Immunosuppressive and monooxygenase induction activities of polychlorinated diphenyl ether congeners in [formula omitted] mice: Quantitative structure-activity relationships

Abstract

The dose-response effects of several polychlorinated diphenyl ether (polyCDE) congeners on the inhibition of the splenic plaque-forming cell (PFC) response to sheep red blood cell antigen and the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities were determined in male C57BL 6 mice. The immunotoxic potencies for the polyCDE congeners (ED50 values for the suppression of PFCs/spleen and PFCs/10 6 cells) followed the order 2,3,3′,4,4′,5-hexaCDE (0.5 and 2.2 μmol/kg)> 3,3′,4,4′,5-pentaCDE (8.8 and 5.1 μmol/kg) > 2,3′,4,4′,5-pentaCDE (21.8 and 14.2 μmol/kg) > 3,3′,4,4′-tetraCDE (50.6 and 28.7 μmol/kg) > 2,2′,4,4′,5,5′-hexaCDE (81.2 and 56.5 μmol/kg) > 2,2′,4,5,5′-pentaCDE (258 and 228 μmol/kg) > 2,2′,4,4′,5,6′-hexaCDE (>400 μmol/kg for both responses). The potencies of the polyCDE congeners as inducers of hepatic microsomal AHH and EROD activities were similar to their immunotoxicities and only one compound, namely, 2,3′,4,4′,5,5′-hexaCDE, did not cause dose-response immunosuppressive effects in the mice. The structure-activity relationships for the polyCDEs exhibited both differences and similarities. For example, the coplanar 3,3′,4,4′-tetraCDE and 3,3′,4,4′,5-pentaCDE congeners were less immunotoxic than their monoortho 2,3′,4,4′,5-pentaCDE and 2,3,3′,4,4′,5-hexaCDE analogs, respectively, and similar results were also observed for their enzyme induction potencies. For the corresponding polychlorinated biphenyls (PCB) congeners the coplanar compounds were significantly more active than their monoortho analogs. In addition, two diortho-substituted compounds, namely, 2,2′,4,5,5′-pentaCDE and 2,2′,4,4′,5,5′-hexaCDE, were also immunotoxic at a dose of 400 μmol/kg whereas, their PCB analogs were inactive. These studies clearly demonstrate that for the polyCDE congeners, increasing ortho-chloro substitution is less effective in reducing the activity of these congeners compared to the well-recognized ortho effects reported for the PCBs. The differences in the structure-activity relationships between polyCDEs and PCBs are related to the ether bridge in the polyCDEs in which the resultant increased bond length beweeen the two phenyl rings thereby diminishes the effects of ortho substituents on the biochemical and toxic potencies of these compounds.