ABSTRACT
Using a combination of in vitro assays we have evaluated whether DDT metabolites can interact with the progesterone receptor pathway in yeast expressing human progesterone receptor (hPR) and in T47D human breast cancer cells which express endogenous hPR. In transactivation assays using both yeast and T47D cells, o,p'-DDT and the metabolites p,p'-DDT, o,p'-DDD, p,p'-DDD, o,p'-DDE, p,p'-DDE, p,p'-DDA, and DDOH inhibited progesterone-induced reporter gene activity in a dose-dependent manner. None of the DDT metabolites functioned as hPR agonists. Whole cell competition binding assays using T47D cells indicated that the inhibitory effects of DDT metabolites on progesterone-dependent activites may occur through both hPR-dependent and hPR-independent pathways. Our results and previous reports of DDT metabolites interacting with estrogen and androgen receptors suggests that this class of environmental chemicals may interact with numerous hormone receptor signaling pathways.
Subject(s)
DDT/toxicity , Insecticides/toxicity , Progesterone/metabolism , Binding, Competitive , DDT/metabolism , Estrogens, Non-Steroidal/metabolism , Estrogens, Non-Steroidal/toxicity , Female , Genes, Reporter/drug effects , Humans , Insecticides/metabolism , Isomerism , Lac Operon/drug effects , Luciferases/antagonists & inhibitors , Luciferases/genetics , Progesterone Congeners/metabolism , Promegestone/metabolism , Receptors, Progesterone/agonists , Receptors, Progesterone/drug effects , Receptors, Progesterone/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/metabolism , Transfection , Tumor Cells, Cultured , beta-Galactosidase/antagonists & inhibitors , beta-Galactosidase/geneticsABSTRACT
Numerous synthetic chemicals have estrogenic activity by interacting with the estrogen receptor. In this report, we test the hypothesis that some estrogenic chemicals may also modulate the human progesterone receptor (hPR) signaling pathway. This was evaluated by examining synthetic chemicals for their ability to modulate the activity of hPR expressed in yeast. The transcriptional activity of hPR was not increased in the presence of several synthetic chemicals. However, the estrogenic chemicals p-nonylphenol and 4-tert-octyphenol, and pentachlorophenol, effectively inhibited the activity of the hPR in yeast. Competition binding studies indicated these chemicals effectively competed with radiolabeled R5020, a synthetic progestin, for binding to the hPR in yeast. These results indicate that some synthetic chemicals directly inhibit the activity of hPR in yeast. The observations that some estrogenic chemicals can also inhibit hPR activity suggest a potential mechanism for the reported potent estrogenic activities of these chemicals.
