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TOXICANT INDUCED CHANGES IN UTERINE & CERVICAL EPITHELIA

有毒物质引起的子宫变化

基本信息

批准号：
3253491
负责人：
Ellen Rorke
金额：
$ 12.99万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-06-12 至 1994-05-31
项目状态：
已结题

项目摘要

The polycyclic aromatic hydrocarbons (PAHs), such as benzo (a) pyrene environmental distribution. Industrial chemicals like halogenated aromatic hydrocarbons are also widespread environmental contaminants. 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is the most important member of this class and is a useful prototype to investigate their mechanism of action. A major public concern is the potential effects of these compounds on female reproductive tract function and fetal development. Although reproductive tract toxicity by these agents has been demonstrated in animal models, very little knowledge is available regarding their direct effects on human female reproductive tract function. We have recently developed human endometrial and ectocervical cell culture systems as models for human reproductive tract epithlelial cell function. These cells respond to the physiologically important sex steroids, estradiol and progesterone, in a manner that mimics the in vivo response. In the present study we plan to utilize these systems to study the effects of TCDD and PAHs on reproductive tract epithelial cell function. Specifically, we will: [1] examine the effects of TCDD, BP, benz (a) anthracene (BA) upon endometrial epithelial cells (EE cell) and ectocervical epithelial cell (ECE cell) differentiation using specific ectocervical cell markers (i.e., involucrin and keratin mRNA and protein, transglutaminase, P450 and related enzymes and DNA modification), [2] determine whether these agents alter EE or ECE cell response to the sex steroids by regulating the levels or affinity of their respective receptors and [3] determine whether the extent of drug metabolism and thus toxic potency differs depending upon the differentiated state of the cells. The ultimate goal of these experiments is to gain new insights into the role that these compounds may play in upsetting normal female reproduction.

多环芳烃（PAHs），如苯并（a）芘环境分布工业化学品，如卤代芳烃碳氢化合物也是广泛的环境污染物。 2,3,7,8- 四氯二苯并对二恶英（TCDD）是其中最重要的成员，类，是研究它们的作用机制的有用原型。公众主要关注的是这些化合物对女性生殖道功能和胎儿发育。虽然这些药剂的生殖道毒性已在动物中得到证实模型，关于其直接影响的知识很少对女性生殖道功能的影响我们最近开发了人类子宫内膜和宫颈细胞培养系统作为人类生殖道上皮细胞功能的模型。这些细胞对生理上重要的性类固醇有反应，雌二醇和孕酮，以模拟体内反应的方式。在本研究中，我们计划利用这些系统来研究其影响对生殖道上皮细胞功能的影响。具体来说，我们将：[1]检查TCDD，BP，奔驰（a）的影响蒽（BA）对子宫内膜上皮细胞（EE细胞）的作用，体外宫颈上皮细胞（ECE细胞）分化使用特异性子宫颈外细胞标记物（即，外皮蛋白和角蛋白mRNA和蛋白质，转氨酶，P450和相关酶和DNA修饰），[2] 确定这些药物是否改变EE或ECE细胞对性别的反应，类固醇通过调节其各自受体的水平或亲和力和[3]确定是否药物代谢的程度，从而毒性效力根据细胞的分化状态而不同。这些实验的最终目标是获得新的见解这些化合物可能在扰乱正常女性生殖方面发挥作用。