o,p'-DDT and its metabolites inhibit progesterone-dependent responses in yeast and human cells.
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.
Klotz
D M
DM
Tulane-Xavier Center for Bioenvironmental Research, Tulane University Medical Center, New Orleans, LA 70112, USA.
Ladlie
B L
BL
Vonier
P M
PM
McLachlan
J A
JA
Arnold
S F
SF
D001667:Binding, Competitive; D003634:DDT / Q000378:metabolism / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000378:metabolism / Q000633:toxicity; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D007536:Isomerism; D007763:Lac Operon / Q000187:drug effects; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000235:genetics; D011374:Progesterone / Q000378:metabolism*; D045167:Progesterone Congeners / Q000378:metabolism; D011397:Promegestone / Q000378:metabolism; D011980:Receptors, Progesterone / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000235:genetics
D004968:Estrogens, Non-Steroidal; D007306:Insecticides; D045167:Progesterone Congeners; D011980:Receptors, Progesterone; D011374:Progesterone; D011397:Promegestone; D003634:DDT; C016340:o,p'-DDT; D008156:Luciferases; D001616:beta-Galactosidase