Davis D, Safe S
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843.
Toxicol Appl Pharmacol. 1988 Jun 15;94(1):141-9. doi: 10.1016/0041-008x(88)90344-4.
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.
在C57BL/6小鼠中测定了2,3,7,8-四氯二苯并 - 对 - 二恶英（TCDD）、2,3,4,7,8-和1,2,3,7,9-五氯二苯并呋喃（PeCDF）、2,3,7,8-和1,3,6,8-四氯二苯并呋喃（TCDF）对脾脏针对绵羊红细胞的空斑形成细胞（PFC）反应的剂量 - 反应免疫抑制作用。2,3,7,8-TCDD、2,3,4,7,8-PeCDF、2,3,7,8-TCDF、1,2,3,7,9-PeCDF和1,3,6,8-TCDF免疫抑制的半数有效剂量（ED50）值分别为2.4、3.0、14.0、710和35,700 nmol/kg，结果证实苯环上氯原子的位置是多氯二苯并呋喃同系物毒性的重要结构决定因素。2,3,7,8-TCDD和2,3,4,7,8-PeCDF与亚免疫毒性剂量的1,3,6,8-TCDF相互作用，导致2,3,7,8-TCDD和2,3,4,7,8-PeCDF的免疫毒性作用显著拮抗。先前的研究还表明，1,3,6,8-TCDF也能拮抗2,3,7,8-TCDD诱导的芳烃羟化酶，竞争性受体结合研究分析表明，1,3,6,8-TCDF作为2,3,7,8-TCDD作用的竞争性部分拮抗剂。发现2,3,7,8-TCDD免疫抑制的拮抗作用取决于1,3,6,8-TCDF的给药时间。采用在抗原前5天给予2,3,7,8-TCDD并在评估脾脏PFC反应前9天给药的方案，在毒素初始剂量后长达5天给予拮抗剂有可能部分拮抗2,3,7,8-TCDD的免疫抑制作用。在抗原后给予1,3,6,8-TCDF不能对2,3,7,8-TCDD的作用提供任何显著保护，这些结果与2,3,7,8-TCDD调节B细胞分化中某些早期事件的假设一致。然而，这些结果并不排除2,3,7,8-TCDD在调节与PFC反应相关的其他细胞过程中的作用。
