Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons
Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons
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DOI：
10.1016/j.freeradbiomed.2008.04.043
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发表时间：
2008-09-01
影响因子：
7.4
通讯作者：
Swenberg, James A.
中科院分区：
文献类型：
--
作者：
Jeong, Yo-Chan;Walker, Nigel J.;Swenberg, James A.
DNA 氧化损伤被认为是与突变和癌症有关的关键事件之一。本研究检测了单次剂量或接触多卤代芳香烃 (PHAH) 1 年后 M(1)dC, 3-(2'-脱氧-β-D-赤式-呋喃戊糖基)-嘧啶并[1,2-a]-嘌呤-10(3H)-one DNA 加合物的积累，以评估氧化 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-对二恶英 (TCDD) 或 PHAH 混合物的雌性小鼠中探讨了 PHAH 暴露对 M(1)dG 加合物数量的影响。这项研究表明，与玉米油对照组相比，单次暴露于 PHAH 对 M(1)dG 加合物的数量没有显着影响。在暴露于 PCB 153、PCB 126 或两者混合物一年的大鼠中，进一步研究了 M(1)dG 加合物在多氯联苯 (PCB) 诱导毒性和致癌性中的作用。 PCB 153，剂量高达 3000 微克/公斤/天。与对照组相比，对暴露大鼠肝脏和脑组织中 M(1)dG 加合物的数量没有显着影响。然而，1000 ng/kg/天的 PCB 126 会导致 M(1)dG 加合物在肝脏中积累。更重要的是，等比例的 PCB 153 和 PCB 126 的共同给药导致肝脏中 M(1)dG 加合物积累的剂量依赖性增加，PCB 126 为 300 至 1000 ng/kg/天，PCB 153 为 300-1000 μg/kg/天。有趣的是，不同量的 PCB 153 与固定量的 PCB 126 的共同给药表现出更多的作用。 M(1)dG 加合物随着 PCB 153 剂量的增加而积累。这些结果与癌症生物测定的结果一致，该结果证明 PCB 126 和 PCB 153 之间对毒性和肿瘤发展具有协同作用。总之，本研究的结果支持这样的假设：氧化性 DNA 损伤在长期接触 PCB 后的毒性和致癌性中起着关键作用。 (c) 2008 Elsevier Inc. 保留所有权利。
Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M(1)dC, 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 M(1)dG 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 M(1)dG adducts compared to the corn oil control group. The role of M(1)dG adducts in polychlorinated biphenyl (PCB)-inducecl 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 mu g/kg/day. had no significant effect on the number of M(1)dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/day of PCB 126 resulted in M(1)dG adduct accumulation in the liver. More importantly, coadministration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M(1)dG adduct accumulation in the liver from 300 to 1000 ng/kg/day of PCB 126 with 300-1000 mu g/kg/day of PCB 153. Interestingly, the coadministration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M(1)dG 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. (c) 2008 Elsevier Inc. All rights reserved.