OXIDATIVE STRESS-INDUCED BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IS MEDIATED BY THE ARYL-HYDROCARBON (AH) RECEPTOR COMPLEX

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its bio isosteres involves binding to a specific TCDD (Aryl hydrocarbon (Ah)) receptor, interaction of this complex with chromatin, and the ultimate production of a pleiotropic response. The mechanism whereby toxic eff ects are produced following interaction of TCDD with the receptor comp lex is not known. Oxidative stress (OS) may play an important role in expression of the toxic manifestations of TCDD. TCDD has been shown to produce a dose- and time-dependent increase in superoxide anion from peritoneal lavage cells (PLC) (primarily macrophage). Therefore, to de termine if TCDD-induced production of superoxide anion by PLC is media ted through the Ah receptor, congenic mice were used which differ at t he Ah locus. One day after the administration of 5, 25, 50 or 125 mu g TCDD/kg p.o. as a single dose, 1.4-, 1.7-, 4.3- and 3.5-fold increase s, respectively, occurred in superoxide anion production by PLC from t he TCDD-responsive C57BL/6J (bb) mice relative to control cells. Howev er, only 125 mu g TCDD/kg produced a significant increase in superoxid e anion formation with PLC from the non-responsive C57BL/6J (dd) strai n of mice (1.7-fold increase). The role of the Ah receptor was further evaluated by utilizing the TCDD-resistant DBA/2 strain of mice, two T CDD congeners and in vitro studies. The combined results indicate that TCDD produces an oxidative stress in mice as measured by production o f superoxide anion, and this effect is controlled in part by the Ah re ceptor complex.