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o,p'-DDT and its metabolites inhibit progesterone-dependent responses in yeast and human cells
D M Klotz1, B L Ladlie, P M Vonier
1Tulane-Xavier Center for Bioenvironmental Research, Tulane University Medical Center, New Orleans, LA 70112, USA.
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.
Insights
DDT metabolites disrupt the progesterone receptor pathway in both yeast and human breast cancer cells. These environmental chemicals act as inhibitors, not activators, suggesting broader endocrine disruption potential.
Area of Science:
- Endocrinology
- Environmental Toxicology
- Molecular Biology
Background:
- DDT (dichlorodiphenyltrichloroethane) is an environmental pollutant with known endocrine-disrupting properties.
- Previous studies indicate DDT metabolites can interact with estrogen and androgen receptors.
Purpose of the Study:
- To investigate the interaction of DDT metabolites with the progesterone receptor (hPR) pathway.
- To determine if DDT metabolites exhibit agonist or antagonist activity on hPR.
Main Methods:
- In vitro transactivation assays using yeast expressing human progesterone receptor (hPR).
- In vitro transactivation assays using T47D human breast cancer cells with endogenous hPR.
- Whole-cell competition binding assays in T47D cells.
Main Results:
- Several DDT metabolites (o,p'-DDT, p,p'-DDT, o,p'-DDD, p,p'-DDD, o,p'-DDE, p,p'-DDE, p,p'-DDA, DDOH) inhibited progesterone-induced reporter gene activity in a dose-dependent manner.
- No DDT metabolites tested acted as hPR agonists.
- Inhibitory effects may involve both hPR-dependent and hPR-independent mechanisms.
Conclusions:
- DDT metabolites can interfere with the progesterone receptor signaling pathway.
- The findings suggest DDT metabolites may have broader endocrine-disrupting effects by interacting with multiple hormone receptors.