Superfund Research Program
Endocrine Disruptors: Mechanistic Studies
Project Leader: Stephen H. Safe
Grant Number: P42ES004917
Funding Period: 2000-2008
Project Summary (2000-2005)
The goal of this project is to investigate the adverse human health effects associated with exposures to endocrine-active industrial chemicals. Based on results of preliminary studies with bisphenol A, researchers hypothesize that different structural classes of xenoestrogens and naturally-occurring estrogenic compounds exhibit "unique" estrogenic activities and unique biology that can not be determined using traditional bioassays. Scientists are improving mechanism-based hazard/risk assessment methods by determining ER-subtype-specific induction of gene expression. Six different structural classes of estrogenic compounds are being investigated in the HepG2 cell assay to determine their specific mechanism-based ER action. Ligand structure-dependent differences are also being determined in a new androgen-dependent assay that distinguishes between E2 and diethylstilbestrol (DES) and may be useful for other xenoestrogens. Ligand-dependent differences in activation of ER alpha vs. ER beta will be determined using new assays developed in this laboratory that involve gene activation through GC-rich Spl binding sites. The results from this research are providing new mechanism-based data on xenoestrogen-mediated ER action and provide a more rational basis for risk/hazard assessment of these compounds.