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: 6314568
• 负责人: ERIO GURPIDE
• 金额: $ 8.37万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6314568
• 关键词: alkaline phosphatase; alternatives to animals in research; cancer risk; carbopolycyclic compound; chemical carcinogen; chlordane; chlorohydrocarbon; dichlorodiphenyltrichloroethane; environmental contamination; hazardous substances; 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.

评估荷尔蒙活动对人类健康的潜在影响 氯代烃，我们将获得雌激素，孕激素 以及提取的河底沉积物的雄激素活性 被有机氯和其他超级基金污染-目标 物质。人类接触的一个主要途径是通过摄入 从河底沉积物中吸收这些化学物质的鱼。 雌激素和其他类似性激素的作用被认为是 解释了已报道的这些化合物与生殖 功能障碍和癌症发病率增加，尤其是乳腺癌。至 然而，大多数环境污染物的激素测试都有 专注于它们的雌激素潜能。我们的假设是，检测到 一系列荷尔蒙和抗荷尔蒙活动的环境 污染物将反映它们对公共健康的潜在风险， 尤其是对生殖功能障碍和癌症。暴露可能会影响 不止一种激素系统，这一结果可能会被 单独评估雌激素活性。 荷尔蒙活性将在(1)三种非极性提取物上确定 港口沉积物(将被收集并对其进行化学表征 项目5)和(2)已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 农药(滴滴涕和氯丹)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。将对重金属进行调查，看看它们是否有可能 抑制激素结合。 雌激素活性(激动剂和拮抗剂)将被测定。 使用我们实验室开发的一种基于雌激素的化验- 井中碱性磷酸酶(AlkP)的特异性诱导 分化的人子宫腺癌细胞系(Ishikawa Var I)。 早孕性将在类似的系统中进行测试，该系统也是在 本实验室采用人乳腺腺癌细胞T47D。一个 将利用人类癌症LNCaP或MFM-223开发促雄激素试验 细胞。化合物的相对荷尔蒙效力将通过以下方式确定 最大反应的计算，以及激动剂和 拮抗剂的IC50值。雌激素检测方法的适用性 环境雌激素已经被证明有能力 测定饲料中异黄酮类植物雌激素的雌激素活性 凯彭。比色技术具有快速、高效、自动化的特点； 它比其他基于细胞增殖的技术更方便。 这需要细胞计数。我们的雌激素检测和那些 以MCF7乳腺细胞系为研究对象。孕激素和雄激素测定 都是基于激素特异性诱导ALKP的相同原理 活动。三种化验方法的互补将使快速有效 在一系列化学品和化学混合物出现时进行筛选 N个危险废物场地。