Superfund Research Program

Structural Requirements for PCB-Induced Estrogenic Activity

Release Date: 12/10/1997

Some twenty-five years ago, polychlorinated biphenyl compounds (PCBs) were first associated with estrogenic activity. Evidence is accumulating that suggests these compounds are capable of interfering with the role of endogenous estrogen hormones in both humans and wildlife. Estrogen disruption by external agents is currently not well understood, however, it is hypothesized that such activity could lead to toxic effects such as cancer, neurological and reproductive effects, and other adverse health outcomes. There is mounting public health concern regarding these possibilities because PCBs are ubiquitous and persistent in the environment.

Past studies suggest that certain structural features, that is, ortho-chlorine and para-hydroxylation may be required for PCB-induced estrogenic activity. These observations provide a putative mechanism for PCB-potentiated human health effects. Scientists at the State University of New York (SUNY) - Albany are evaluating the estrogenic potential of PCBs and their metabolites by determining the metabolic mechanisms involved in PCB-induced estrogenic activity. These scientists propose that some PCBs are estrogenic and that this estrogenicity is dependent on the specific structure of the PCB and on its cytochrome P450 catalyzed metabolism to a hydroxylated metabolite. Testing of this hypothesis has been accomplished by determining the binding affinity of PCBs to the estrogen receptor, studying uterine weight increases in PCB-exposed rats, and evaluating the PCB-induced development of estrogen-dependent cell proliferation in cultures of MCF-7 human breast cell lines. The MCF-7 cell line is a well- established model of estrogen-responsive cells.

The 2,2',6,6'-tetrachlorobiphenyl (TCB) congener was examined to establish the role of tetra ortho substitution on estrogenic activity. This chlorine substitution pattern represents a non-planar compound and the data regarding the estrogenic activity of this compound would provide a basis for comparison for meta- and/or para-hydroxylated metabolites of this congener. The results of the experiments indicated no apparent estrogen receptor binding by TCB, which was consistent with other reports. However, this congener did exhibit significant estrogenic activity in both the in vitro MCF-7 assay and the in vivo uterotropic assay. Current studies are underway to determine whether low levels of hydroxylation occurring in tissues or subcellular preparations could result in estrogen receptor binding and thereby explain the estrogenic responses in the MCF-7 and uterotropic systems.

Additionally, the scientists examined the effect of mixtures of two hydroxylated PCBs (2,3,4,5-tetrachloro-4'-biphenylol and 2,4,6-trichloro-4'-biphenylol) on estrogenic activity because recent research reported that this combination elicited synergistic estrogenic effects six to ten times the activity of that of the individual congeners combined. Examination of the mixture of congeners indicated an absence of synergism in the MCF-7 assay and the estrogen binding assay. In addition, no evidence of synergistic activity was found in examination of a combination of 17 beta-estradiol and 2,4,6,-trichloro-4'-biphenylol in these assays. These results suggest that mixtures of two estrogenic hydroxylated PCBs were no more potent than addition of individual effects. More importantly, these results show that effective concentrations of an estrogenic hydroxylated PCB neither increased the maximum effect of 17 beta-estradiol nor resulted in synergistic activity. Based on these in vitro studies, greater than additive effects are not expected from exposure to PCB mixtures.

These studies are significant in that they elucidate the mechanism of estrogenic modulation of PCBs and demonstrate that there may not be a synergistic response to exposure to PCB mixtures. Results obtained from this research have refined the structural requirements for PCB-induced estrogenic activity and established the level of potency of the active congener relative to 17 beta-estradiol. With this information, scientists can determine which forms of PCBs are most harmful to human health and the environment, and thus remediation efforts can be targeted at these compounds and pathways.

For More Information Contact:

John F Gierthy
Wadsworth Center, New York State Department of Health
Empire State Plaza
Wadsworth Center
Albany, New York 12201
Phone: 518-474-8195

To learn more about this research, please refer to the following sources:

  • Gierthy JF, Arcaro KF, Floyd M. 1997. Assessment of PCB estrogenicity in a human breast cancer cell line. Chemosphere 34(5-7):1495-1505. PMID:9134682

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