Polychlorinated biphenyls (PCBs) are organic chemicals that were traditionally produced and widely used in industry as mixtures and are presently formed as by-products of pigment and dye manufacturing. They are known to persist and bioaccumulate in the environment. Some have been shown to induce liver cancer in rodents. Although the mechanism of the toxicity of PCBs is unknown, it has been shown that they increase oxidative stress, including lipid peroxidation. The authors hypothesised that oxidative stress-induced DNA damage could be a contributor for PCB carcinogenesis and analysed several DNA adducts in female Sprague-Dawley rats exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB 153), and a binary mixture (PCB 126 + 153) for 14, 31, and 53 wks. Eight adducts were measured to profile oxidative DNA lesions, including 8-oxo-deoxyguanosine (8-oxo-dG), 1,N(6)-ethenodeoxyadenosine (1,N(6)-?dA), N(2),3-ethenoguanine (N(2),3-?G), 1,N(2)-ethenodeoxyguanosine (1,N(2)-?dG), as well as malondialdehyde (M1dG), acrolein (AcrdG), crotonaldehyde (CrdG), and 4-hydroxynonenal-derived dG adducts (HNEdG) by LC-MS/MS analysis. Statistically significant increases were observed for 8-oxo-dG and 1,N(6)-?dA concentrations in hepatic DNA of female rats exposed to the binary mixture (1000 ng/kg/day + 1000 ?g/kg/day) but not in rats exposed to PCB 126 (1000 ng/kg/day) or PCB 153 (1000 ?g/kg/day) for 14 and 31 wks. However, exposure to PCB 126 (1000 ng/kg/day) for 53 weeks significantly increased 8-oxo-dG, 1,N(6)-?dA, AcrdG, and M1dG. Exposure to PCB 153 (1000 ?g/kg/day) for 53 weeks increased 8-oxo-dG, and 1,N(6)-?dA. Exposure to the binary mixture for 53 weeks increased 8-oxo-dG, 1,N(6)-?dA, AcrdG, 1,N(2)-?dG, and N(2),3-?G significantly above control groups. Increased hepatic oxidative DNA adducts following exposure to PCB 126, PCB 153, or the binary mixture shows that an increase in DNA damage may play an important role in hepatic toxicity and carcinogenesis in female Sprague-Dawley rats.
Authors: Mutlu E, Gao L, Collins LB, Walker NJ, Hartwell HJ, Olson JR, Sun W, Gold A, Ball LM, Swenberg JA. ;Full Source: Chemical Research in Toxicology. 2016 Jul 20. [Epub ahead of print] ;