Fetal thymus organ culture as an in vitro model for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.
Fetal thymuses from C57BL/6 (B6) and DBA/2J (D2) mice from gestation day 14 or 15 were explanted and grown for 2 and 6 days in culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and a number of its congeners, known ligands of the Ah receptor (Ah, designating genetic locus for aryl hydrocarbon responsiveness). TCDD and 2,3,7,8-tetrachlorodibenzofuran (TCDBF) showed the same toxicity to B6 thymuses with a 50% inhibition of lymphoid development (EC50) at 10(-10) M concentration. 3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) was only 2-10 times less effective, while the EC50 of 3,3',4,4'-tetrachlorobiphenyl (TCB) was around 10(-8) M (100 times higher than that of TCDD). TCBs with chlorine atoms in the position close to the biphenyl bridge were nontoxic even at 10(-5) M concentration. Thymuses exposed to TCDD, TCDBF, and TCAOB in vivo at teratogenic doses given to the mothers and explanted 24-48 hr later were smaller and inhibited in their early in vitro growth, but recovered slowly (less rapid for TCDD) as judged by lymphoid cell counts and [3H]thymidine incorporation. These results indicate a good correlation for this group of compounds between their activity as ligands of the Ah receptor and toxicity in vitro. Other ligands of the Ah receptor, namely 3-methylcholanthrene and beta-naphthoflavone, were inactive at the highest concentrations tested (10(-6) M). Thymuses from D2 mice, considered Ah receptor-defective, were nonsensitive to TCDD at the concentrations used (up to 3 X 10(-8) M) after 2 days in culture, indicating more than 100 times lower sensitivity as compared to B6 thymuses. After 6 days in culture, their sensitivity was however only 1 order of magnitude lower than that of B6 thymuses. Therefore "low sensitivity" of D2 thymuses may be at least partially overcome by prolonged exposure to TCDD in vitro.
D000818:Animals; D004147:Dioxins / Q000633:toxicity*; D005260:Female; D005333:Fetus; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009924:Organ Culture Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity*; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins