In this project, we propose that long-term exposure of rats to 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), induces oxidative stress in the brain and hepatic tissues of those in rats. Similar effects, though smaller than those induced by TCDD, can be also produced in the same tissues, following exposure to the TCDD congeners. Also, TCDD-induced oxidative stress in brain and hepatic tissues can be modulated by simultaneous exposure to TCDD and its congeners. To test this hypothesis, groups of female Harlan Sprague-Dawley rats will be treated daily at the NIEHS, with different doses of TCDD, 2,3,4,7,8- pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or combinations of various concentrations of TCDD + PeCDF + PCB 126, for 13 to 30 weeks. At the end of the treatment periods, rats will be sacrificed at the NIEHS, and specimens from brain and hepatic tissues of those rats will immediately shipped to our laboratories, over dry ice. The biomarkers of oxidative stress will be determined in those tissues within a period of no longer than 6 weeks following the receipt of the specimens. The formation of reactive oxygen species in those tissues will be determined, using the cytochrome c and the idonitrotetrazolium violet (INT) reduction assays, and the induction of the processes of lipid peroxidation and DNA-single strand breaks (SSB) will be measured, using the thiobarbituric acid reactive substances (TBARS) assay and the alkaline elution technique, respectively. The ED-50 values of those chemicals in each tissue, will be calculated and compared. To our knowledge, the study will be the first to quantitatively estimate and compare the amount of oxidative tissue damage in the hepatic and brain tissues of rats, following long-term exposure to TCDD and/or its congeners. The study will also provide basis for future investigations on the involvement of this mechanism in the neurobehavioral changes and other toxic effects of TCDD and its congeners, in the TCDD-exposed human populations.
