Correlations between polychlorinated biphenyl immunotoxicity, the aromatic hydrocarbon locus, and liver microsomal enzyme induction in C57BL/6 and DBA/2 mice.
The suppression of the antibody response by polychlorinated biphenyls (PCB) in mice is dependent on the planarity of the PCB molecule and on the expression of the aromatic hydrocarbon (Ah) receptor. In this study, the hypothesis that this form of immunotoxicity is a consequence of the activation of the Ah gene complex and that other compounds which are Ah receptor ligands would also be immunotoxic was tested. 2,2',4,4'-Tetrachlorobiphenyl (TCB), 2,3,3',4,4',5-hexachlorobiphenyl (HCB), phenobarbital (PB), or beta-naphthoflavone (BNF) was given ip to either C57BL/6 (B6,Ahb/Ahb) or DBA/2 (D2, Ahd/Ahd) mice 2 days before immunization with sheep erythrocytes. Organ weights, histopathology, hemagglutinating antibody titers, and the splenic direct antibody plaque-forming cell (PFC) response were evaluated on Day 5. Hepatic aryl hydrocarbon hydroxylase (AHH) induction by these compounds and by 2,2',5,5'-TCB and 3,3',4,4'-TCB was measured as an indicator of Ah receptor binding and subsequent activation of the Ah gene complex by methylcholanthrene-type inducers, while aminopyrine N-demethylase (APND) was measured as an indicator of PB-type induction. 2,2',4,4'-TCB and PB had no effects on the immune parameters of either strain but induced APND activity in both strains. 2,2',5,5'-TCB slightly induced APND activity in B6 mice. 2,3,3',4,4',5-HCB caused a 70% suppression of PFC per spleen, decreased the serum antibody titer, elevated cytochrome P-450 levels (193%), induced both APND (165%) and AHH (217%) activity in B6 mice, but it induced only APND (156%) activity in D2 mice. 3,3',4,4'-TCB elevated cytochrome P-450 levels (210%) and induced both APND (129%) and AHH (321%) activities in B6 mice but only increased APND activities (115%) in D2 mice. BNF elevated cytochrome P-450 (144%), caused a 49% suppression in PFC per spleen, and induced both APND (156%) and AHH (248%) activities but only in B6 mice. These results support the hypothesis that the immunotoxicity caused by halogenated and polycyclic aromatic hydrocarbons is a consequence of activation of the Ah gene complex and suggests that this toxic effect can be initiated by any Ah receptor ligand.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D006384:Hemagglutination / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D009929:Organ Size; D011078:Polychlorinated Biphenyls / Q000276:immunology* / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology
D011422:Propionates; C011677:benoxaprofen; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; D000633:Aminopyrine N-Demethylase