The accumulation of oxidative DNA damage has been hypothesized as a key event in chemical carcinogenesis. In this study, oxidative DNA damage was evaluated in the livers of rats exposed to vinyl chloride (VC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB153). Eight oxidative DNA adducts were measured, 8-hydroxyl-2'-deoxyguanosine (8-OHdG), 1, N6-etheno-2'-deoxyadenosine (ϵdA), N2, 3-ϵG, 1, N2-etheno-2'-deoxyguanosine (1, N2-ϵdG), 3-(2'-deoxy-β-d-erythro-pentofuranosyl) pyrimido[1,2-α]purin-10(3H) (M1dG), acrolein, crotonaldehyde and 4-HNE-derived dG adducts (assigned as AcrdG, CrdG, and 4-HNEdG respectively).
ϵdA is one of the promutagenic DNA adducts formed by VC, which can also be formed by lipid peroxidation. In this study, both adult and weanling Sprague-Dawley rats were exposed to 1100 ppm (13C 2)-VC for 1 week (6 h/day, 5 days/week). The results indicated that NA-ϵdA concentration did not show significant difference in the liver of adult and weanling rats after VC exposure. The distribution pattern of (13C2)-ϵdA in liver, lung and kidney indicated that liver was the dominant target organ for VC toxicity in both adult and weanling rats. ROS-induced DNA adducts were detected in the liver of female intact, ovariectomized (OVX) and male Sprague-Dawley rats, including 8-OHdG, 1, N6-ϵdA, AcrdG, and CrdG. These animals were exposed to TCDD for 30 weeks after diethylnitrosamine (DEN) initiation. Induction of these adducts was consistently found in liver DNA of TCDD-treated intact female rats and 17β-estradiol (E2) supplemented OVX female rats, but not detected in OVX rats without E 2 supplement or male rats. These results further confirmed that the induction of these adducts occurs via a sex-specific and estrogen-dependent mechanism reported previously. Oxidative DNA damage was measured in liver DNA of female Sprague-Dawley rats following 53-week exposure of PHAHs, including PCB153, PCB126, TCDD, and the ternary mixture of TCDD, PCB126 and PeCDF. Increases of 8-OHdG, N2, 3-ϵG and 1, N6-ϵdA were observed in PCB153 or PCB126 exposed animals. Significant increases of 1, N6-ϵdA were observed in all animals exposed to TCDD and the ternary mixture. Increases of 1, N 2-ϵdG, CrdG, AcrdG, 4-HNEdG and M1dG were detected in animals exposed to the ternary mixture, but not the TCDD treated rats compared to the control.
|Advisor:||Swenberg, James A.|
|Commitee:||Ball, Louise, Gold, Avram, Nakamura, Jun, Swenberg, James A., Walker, Nigel J.|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Environmental Sciences & Engineering|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 73/01, Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Environmental Health|
|Keywords:||DNA adducts, Oxidative DNA damage, Polyhalogenated aromatic hydrocarbons, Reactive oxygen species, Tetrachlorodibenzo-p-dioxin, Vinyl chloride|
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