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: 3734001
• 负责人: AINSLEY WESTON
• 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/3734001
• 关键词: benzene; breast neoplasms; clone cells; cytochrome P450; environmental contamination; estradiol; female; halobiphenyl /halotriphenyl compound; 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.

某些对环境具有持久性的氯代烃， 特殊的多氯联苯和双(4-氯苯基)-1，1，1- 三氯乙烷(DDT)衍生的化合物近年来被认为是 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 这些化合物的性质被认为与 乳腺癌发生的病因途径。然而，实验室- 正常人可能潜在分子机制的基础研究 乳腺上皮细胞一直很少。 研究氯代烃可能参与的机理 女性乳腺癌的病因，这个项目将评估 这些化合物在正常人体内改变致癌物代谢的能力 人乳腺上皮细胞。健康人乳腺上皮细胞 女性可作为乳房缩小整形手术后的废弃组织 在我们研究所。这些组织将用于这项研究。这个 细胞材料将通过粗切和酶法释放。 消化。细胞将进行8-10代的繁殖以获得 整个实验需要足够的细胞。这些细胞将与 或者：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地沉积物提取物(来自 项目5)含有多氯联苯、多环芳烃 碳氢化合物和支链烷烃。然后新陈代谢、活化和 三种放射性标记致癌物之一的DNA加合物的形成 潜在致癌物：苯并[a]芘、苯或17β-雌二醇 这些正常的人类乳腺上皮细胞将被研究。致癌物质- DNA加合物将通过酶消化和高效分离得到 液体色谱学。加入物鉴定将由联合- 用现有的标准进行层析。加合物的水平将是 由液体闪烁计数测定。如果发生了 检测到未知加合物，大规模培养来自具有 新陈代谢激活的高倾向将用于准备 用于质谱学分析的材料。代谢物存在于 媒体也将被类似地分析。通过这些手段，个人之间和 不同种族(非裔美国人、拉丁裔和高加索人)在 正常人乳腺的代谢诱导性和致癌物代谢 上皮细胞将被确定。 该项目将与本计划的其他组成部分一起， 阐明环境氯代烃在环境污染中的作用 女性乳腺癌的病因学。