Superfund Research Program
PCB Estrogenicity in Human Breast Cells
Project Leader: John F. Gierthy (Wadsworth Center, New York State Department of Health)
Grant Number: P42ES004913
Funding Period: 1995 - 2000
- Project Summary
Final Progress Reports
Polychlorinated biphenyls (PCBs) are metabolized by hydroxylation; some of these hydroxylated metabolites exhibit estrogen-like activity in animal models. Because PCBs may have effects on human health, it is of interest to determine if human tissues also metabolize PCBs to potentially estrogenic metabolites. In this study project investigators have examined metabolites of seven PCBs with different degrees and positions of chlorination, generated by human liver microsomal reaction mixtures (MRM), and tested their affinity for human recombinant estrogen receptor-a (ER) before and after HPLC fractionation. Two of the three MRMs with di-chloro-biphenyls (BPs, 2,5BP and 3,4BP), one of the three MRMs with tetra-BPs (2,6,2',6'BP), and one hexa-BP (2,4,6,2',4',6'BP) generated metabolites that competed for ER. HPLC of the ER-binding MRMs generated fractions that also exhibited ER-binding. This study shows the usefulness of combining in vitro metabolism and an ER-binding assay in initial identification of PCBs with estrogen-modulating potential.
Toxaphene Is Not Estrogenic in the MCF-7 Focus Assay
Toxaphene is a complex mixture of chlorinated boranes, bornenes and bornadienes. It was heavily used in the US as an insecticide until its ban in 1982. Toxaphene is one of the most abundant organochlorine pesticides in Arctic aquatic life and is one of the major contaminants of fish from the Great Lakes as well as other small and large lakes around the world. The widespread distribution and abundance of toxaphene attests to its continued input and persistence in the environment.
Recently it has been suggested that toxaphene, either alone or in a binary mixture with other pesticides, acts as an estrogen. Other reports have concluded that toxaphene is either non estrogenic or very weakly estrogenic. Because of the public concern over environmental estrogens we have examined the estrogenicity of toxaphene in two human-based assays. Researchers tested toxaphene in the MCF-7 focus assay and in a competitive binding assay using recombinant human estrogen receptor.
Results from the MCF-7 focus assay showed: 1) toxaphene alone was not estrogenic between the concentrations of 0.5 nM and 10 uM, 2) there was no synergism between toxaphene and either dieldrin, endosulfan, or chlordane, and 3) toxaphene was weakly antiestrogenic (it reduced the number of foci produced by 1 nM 17 b-estradiol). Results from the competitive binding assay showed 1) toxaphene alone did not bind to the human estrogen receptor, and 2) toxaphene in binary combinations with other pesticides also did not bind to the human estrogen receptor. These data do not support the hypothesis that toxaphene is estrogenic. Indeed, toxaphene was found to be a weak antiestrogen which is in agreement with published results showing that toxaphene increases the metabolism of estrone and inhibits the increase in estrone-dependent uterine wet weight in immature rats. Further studies will address the estrogenicity and/or antiestrogenicity of toxaphene in wildlife populations.