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

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.