调节人类细胞中的雌激素活性。具体而言，我们将：1）确定PCB和PAH相关复合物混合物的雌激素和抗源性活性。从人体组织中检测到的PCB和PAH的组成的沉积物样品和混合物中的提取物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，并评估对单个成分活性的了解是否足以预测混合物的活性。要研究的机制包括，雌激素受体（ER）结合，ER水平的调节，PCBS和PAHS中17-雌二醇代谢的代谢和乳腺癌细胞中的代谢。相互作用的性质将使用完整的剂量反应曲线和概率分析探索。 3）确定混合物的雌激素和抗雌激素活性在人肝微粒体中的代谢改变的程度，并鉴定主要的活性代谢物。由人肝微粒体孵育产生的代谢产物，并鉴定主要的活性代谢产物。由人肝微粒体中孵育产生的代谢产物将测试其在人类乳腺癌细胞中的雌激素和抗雌激素活性。从这些研究中获得的知识将提供有关暴露于环境雌激素与健康风险之间关系的洞察力。

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