Immunotoxic effects of polychlorinated diphenyl ethers, biphenyls and dibenzofurans : quantitative structure-activity relationships and role of the Ah receptor

Typescript (photocopy).The role of the aryl hydrocarbon (Ah) receptor in mediating the immunotoxic effects of several polychlorinated diphenyl ethers (PCDEs), polychlorinated biphenyls (PCBs), and alkyl-substituted polychlorinated dibenzofurans (PCDFs) on the murine splenic plaque-forming cell (PFC) response to the T-cell dependent antigen, sheep red blood cells (SRBCs) was investigated. The quantitative structure-immunotoxic and structure-induction activities for eight PCDE congeners were examined in C57BL/6 (Ah responsive) mice, and the results showed that the PCDEs exhibited different structure-activity relationships that differed from those previously reported for the structurally-related PCBs. Four of these PCDE congeners were tested in DBA/2 (Ah non-responsive) mice, and the results showed that additional mechanisms other than the Ah receptor may be involved in the immunosuppression by these compounds, since certain congeners were approximately equipotent in both strains. The potencies of these PCDE congeners were compared to 2,3,7,8-TCDD and toxic equivalency factors (TEFs) were proposed. Studies of the higher chlorinated PCDEs and PCBs were also carried out in C57BL/6 mice. All of the compounds caused dose-dependent immunosuppression; however, only one of the PCDE congeners, namely $2,2',3,3',4,4',5,6,6'-nonaCDE, significantly induced high levels of hepatic microsomal ethoxyresorufin-O-deethylase activity, and none of the PCBs induced these activities at any of the doses tested. These results indicate the involvement of additional factors other than the Ah receptor in mediating the immunotoxic effects observed for the higher chlorinated compounds. The dose-response immunotoxic effects of the laterally-substituted PCB congeners were examined in C57BL/6 mice, and the relative immunotoxicity of these compounds was similar to their potencies for other Ah receptor-mediated responses. The immunosuppressive activity of several alkyl-substituted PCDFs was also investigated in C57BL/6 mice; these compounds exhibited a wide range of potencies which were not entirely overlapping with their relative activities for other Ah receptor-mediated responses including antiestrogenicity in the female rat uterus, induction of EROD activity in the rat, and Ah receptor binding in rat cytosol. These data also suggest that the immunosuppression caused by these compounds in C57BL/6 mice may not be mediated through the Ah receptor