EFFECTS OF PCB-CONTAINING RIVER SEDIMENTS ON CARCINOGEN METABOLISM

含多氯联苯的河流沉积物对致癌物代谢的影响

• 批准号: 6239741
• 负责人: AINSLEY WESTON
• 金额: $ 11.25万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6239741
• 关键词: benzene; breast neoplasms; clone cells; cytochrome P450; environmental contamination; estradiol; female; halobiphenyl /halotriphenyl compound; hazardous substances; hormone analog; hormone metabolism; human subject; human tissue; industrial waste; mammary epithelium; mass spectrometry; neoplasm /cancer epidemiology; neoplastic cell; steroid hormone analog; toxin metabolism; water environment; water pollution

Certain environmentally persistent chlorinated hydrocarbons, in particular polychlorinated biphenyls and bis(4-chlorophenyl)-1,1,1- trichloroethane (DDT)-derived compounds have been associated in recent epidemiological studies with an increased incidence of breast cancer among women in the US. The known estrogenic and anti-estrogenic properties of these compounds have been hypothesized to be involved in the etiologic pathway of breast carcinogenesis. However, laboratory- based studies of possible underlying molecular mechanisms in normal human mammary epithelial cells have been few. To study mechanisms by which chlorinated hydrocarbons may be involved in the etiology of cancer of the female breast, this project will evaluate the ability of these compounds to alter carcinogen metabolism in normal human mammary epithelial cells. Mammary epithelial cells from healthy women are available as discard tissues following reduction mammoplasty in our institute. These tissues will be used in this study. The cellular material will be released by coarse dissection and enzymic digestion. The cells will be propagated for 8 - 10 passages to obtain enough cells for an entire experiment. The cells will be incubated with either: 1) Aroclor 1254, a commercial polychlorinated biphenyl mixture or 2) a non-polar sediment extract from New York City waterways (from Project 5) containing polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and branched alkanes. Then the metabolism, activation and formation of DNA-adducts of one of three radiolabeled carcinogens or potential carcinogens: benzo[a]pyrene, benzene or 17beta-estradiol in these normal human mammary epithelial cells will be studied. Carcinogen- DNA adducts will be isolated by enzymic digestion and high performance liquid chromatography. Adduct identification will be made by co- chromatography with available standards. Levels of adducts will be determined by liquid scintillation counting. In the event that an unknown adduct is detected, large-scale cultures from individuals with a high propensity for metabolic activation will be used to prepare materials for analysis by mass spectrometry. Metabolites present in the media will be analyzed similarly. By these means, interindividual and inter-racial (African-American, Latino and Caucasian) variations in metabolic inducibility and carcinogen metabolism in normal human mammary epithelial cells will be determined. This project, in concert with other components of this Program, will elucidate the role of environmental chlorinated hydrocarbons in the etiology of female breast cancer.

某些环境持久性氯化碳氢化合物， 特别是多氯联苯和双（4-氯苯基）-1，1，1- 三氯乙烷（DDT）衍生化合物已与最近 乳腺癌发病率增加的流行病学研究 在美国的女性中。 已知的雌激素和抗雌激素 这些化合物的性质已经被假设为涉及 乳腺癌发生的病因学途径。 然而，实验室- 基于正常人中可能的潜在分子机制的研究 乳腺上皮细胞很少。 研究氯化碳氢化合物可能参与 女性乳腺癌的病因，该项目将评估 这些化合物改变正常人中致癌物质代谢的能力 人乳腺上皮细胞 健康人乳腺上皮细胞 女性可以作为乳房缩小成形术后的废弃组织 在我们的研究所。 这些组织将用于本研究。 的 细胞物质将通过粗解剖和酶解释放出来， 消化. 细胞将繁殖8 - 10代，以获得 足够做整个实验的细胞 细胞将与 1）Aroclor 1254，一种商用多氯联苯混合物 或2）来自纽约市水道的非极性沉积物提取物（来自 项目5）含多氯联苯、多环芳烃 烃和支链烷烃。 然后是新陈代谢，激活， 形成三种放射性标记致癌物之一的DNA加合物，或 潜在致癌物：苯并[a]芘、苯或17 β-雌二醇 将研究这些正常的人乳腺上皮细胞。 致癌物- DNA加合物将通过酶消化和高效分离 液相色谱法 加合物鉴定将由共同- 用可用标准品进行色谱分析。 加合物的水平将 通过液体闪烁计数测定。 如果一个 检测到未知加合物，从患有 高代谢活化倾向将用于制备 用于质谱分析的材料。 存在于 媒体也将进行类似的分析。 通过这些手段， 种族间（非裔美国人、拉丁美洲人和高加索人） 正常人乳腺癌组织中代谢诱导物和致癌物的代谢 将确定上皮细胞。 该项目将与本方案的其他组成部分一起， 阐明环境中的氯化碳氢化合物在 女性乳腺癌的病因。