Immunosuppressive activities of polychlorinated biphenyls in C57BL/6N mice: structure-activity relationships as Ah receptor agonists and partial antagonists.
The immunosuppressive activity of polychlorinated biphenyl (PCB) congeners is structure-dependent and 2 classes of compounds, namely the coplanar (class I) and monoortho coplanar (class II) congeners exhibit immunotoxicity. This study extends the structure-immunotoxicity relationships for PCBs by investigating representative congeners from the following structural classes of PCBs: monoortho coplanar (2,3,3',4,4',5-hexachlorobiphenyl, class II); monoortho coplanar minus a single parachloro group (2,3,3',4,5,5'-hexachlorobiphenyl and 2,3,3',4,5'-pentachlorobiphenyl, class III); diortho coplanar (2,3',4,4',5',6-hexachlorobiphenyl, class IV); triortho coplanar (2,2',4,4',5,6'-hexachlorobiphenyl, class V) and a tetraortho-substituted PCB (2,2',4,4',6,6'-hexachlorobiphenyl, class VI). The effects of these compounds on the splenic plaque forming cell response to sheep red blood cells was determined in 7-8 week old male C57BL/6N mice. The results showed that the class II-IV congeners were immunotoxic and with only one exception these compounds also induced hepatic microsomal aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase activities and displaced [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from the cytosolic aryl hydrocarbon (Ah) receptor in competitive binding assays. These results thus extend the structure-activity relationships for PCBs as Ah receptor agonists. The interaction of these PCB congeners with an ED70-90 dose of TCDD (3.7 nmol/kg) showed that only one structural class of compounds, namely class III, partially antagonized TCDD-mediated immunotoxicity.
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Department of Veterinary Physiology, Texas A&M University, College Station 77843.
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D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D011078:Polychlorinated Biphenyls