STIMULATION OF NADPH-DEPENDENT REACTIVE OXYGEN SPECIES FORMATION AND DNA-DAMAGE BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IN RAT PERITONEAL-LAVAGE CELLS

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] and its con geners involves binding to a specific TCDD [Ah] receptor, interaction of this complex with chromatin, and the ultimate production of pleiotr opic responses. The mechanism whereby these effects are produced follo wing interaction of TCDD with the receptor complex is not known. Oxida tive stress following the production of reactive oxygen species (ROS) may play an important role in the toxic manifestations of TCDD. Thus, the dose and time-dependent effects of TCDD on the production of super oxide anion by peritoneal lavage cells (primarily macrophages) from ra ts were examined. A maximum increase in superoxide anion production oc curred on day 1 after treatment in rats with 50 and 125 mug TCDD/kg. A t 6 h after a single dose of 125 mug TCDD/kg, a 2.4-fold increase in s uperoxide anion production was observed in peritoneal lavage cells fro m rats. A single dose of 5 mug TCDD/kg had no effect on superoxide ani on production by peritoneal lavage cells. A significant increase in DN A single strand breaks within peritoneal lavage cells occurred at 12 h after the oral administration of 50 mug TCDD/kg, and a maximum increa se in DNA single strand breaks was observed on days 3-5 after treatmen t. No DNA damage was detected at a dose of 5 mug TCDD/kg. No differenc e was observed with respect to dose and time in the composition of the peritoneal lavage cells. The results clearly indicate that the oral a dministration of TCDD activates peritoneal lavage cells in rats, and t hat the activation precedes the formation of DNA single strand breaks. The results support the hypothesis that the tissue damage by TCDD may be due, at least in part, to the formation of reactive oxygen species , and macrophages may serve as one source of reactive oxygen species i n response to TCDD.