Examination of the estrogenicity of 2,4,6,2',6'-pentachlorobiphenyl (PCB 104), its hydroxylated metabolite 2,4,6,2',6'-pentachloro-4-biphenylol (HO-PCB 104), and a further chlorinated derivative, 2,4,6,2',4',6'-hexachlorobiphenyl (PCB 155).

Abstract

Several studies have reported that polychlorinated biphenyls (PCBs) exhibit estrogenic activity; however, it is not clear if these responses are associated with the polychlorinated hydrocarbon or its hydroxylated metabolite. In order to further test this hypothesis, a battery of in vitro and in vivo assays were used to investigate the estrogenic and antiestrogenic activities of 2,4,6,2',6'-pentachlorobiphenyl (PCB 104), its para-hydroxylated derivative 2,4,6,2',6'-pentachloro-4-biphenylol (HO-PCB 104), and its para-chlorinated derivative 2,4,6,2',4',6'-hexachlorobiphenyl (PCB 155). PCB 104 was found to 1) compete with tritiated 17beta-estradiol (E2) for binding to the mouse uterine estrogen receptor (ER); 2) induce gene expression in MCF-7 human breast cancer cells transiently transfected with the Gal4-human ER chimeric construct (Gal4-HEGO) and the Gal4-regulated luciferase reporter gene (17m5-G-Luc); and 3) increase MCF-7 cell proliferation in a dose-dependent manner. HO-PCB 104 exhibited greater estrogenic activity than PCB 104 in the in vitro assays examined. However, gas chromatographic-mass spectrophotometric analysis of extracts prepared from MCF-7 cells incubated with PCB 104 failed to detect the presence of the expected major metabolite HO-PCB 104. The estrogenic activity of the para-chlorinated derivative, PCB 155, was minimal compared to PCB 104 and HO-PCB 104, but it did exhibit significant antiestrogenic activity following co-treatment with 1 nM E2. Co-treatment of PCB 104 with 1 nM E2 had no effect on reporter gene expression compared to E2 alone, while 10 microM HO-PCB 104 exhibited additivity with 1 nM E2. At a dose of 202 mg/kg,PCB 104 increased uterine wet weight in ovariectomized CD-1 mice and induced vaginal epithelial cell cornification at 202, 16, and 1.7 mg/kg in a dose-dependent manner. These studies demonstrate that in addition to the hydroxylated metabolites, selected parent PCB congeners may also exhibit estrogenic and antiestrogenic activities.

• Authors: M R Fielden, I Chen, B Chittim, S H Safe, T R Zacharewski
• Journal: Environmental health perspectives (Environ Health Perspect) Vol. 105 Issue 11 Pg. 1238-48 (Nov 1997) ISSN: 0091-6765 [Print] United States
• PMID: 9370515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Estrogen
• Estradiol
• Polychlorinated Biphenyls

Topics

• Animals
• Binding, Competitive
• Breast Neoplasms (etiology, genetics)
• Cell Division (drug effects)
• Dose-Response Relationship, Drug
• Estradiol (pharmacology, physiology)
• Female
• Gene Expression (drug effects)
• Humans
• In Vitro Techniques
• Mice
• Polychlorinated Biphenyls (adverse effects, metabolism, pharmacology)
• Receptors, Estrogen (drug effects, physiology)
• Uterus (cytology, drug effects)
• Vagina (cytology, drug effects)