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

Publication ,  Journal Article
Ramamoorthy, K; Vyhlidal, C; Wang, F; Chen, I; Safe, S; McDonnell, DP; Leonard, LS; Gaido, KW
Published in: Toxicol Appl Pharmacol
November 1997

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 17beta-estradiol (E2) (0.02 microg/kg/day x3) resulted in increased uterine wet weight, peroxidase activity and progesterone receptor binding. Treatment with 18, 73, 183 or 366 micromol/kg (x3) 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 as 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 10(3) to 10(4) 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 beta-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.

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Published In

Toxicol Appl Pharmacol

DOI

ISSN

0041-008X

Publication Date

November 1997

Volume

147

Issue

1

Start / End Page

93 / 100

Location

United States

Related Subject Headings

  • Uterus
  • Tumor Cells, Cultured
  • Transfection
  • Toxicology
  • Saccharomyces cerevisiae
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Polychlorinated Biphenyls
  • Peroxidases
  • Mice
 

Citation

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Ramamoorthy, K., Vyhlidal, C., Wang, F., Chen, I., Safe, S., McDonnell, D. P., … Gaido, K. W. (1997). Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol. Toxicol Appl Pharmacol, 147(1), 93–100. https://doi.org/10.1006/taap.1997.8281
Ramamoorthy, K., C. Vyhlidal, F. Wang, I. Chen, S. Safe, D. P. McDonnell, L. S. Leonard, and K. W. Gaido. “Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol.Toxicol Appl Pharmacol 147, no. 1 (November 1997): 93–100. https://doi.org/10.1006/taap.1997.8281.
Ramamoorthy K, Vyhlidal C, Wang F, Chen I, Safe S, McDonnell DP, et al. Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol. Toxicol Appl Pharmacol. 1997 Nov;147(1):93–100.
Ramamoorthy, K., et al. “Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol.Toxicol Appl Pharmacol, vol. 147, no. 1, Nov. 1997, pp. 93–100. Pubmed, doi:10.1006/taap.1997.8281.
Ramamoorthy K, Vyhlidal C, Wang F, Chen I, Safe S, McDonnell DP, Leonard LS, Gaido KW. Additive estrogenic activities of a binary mixture of 2',4',6'-trichloro- and 2',3',4',5'-tetrachloro-4-biphenylol. Toxicol Appl Pharmacol. 1997 Nov;147(1):93–100.
Journal cover image

Published In

Toxicol Appl Pharmacol

DOI

ISSN

0041-008X

Publication Date

November 1997

Volume

147

Issue

1

Start / End Page

93 / 100

Location

United States

Related Subject Headings

  • Uterus
  • Tumor Cells, Cultured
  • Transfection
  • Toxicology
  • Saccharomyces cerevisiae
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Polychlorinated Biphenyls
  • Peroxidases
  • Mice