DISRUPTION OF ESTROGENIC RESPONSES BY PCB-PAH MIXTURES

人们普遍担心，接触环境中的化学品可能与观察到的乳腺癌发病率上升有关。 令人关注的化学品包括多氯联苯和多环芳烃，它们有可能破坏雌激素反应。很难预测接触这些化学品的复杂混合物对健康的影响，因为多氯联苯和多环芳烃的个别同源物可能具有雌激素或抗雌激素作用，并通过各种可能导致累加、拮抗或协同效应的机制发挥作用。此外，微生物对多氯联苯的还原脱氯以及多氯联苯和多环芳烃在体内的代谢转化，可能会大大改变这些混合物的活性。据推测，多氯联苯的还原脱氯增加所得混合物的雌激素活性，多氯联苯和多环芳烃的代谢进一步改变这些混合物的雌激素和抗雌激素活性。因此，本提案的目的是确定多氯联苯和多环芳烃的混合物如何相互作用和调节人体细胞中的雌激素活性。具体来说，我们将：1）确定相关的多氯联苯和多环芳烃的复杂混合物的雌激素和抗雌激素活性。反映在人体组织、食物和水中检测到的多氯联苯和多环芳烃成分的沉积物样本和混合物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)确定多氯联苯和多环芳烃的混合物如何改变雌激素活性，并评估单个组分的活性知识是否足以预测混合物的活性。研究的机制包括雌激素受体（ER）结合、ER水平调节、17-雌二醇代谢、PCBs和PAHs在乳腺癌细胞中的代谢。将使用全剂量-反应曲线和概率单位分析探索相互作用的性质。3)确定混合物的雌激素和抗雌激素活性在人肝微粒体中代谢改变的程度，并鉴定主要活性代谢物。在人肝微粒体中孵育产生的代谢产物，并鉴别主要活性代谢产物。将检测在人肝微粒体中孵育产生的二甲双胍在人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深入了解暴露于环境雌激素和健康风险之间的关系。

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.