Superfund Research Program

Endocrine Disrupters

Project Leader: Stephen H. Safe
Grant Number: P42ES004917
Funding Period: 2000-2008

Project-Specific Links

Final Progress Reports

Year:   2007  2004 

Hormonal, phytochemical and synthetic estrogenic compounds are structurally diverse chemicals that potentially exhibit tissue-selective estrogen receptor (ER) agonist and antagonist activities.  Dr. Safe’s research team hypothesizes that phytoestrogens and synthetic xenoestrogens resemble selective ER modulators (SERMs) and have initiated studies on structurally diverse organic xenoestrogens and metalloestrogens in breast cancer cells transfected with 17β-estradiol (E2)-responsive constructs containing GC-rich (pSp1₃) estrogen-responsive elements (pERE₃).  The results clearly demonstrate that both sets of estrogenic compounds exhibit highly variable activities that depend on promoter (pERE₃ vs. pSp1₃), cell (ZR-75 vs. MCF-7) context, and wild-type vs. variant ERα expression plasmid.  E2, sodium arsenite (100 μM), nickel chloride (10 - 100 μM), cadmium chloride (1 - 10 μM), and cobaltous chloride (10 - 100 μM) enhanced transactivation in MCF-7 cells transfected with pERE₃, whereas sodium selenite and sodium vanadate were inactive.  In contrast, sodium arsenite, nickel chloride, cadmium chloride, cobaltous chloride, sodium vanadate, but not sodium selenite, induced transactivation in MCF-7 cells transfected with pSp1₃.  Current studies are focused on further delineating mechanistic differences among metalloestrogens/organic xenoestrogens in both in vitro and in vivo models.