Jeong Yo-Chan, Walker Nigel J, Burgin Deborah E, Kissling Grace, Gupta Mayetri, Kupper Lawrence, Birnbaum Linda S, Swenberg James A
Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, NC 27599, USA.
Free Radic Biol Med. 2008 Sep 1;45(5):585-91. doi: 10.1016/j.freeradbiomed.2008.04.043. Epub 2008 May 15.
Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M1dG, 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, DNA adducts after single dose or 1-year exposure to polyhalogenated aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M1dG adducts was explored initially in female mice exposed to a single dose of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M1dG adducts compared to the corn oil control group. The role of M1dG adducts in polychlorinated biphenyl (PCB)-induced toxicity and carcinogenicity was further investigated in rats exposed for a year to PCB 153, PCB 126, or a mixture of the two. PCB 153, at doses up to 3000 microg/kg/day, had no significant effect on the number of M1dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/day of PCB 126 resulted in M1dG adduct accumulation in the liver. More importantly, coadministration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M1dG adduct accumulation in the liver from 300 to 1000 ng/kg/day of PCB 126 with 300-1000 microg/kg/day of PCB 153. Interestingly, the coadministration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M1dG adduct accumulation with higher doses of PCB 153. These results are consistent with the results from cancer bioassays that demonstrated a synergistic effect between PCB 126 and PCB 153 on toxicity and tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.
氧化性DNA损伤被认为是参与突变和癌症发生的关键事件之一。本研究检测了单剂量或经1年多卤代芳烃（PHAH）暴露后M1dG（3-(2'-脱氧-β-D-赤藓糖基)-嘧啶并[1,2-a]嘌呤-10(3H)-酮）DNA加合物的积累情况，以评估氧化性DNA损伤在PHAH毒性和致癌性中的潜在作用。最初在暴露于单剂量2,3,7,8-四氯二苯并-对-二噁英（TCDD）或PHAH混合物的雌性小鼠中探究PHAH暴露对M1dG加合物数量的影响。该研究表明，与玉米油对照组相比，单次暴露于PHAH对M1dG加合物数量无显著影响。在暴露于PCB 153、PCB 126或二者混合物1年的大鼠中，进一步研究了M1dG加合物在多氯联苯（PCB）诱导的毒性和致癌性中的作用。与对照组相比，剂量高达3000μg/kg/天的PCB 153对暴露大鼠肝脏和脑组织中M1dG加合物数量无显著影响。然而，1000ng/kg/天的PCB 126导致肝脏中M1dG加合物积累。更重要的是，以相等比例共同给予PCB 153和PCB 126，随着PCB 126剂量从300至1000ng/kg/天以及PCB 153剂量从300至1000μg/kg/天，肝脏中M1dG加合物积累呈剂量依赖性增加。有趣的是，将不同量的PCB 153与固定量的PCB 126共同给予时，随着PCB 153剂量增加，M1dG加合物积累更多。这些结果与癌症生物测定结果一致，后者表明PCB 126和PCB 153在毒性和肿瘤发生方面具有协同作用。总之，本研究结果支持以下假设：长期PCB暴露后，氧化性DNA损伤在毒性和致癌性中起关键作用。
