ENVIRONMENTAL CHEMICAL AND OXIDATIVE STRESS INDUCED DNA DAMAGE & CARCINOGENESIS

外源性氧化应激可诱导细胞DNA的内源性氧化损伤， 化学毒性和/或炎症，据推测 突变频率（MF）和突变可能是固定的和克隆的 通过诱导细胞增殖而扩大（多阶段致癌作用）。 我们的目标是确定突变频率， 在转基因ZAP/lacIq小鼠（C57 B1/6背景）中使用λ 用选定的遗传毒性或非遗传毒性处理后的穿梭载体 诱导增生伴或不伴相关炎症的化学物质 作为基因组DNA损伤的模型。 靶转基因从 通过将小鼠基因组DNA暴露于 体外包装提取物，感染修复缺陷型宿主E.杆菌和 培养。 在lacI靶基因中具有突变的噬菌体形式为有色 斑块，而那些与非突变的靶基因形成无色斑块。 我们通过测定肝脏中的突变频率开始了这些研究 在乙基亚硝基脲或溶剂暴露和诱导快速 2/3肝部分切除术后肝细胞增殖。 烧蚀 肝脏作为To和未处理的对照。 8天后（100%） 肝质量恢复）EtNU后肝切除术MF增加4.4倍 相比之下，单独肝切除术或EtNU和假手术的约1.9或1.7倍 肝切除 使用苯、对克立西定、 1，2，3-三氯丙烷和4-乙烯基-1-环己烯二环氧化物正在进行 分析. 通过这种研究策略，我们希望能够提供 对DNA化学和/或内源性氧化损伤的认识， 可能的致癌机制。

Endogenous oxidative injury to cellular DNA may be induced by exogenous chemical toxicity and/or inflammation and has been speculated to contribute to mutation frequency (MF) and mutations that may be fixed and clonally expanded (multistage carcinogenesis) by induced cellular proliferation. Our goal is to determine the mutation frequency and to characterize mutations in transgenic ZAP/lacIq mice (C57B1/6 background) using a lambda shuttle vector after treatment with selected genotoxic or non-genotoxic chemicals that induce hyperplasia with and without associated inflammation as a model for genomic DNA damage. The target transgene is recovered from treated transgenic mice by exposing the mouse genomic DNA to lambda in vitro packaging extracts, infecting repair deficient host E. coli, and culturing. Phage with mutations in the lacI target gene form colored plaques, while those with non-mutated target genes form colorless plaques. We have initiated these studies by determining mutation frequency in liver after ethylnitrosourea or vehicle exposure and induction of rapid hepatocellular proliferation following 2/3 partial hepatectomy. Ablated liver served as the To and untreated control. After 8 days (100% restoration of liver mass) EtNU followed by hepatectomy increased MF 4.4X compared to ~1.9 or 1.7X for hepatectomy alone or EtNU and sham hepatectomy. Additional studies performed with benzene, p-cresidine, 1,2,3-trichloropropane and 4-vinyl-1-cyclohexene diepoxide are undergoing analysis. Using this research strategy we expect to be able to provide insight on chemical and/or endogenous oxidative damage to DNA and this possible mechanism of carcinogenesis.