Immunosuppressive activities of polychlorinated dibenzofuran congeners: quantitative structure-activity relationships and interactive effects.
The dose-response immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8- and 1,2,3,7,9-pentachlorodibenzofuran (PeCDF), 2,3,7,8- and 1,3,6,8-tetrachlorodibenzofuran (TCDF) on the splenic plaque-forming cell (PFC) response to sheep red blood cells were determined in C57BL/6 mice. The ED50 values for immunosuppression were 2.4, 3.0, 14.0, 710, and 35,700 nmol/kg for 2,3,7,8-TCDD, 2,3,4,7,8-PeCDF, 2,3,7,8-TCDF, 1,2,3,7,9-PeCDF, and 1,3,6,8-TCDF, respectively, and the results confirmed that lateral chlorine substitutions were important structural determinants for the toxicity of the polychlorinated dibenzofuran congeners. Interaction of both 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF with subimmunotoxic doses of 1,3,6,8-TCDF resulted in significant antagonism of the immunotoxic effects of both 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF. Previous studies have also demonstrated that 1,3,6,8-TCDF also antagonizes the induction of aryl hydrocarbon hydroxylase by 2,3,7,8-TCDD and analysis of competitive receptor binding studies suggests that 1,3,6,8-TCDF acts as a competitive partial antagonist of the action of 2,3,7,8-TCDD. The antagonism of 2,3,7,8-TCDD immunosuppression was found to be dependent on the timing of administration of 1,3,6,8-TCDF. Using a protocol in which 2,3,7,8-TCDD is administered 5 days prior to the antigen and 9 days prior to assessing the splenic PFC response, it was possible to partially antagonize the immunosuppressive effects of 2,3,7,8-TCDD by administering the antagonist up to 5 days after the initial dose of the toxin. Administration of 1,3,6,8-TCDF after the antigen does not afford any significant protection from the effects of 2,3,7,8-TCDD and these results are consistent with the hypothesis that 2,3,7,8-TCDD modulates some early event in B-cell differentiation. However, these results do not exclude a role for 2,3,7,8-TCDD in modulating other cellular processes associated with the PFC response.
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Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843.
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D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology* / Q000633:toxicity; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011108:Polymers; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors
D001572:Benzofurans; D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D011108:Polymers; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; C016068:polychlorodibenzofuran