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 bioisosteres 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 effects are produced following interaction of TCDD with the receptor complex 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 determine if TCDD-induced production of superoxide anion by PLC is mediated through the Ah receptor, congenic mice were used which differ at the Ah locus. One day after the administration of 5, 25, 50 or 125 micrograms TCDD/kg p.o. as a single dose, 1.4-, 1.7-, 4.3- and 3.5-fold increases, respectively, occurred in superoxide anion production by PLC from the TCDD-responsive C57BL/6J (bb) mice relative to control cells. However, only 125 micrograms TCDD/kg produced a significant increase in superoxide anion formation with PLC from the non-responsive C57BL/6J (dd) strain 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 TCDD congeners and in vitro studies. The combined results indicate that TCDD produces an oxidative stress in mice as measured by production of superoxide anion, and this effect is controlled in part by the Ah receptor complex.
Alsharif
N Z
NZ
School of Pharmacy and Allied Health, Creighton University Health Sciences Center, Omaha, NE 68178.
Lawson
T
T
Stohs
S J
SJ
D000818:Animals; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009580:Nitroblue Tetrazolium / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010529:Peritoneal Cavity / Q000166:cytology; D010533:Peritoneal Lavage; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*
D003574:Cytochrome c Group; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D009580:Nitroblue Tetrazolium; C000925:2,7-dichlorodibenzo-4-dioxin; D011078:Polychlorinated Biphenyls