HORMONAL ACTIVITY OF CHLORINATED HYDROCARBONS FROM NEW YORK HARBOR SEDIMENTS

纽约港沉积物中氯化烃的激素活性

• 批准号: 3734000
• 负责人: ERIO GURPIDE
• 金额: --
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3734000
• 关键词: alkaline phosphatase; alternatives to animals in research; cancer risk; carbopolycyclic compound; chemical carcinogen; chlordane; chlorohydrocarbon; dichlorodiphenyltrichloroethane; environmental contamination; heavy metals; pesticides; receptor binding; receptor expression; reproductive system disorder; steroid hormone receptor; water environment

To evaluate potential for human health effects from hormonal activity of chlorinated hydrocarbons, we will access estrogenicity, progestagenicity and androgenicity of extracted river bottom sediments that are known to be contaminated by organochlorines and other Superfund-targeted substances. A major route of human exposure is through consumption of fish which absorb these chemicals from river bottom sediments. Estrogenic and other sex-hormone like action has been postulated to account for reported associations of these compounds with reproductive dysfunction and increased rates of cancer, especially breast cancer. To date, however, most hormonal tests of environmental contaminants have focussed on their estrogenic potential. Our hypothesis is that detection of a range of hormonal and anti-hormonal activities of environmental contaminants will reflect their potential for public health risks, especially for reproductive dysfunction and cancer. Exposure may affect more than one hormone system, an outcome that could be missed by evaluating estrogenic activity alone. Hormonal activity will be determined on (1) non-polar extracts of three harbor sediments (which will be gathered and chemically characterized in Project 5) and (2) pure chemicals and mixtures of components identified in (1). Chemicals of interest are the organochlorines including pesticides (DDT and chlordane) and polychlorinated biphenyls (mixtures and individual congeners), other halogenated hydrocarbons (chlorinated ethylenes), polycyclic aromatic hydrocarbons, and plasticizers, including alkyl phenols. Heavy metals will be investigated for their potential to inhibit hormone binding. Estrogenic activity (both agonist and antagonist) will be determined using an assay developed in our laboratory that is based on estrogen- specific induction of alkaline phosphatase (AlkP) in a well- differentiated human uterine adenocarcinoma cell line (Ishikawa Var I). Progestagenicity will be tested in a similar system, also developed in our laboratory, using human breast adenocarcinoma T47D cells. An androgenicity assay will be developed using human cancer LNCaP or MFM-223 cells. Relative hormonal potencies of compounds will be determined by computation of maximal response, as well as EC50 values for agonists and IC50 values for antagonists. The applicability of the estrogen assay to environmental estrogens has already been demonstrated by its ability to measure the estrogenicity of dietary isoflavonoid phytoestrogens and kepone. The colorimetric technique is rapid, efficient and automatable; it is more expedient than other techniques based on cell proliferation that require cell counting. Our estrogen assay is as sensitive as those based on MCF7 breast cell lines. The progestagenic and androgenic assays are based on the same principle of hormone-specific induction of ALKP activity. The complement of three assays will allow rapid efficient screening of an array of chemicals and of chemical mixtures as they occur n hazardous waste sites.

评价以下激素活性对人类健康的潜在影响： 氯代碳氢化合物，我们将获得雌激素， 和雄激素的提取河底沉积物，已知， 受到有机氯和其他超级基金目标的污染 物质. 人类接触的一个主要途径是通过食用 鱼类从河底沉积物中吸收这些化学物质。 雌激素和其他类似性激素的作用被认为是 解释了这些化合物与生殖 功能障碍和癌症发病率增加，尤其是乳腺癌。 到 然而，迄今为止，大多数环境污染物的激素测试 专注于它们的雌激素潜能 我们的假设是 一系列激素和抗激素活动的环境 污染物将反映其潜在的公共健康风险， 尤其是生殖功能障碍和癌症。 暴露可能会影响 一个以上的激素系统，一个可能被忽视的结果， 单独评估雌激素活性。 激素活性将在（1）三种非极性提取物中测定 港口沉积物（将收集并进行化学表征， 项目5）和（2）确定的纯化学品和成分混合物 在（1）中。 感兴趣的化学品是有机氯，包括 杀虫剂（滴滴涕和滴滴涕）和多氯联苯（混合物 和个别同系物）、其他卤代烃（氯化 乙烯）、多环芳烃和增塑剂，包括 烷基酚 重金属将被调查其潜力， 抑制激素结合。 将测定雌激素活性（激动剂和拮抗剂） 使用我们实验室开发的一种基于雌激素的检测方法， 特异性诱导的碱性磷酸酶（AlkP）在一个良好的- 分化的人子宫腺癌细胞系（石川Var I）。 将在类似的系统中测试孕激素，该系统也是在 我们实验室，使用人乳腺癌T47 D细胞。 一个 将使用人癌LNCaP或MFM-223开发雄激素原性测定 细胞 化合物的相对激素效力将通过以下测定： 计算激动剂的最大反应以及EC 50值， 拮抗剂的IC 50值。 雌激素测定法的适用性， 环境雌激素已经被证明具有以下能力： 测量饮食中的非甾体植物雌激素的雌激素活性， 开蓬 比色法快速、高效、自动化程度高; 它比其他基于细胞增殖的技术更方便， 需要细胞计数 我们的雌激素检测和那些 基于MCF 7乳腺细胞系。 孕激素和雄激素测定 基于ALKP的细胞特异性诱导的相同原理 活动 三种检测方法的互补将允许快速有效的 筛选一系列化学品和化学混合物 n危险废物场地。