Immunotoxicity of the halogenated aromatic hydrocarbons- QSARs and interactive effects

Abstract

The role of the aryl hydrocarbon (Ah) receptor in mediating the immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and related halogenated aromatic hydrocarbons (HAHs) on the murine splenic plaque-forming cell (PFC) response to the T-cell dependent antigen, sheep red blood cell (SRBC), was investigated in this research. Both the in vivo and in vitro (Mishell-Dutton) models for this immunotoxic response were utilized in these studies. The in vivo structure-immunotoxicity relationships for a series of five polychlorinated dibenzofurans (PCDFs) and seven polychlorinated biphenyls (PCBs) were evaluated in C57BL/6 (Ah-responsive) mice and the results showed that there was a good correlation with previous structure-activity relationship studies for other putative Ah receptor-mediated responses. In addition, the partial antagonism of 2,3,7,8-TCDD-induced suppression of the in vivo PFC response by 1,3,6,8-TCDF, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF), several commercial PCB mixtures, and the selected PCB congeners was observed in C57BL/6 mice and these data also support a receptor-mediated mechanism of action. Studies utilizing spleen cell cultures from both C57BL/6 (Ah-responsive) and DBA/2 (Ah-nonresponsive) mice for the splenic PFC response to SRBCs did not support an Ah receptor-mediated mechanism of action for HAH-induced immunosuppression. The same series of PCDF congeners which were investigated in vivo were also evaluated in the in vitro model and the data showed an absence of a structure-dependent immunosuppression by the PCDFs. These results contrasted with those obtained the in vivo studies and suggested the mode of action was independent of the Ah receptor protein. Moreover, studies on the partial antagonism of 2,3,7,8-TCDD-induced immunosuppression by 2,2',4,4',5,5'-HCBP and α-naphthoflavone also did not support a receptor-mediated mechanism of action for the in vitro model.