Harper N, Howie L, Connor K, Arellano L, Craig A, Dickerson R, Safe S
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.
Fundam Appl Toxicol. 1993 May;20(4):496-502. doi: 10.1006/faat.1993.1060.
The dose-response effects of 2,2',3,3',4,5,5',6,6'-2,2',3,3',4,4',5,6,6'- and 2,2',3,3',4,4',5,5',6- nonachlorodiphenyl ether (non-aCDE) and decachlorodiphenyl ether (decaCDE) on the splenic plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) and the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was determined in aryl hydrocarbon (Ah)-responsive C57BL/6 and less Ah-responsive DBA/2 mice. All the congeners exhibited immunotoxicity at doses between 2.5 and 10 mumol/kg in C57BL/6 mice whereas in DBA/2 mice doses > or = 25 mumol/kg were required to cause inhibition of the PFC response to SRBCs. The results also showed that the nonaCDE isomers and decaCDE were more active as inducers of hepatic EROD activity in C57BL/6 than DBA/2 mice; however, there was not a correlation between the induced EROD activity and the CYP1A1 and CYP1A2 mRNA levels in the C57BL/6 mice. These data suggested that the immunotoxicity of these compounds was mediated through the Ah receptor. However, the results showed that the immunotoxicity of the nonaCDE isomers and decaCDE was unexpectedly high compared to that of lower chlorinated diphenyl ethers and there were no apparent structure-activity relationships among the higher chlorinated congeners. This suggests that some of the immunosuppressive effects observed for the nonaCDE isomers and decaCDE may be Ah receptor-independent.
在芳烃（Ah）反应性的C57BL/6小鼠和Ah反应性较低的DBA/2小鼠中，测定了2,2',3,3',4,5,5',6,6'-2,2',3,3',4,4',5,6,6'-和2,2',3,3',4,4',5,5',6-九氯二苯醚（非aCDE）以及十氯二苯醚（十氯CDE）对脾脏空斑形成细胞（PFC）对绵羊红细胞（SRBC）反应的剂量-反应效应，以及对肝微粒体乙氧芴香豆素O-脱乙基酶（EROD）活性的诱导作用。在C57BL/6小鼠中，所有同系物在2.5至10 μmol/kg的剂量下均表现出免疫毒性，而在DBA/2小鼠中，需要≥25 μmol/kg的剂量才能抑制PFC对SRBC的反应。结果还表明，在C57BL/6小鼠中，非aCDE异构体和十氯CDE作为肝EROD活性诱导剂比DBA/2小鼠更具活性；然而，在C57BL/6小鼠中，诱导的EROD活性与CYP1A1和CYP1A2 mRNA水平之间没有相关性。这些数据表明，这些化合物的免疫毒性是通过Ah受体介导的。然而，结果表明，与低氯代二苯醚相比，非aCDE异构体和十氯CDE的免疫毒性意外地高，并且在高氯代同系物之间没有明显的构效关系。这表明，观察到的非aCDE异构体和十氯CDE的一些免疫抑制作用可能与Ah受体无关。
