Antiestrogenic and immunotoxic effects of polychlorinated dibenzo-p-dioxins and dibenzofurans : mechanistic studies

Typescript (photocopy).Polychlorinated dibenzo-p-dioxins and dibenzofurans are environmental contaminants which elicit a number of toxic and biochemical effects including immunotoxicity, hepatic microsomal monooxygenase induction and enodcrine effects. The dose-response effects of 4 heptachlorodibenzofurans (HpCDF) on the splenic plaque forming cell (PFC) response to sheep erythrocytes and on the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-Odeethylase (EROD) were determined in male C57B1/6 mice. The 2,3,7,8-substituted HpCDF isomers (1,2,3,4,6,7,8- and 1,2,3,4,7,8,9-HpCDF) were significantly more potent than the isomers which contained only three lateral chlorine groups and the results were similar using either a multiple dosing (10) or a single dosing regimen. The 2.3.7.8-substituted HpCDFs were approximately one-tenth as potent as 2,3,7,8- tetrachloro-dibenzo-p-dioxin (2,3,7,8-TCDD). The antiestrogenic activity of 15 alkylated dibenzo-p-dioxins and dibenzofurans were investigated in the female Sprague-Dawley rat uterus. All of the compounds tested exhibited similar antiestrogenic potencies, however one congener, namely 6-isopropyl1.3.8-trichlorodibenzofuran showed relatively high antiestrogenic potency but was a poor inducer of hepatic microsomal EROD activity (a measure of toxicity). The estrogenic properties of 6-nitro-1,3,8-trichlorodibenzofuran (6-NCDF) were also investigated. Administration of 6-NCDF caused a dose- and time-dependent increase in uterine wet weight, cytosolic and nuclear estrogen (ER) and progesterone receptor (PR) levels in immature female Sprague-Dawley rats. In contrast, 6-NCDF did not increase uterine peroxidase or epidermal growth factor receptor binding activities. 2.3.7.8-TCDD, a known antiestrogen inhibited the uterotrophic effect but not the increase in uterine ER and PR binding activity induced by 6-NCDF. 6-NCDF competitively bound to the uterine Ah receptor but not to the ER or the PR. The effects of 2,3,7,8-TCDD on androgen receptor binding were measured in both male and female Sprague-Dawley rats. 2,3,7,8-TCDD caused a significant increase in the AR binding activity in the urogenital sinus of adult male rats. In 21-day old male and female rats, 2,3,7,8-TCDD caused a significant increase in the cytosolic AR binding in the testes and the uterus