Elsevier

Toxicology

Volume 69, Issue 2, 1991, Pages 187-197
Toxicology

6-Alkyl-1,3,8-trichlorodibenzofurans as antiestrogens in female Sprague-Dawley rats

https://doi.org/10.1016/0300-483X(91)90230-XGet rights and content

Abstract

The comparative antiestrogenic effects of 6-methyl-1,3,8-trichlorodibenzofuran (MCDF), 6-t-butyl-1,3,8-trichlorodibenzofuran (triCDF) and 6-cyclohexyl-1,3,8-triCDF were determined in immature female Sprague-Dawley rats. Treatment of the animals with 17β-estradiol (0.33 μmol/kg × 2) caused an increase in uterine cytosolic and nuclear estrogen and progesterone receptor levels, uterine peroxidase activity, uterine wet weights and uterine epidermal growth factor (EGF) receptor binding activity and steady state EGF receptor mRNA levels. MCDF and 6-t-butyl-1,3,8-triCDF, two compounds which exhibit moderate aryl hydrocarbon (Ah) receptor binding affinity were also administered (100 μmol/kg) to the female rats in the presence or absence of 17β-estradiol. The results of these studies show that both compounds decrease the constitutive and 17β-estradiol-induced responses noted above. In contrast, 6-cyclohexyl-1,3,8-triCDF, a congener which exhibits low Ah receptor binding, was inactive as an antiestrogen. These studies clearly demonstrate that selected 6-alkyl-1,3,8-triCDFs elicit a broad spectrum of antiestrogenic activity in immature female rats. Moreover, in contrast to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which also is a potent antiestrogen, the 6-alkyl-1,3,8-triCDFs are relatively non-toxic and can serve as prototypes for the future development of a new class of antiestrogens with potential for clinical applications.

References (24)

Cited by (21)

  • Effects of the aryl hydrocarbon receptor agonist 3-methylcholanthrene on the 17β-estradiol regulated mRNA transcriptome of the rat uterus

    2017, Journal of Steroid Biochemistry and Molecular Biology
    Citation Excerpt :

    Nevertheless, initial evidence for the antiestrogenic effect of the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stems from uterotrophic assays, [11–13] showing that treatment with TCDD and other AHR ligands caused a decreased responsiveness of uterine wet weight to E2 and decreased hepatic and uterine ER and PR levels, leading to a diminished activity of the associated pathways. Furthermore antiestrogenic effects of TCDD in the uterus have been shown on a number of additional endpoints like peroxidase activity and EGFR binding activity [14,15]. This suggests that antiestrogenic effects of AHR ligands are of a global nature rather than being limited to the regulation of the expression of a small number of specific genes, but this has not been confirmed to date.

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