Additive estrogenic activities of a binary mixture of 2',4',6'-Trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol

K. Ramamoorthy, C. Vyhlidal, F. Wang, I. C. Chen, S. Safe, D. P. McDonnell, L. S. Leonard, K. W. Gaido

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

The estrogenic activity of 2',4',6'-trichloro-4-biphenylol (HO-PCB3), 2',3',4,5'-tetrachloro-4-biphenylol (HO-PCB4), and an equimolar mixture of both compounds (HO-PCB3/HO-PCB4) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 and MDA-MB-231 human breast cancer cells, HepG2 cells, and in a yeast-based reporter gene assay. Treatment of the animals with 17β-estradiol (E2) (0.02 μg/kg/day x 3) resulted in increased uterine wet weight, peroxidase activity and progesterone receptor binding. Treatment with 18, 73, 183 or 366 μmol/kg (x 3) doses of HO-PCB3, HO-PCB4, or HO-PCB3/HO-PCB4 (equimolar) caused a dose-dependent increase in estrogenic activity; a maximal-induced response was not observed at any dose and the activity of the mixture was additive. Binding of E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 to the mouse uterine estrogen receptor (ER) was determined in a competitive binding assay using [3H]E2 os the radioligand. The IC50 values were 1.1 x 10-8, 3.4 x 10-6, 9.9 x 10-7, and 4.25 x 10-6 M, respectively. HO-PCB3 and HO-PCB4 maximally induced MCF-7 cell proliferation, rat creatine kinase, and human complement C3 (C3-LUC) reporter gene activity at concentrations of 10-5 to 10-6 M, and these compounds were 103 to 104 less potent than E2. The HO-PCB3/HO-PCB4 mixture was active at the high concentration (10-5 M) and was additive for these responses. HO-PCB3 and HO-PCB4 also exhibited estrogenic activity in human HepG2 cells cotransfected with C3-LUC and an ER expression plasmid, and the estrogenic activity of the HO-PCB mixture was additive. Similar results were obtained in yeast transformed with the human ER and a double estrogen responsive element upstream of the P-gal reporter gene. The effects of variable ER expression on the potential synergistic interactions of HO-PCB3/HO-PCB4 were investigated in HepG2 cells cotransfected with C3-LUC (405 ng/well) and variable amounts of ER expression plasmid (270, 27, 2.7, or 0.27 ng/well). The results show that as ER levels decreased, the magnitude of the induction response by E2, HO-PCB3, HO-PCB4, and HO-PCB3/HO-PCB4 also decreased. However, the activities of the HO-PCB mixture were additive at high and low levels of ER. Similar results were obtained in MDA-MB-231 cells cotransfected with C3-LUC and variable amounts of ER expression plasmid. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus; MCF-7, HepG2, and MDA-MBA-231 human cancer cells; and a yeast based-reporter gene assay, both HO-PCB3 and HO-PCB4 exhibited estrogenic activity. The estrogenic activity of an equimolar mixture of these compounds was additive at high and low levels of ER expression.

Original languageEnglish (US)
Pages (from-to)93-100
Number of pages8
JournalToxicology and Applied Pharmacology
Volume147
Issue number1
DOIs
StatePublished - Nov 1997
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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