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.
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