氡和晚期混合裂变产物遗传毒效应的比较研究
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摘要
目的:探讨不同类型辐射体在遗传损伤特点、剂量-效应关系和作用机制等方面的差异,为放射性核素遗传毒性的安全评价提供实验依据。
方法:采用HD-3型多功能移动式氡室对24只Wistar大鼠动态吸入染毒,分为对照组和三个实验组,累积暴露剂量分别为60、90、120工作水平月(WLM)。链酶蛋白酶消化加细胞刷刷洗法提取大鼠气管-支气管上皮细胞,心脏穿刺取血以获得外周血淋巴细胞,同时取肺组织经甲醛固定。多核细胞法和胞松素阻滞微核法分别检测外周血淋巴细胞和气管-支气管上皮细胞的hprt突变和微核发生情况。气管-支气管上皮细胞在改良的F12培养基中培养,后进入转化细胞筛选,得到的转化细胞系在第8代时收集细胞用于RT-PCR检测,在传代结束时收集细胞用于Western Blot分析。采用链酶亲和素-过氧化物酶复合物免疫组织化学法测定肺组织p53和p16蛋白,链酶抗生物素蛋白-过氧化酶法测定cox-2的表达。48只Wistar大鼠用于晚期混合裂变产物染毒,随机分成1个对照组,4个不同累积剂量实验组和4个不同剂量率实验组。经大鼠尾静脉注入放射性比活度为(3.4023×105)Bq/ml的混合裂变产物,注入后间隔3,9,15,21d心脏穿刺取血;各剂量率组大鼠经尾静脉分别注入不同放射性比活度的混合裂变产物,注入后相应时间(累积剂量近于相等)心脏穿刺取血。以体细胞hprt突变和微核发生为效应终点,对氡和晚期混合裂变产物内照射的遗传毒效应进行比较毒理学研究。实验数据采用SPSS10.0统计软件包分析,并拟合剂量-效应曲线。
结果:随着氡累积暴露量的增加,外周血淋巴细胞和气管-支气管上皮细胞的hprt突变频率均相应增加,有明显的剂量-效应关系,拟合的函数方程为y=1.785×10-5x2+0.001174x+1.054和y=3.538×10-5x2+0.0008338x+1.032 ;微核率变化的函数方程分别为直线模型和直线平方模型:y = 0.1272x + 2.6546和y = 0.0006x2 - 0.0203x + 4.8598。气管-支气管上皮细胞经筛选培养,在90WLM和120WLM实验组大鼠各得到一个转化细胞系,命名为A和B。检测结果显示,p53和cox-2基因的mRNA和蛋白表达水平上调,而p16基因的mRNA和蛋白表达水平下调。肺组织免疫组化结果表明,p53蛋白的阳性表达率和cox-2的表达量均随暴露剂量的增加而增加,p16蛋白的阳性表达率在暴露剂量达90WLM后开始下降。随着混合裂变产物累积剂量和剂量率的增加, MNR随之增加,均可拟合为二次多项式,分别为y = 4.5407+1.3958x-0.0266x2和y = 4.5659+0.5167x-0.0034x2。对上述结果比较毒理学分析表明:晚期混合裂变产物作用时,单位剂量诱发的hprt突变频率和微核率的改变在低剂量区较明显;氡暴露时,单位剂量诱发的hprt突变频率和微核率随剂量改变不同,hprt突变频率有一明显的敏感剂量区间,而微核率则随剂量增加而明显升高。但同一剂量点hprt突变频率与微核率的比值随剂量增加而降低,氡和混合裂变产物有相同的变化趋势。
结论:
1.在氡诱发大鼠气管-支气管上皮细胞转化过程中,p53、p16和cox-2基因可能发挥了重要的作用。氡暴露后,hprt突变率和微核率均呈现良好的剂量-效应关系,有望成为氡暴露的生物剂量计和遗传毒性标志物。对两者的联合检测,应在敏感剂量区间进行。
2.微核、DNA损伤和hprt突变可作为晚期混合裂变产物内照射的敏感指标,并有明显的剂量效应关系,有可能成为晚期混合裂变产物遗传毒性评价和剂量估算的效应标志物,但在低剂量区较为适用。
3.氡和混合裂变产物内照射时,由于它们的进入途径和辐射类型不同,以外周血淋巴细胞hprt突变和微核发生为遗传损伤检测指标时,尽管具有不同的剂量-效应关系,但也有一些共性的辐射损伤特点,即hprt突变率/微核率均随剂量增加而减少,提示,随剂量增加有更多的遗传物质的片段性丢失。
Objective To compare differences in genetic effects and dose-effect relationship induced by different radionuclides to provide experimental date for evaluating on their genetic toxicity.
Methods Twenty-four Wistar male rats were randomly divided into one control group and three radon inhaled groups(60, 90, and 120 working level month(WLM)), with each group of 6 rats. All the radon-exposed rats were exposed in the HD-3 multifunctional radon-room. The tracheal-bronchial epithelial(TBE) cells were isolated using pronase digestion and cell brushing, and the blood samples were obtained by cardiac puncture. Genetic toxicity of radon and late fussion products was detected by measuring the biological endpoints of hypoxanthine phosphoribosyl transferase (hprt) mutation and micronuclei(MN) rate and DNA damage. The micronuclei rate(MNR) was detected by cytokinesis-blocked(CB) micronuclei assay, and the hprt mutation was detected according to the multinucleated cells method, and DNA damage was detected by single cell gel electrophoresis(SCGE). The tracheal-bronchial epithelial cells were cultured in F12 media, and screened in selective F12 media. The transformed cell lines were collected at 8th generation for reversed transcript polymerase chain reaction(RT-PCR) , and confirmed with western blot assay. The p53 and p16 expression of lung tissue were detected according to strept actividin-biotin complex(SABC) method, and cox-2 expression was detected by the streptavidin-peroxidase(SP) method. SPSS 10.0 was used for statistical analysis on dose-effect and dose-rate-effect relationship.
Results About 1.30×106 tracheal-bronchial epithelial cells were obtained from each rat with a cell survival rate of 84.19 percent. The mutant frequency(y) of hprt in the lymphocytes and tracheal-bronchial epithelial cells increased with the accumulated doses(x), which could be described by the following functions: y = 4E-05x2 + 0.0008x + 1.0324; and y = 2E-05x2 + 0.0012x + 1.0538. The dose-effect relationship between the accumulated doses(x) and the MN rates (y) of the lymphocytes and the epithelial cells were given by the following functions: y = 0.1272x + 2.6546; and y = 0.0006x2 - 0.0203x + 4.8598. Two transformed cell lines from 90 and 120 WLM dose group rats were obtained and named as A and B. in which the expression of the p53 and cox-2 mRNA increased, while the expression of p16 decreased. The expression of p53 and cox-2 protein also increased and p16 decreased in a dose dependent manner. The relationships between MNR and accumulative doses or dose rate induced by late fission products could be described by y = 4.5407+1.3958x-0.0266x2 and y = 4.5659+0.5167x-0.0034x2 respectively. Comparative analysis revealed that the hprt mutation and MNR induced by unit dose fission products changed significantly at the low-dose region, while the effect induced by unit radon presented different features.The hprt/MNR of the same dose decreased for both radon and fission products.
Conclusions
1. p53, p16 and cox-2 gene may play an important role in tracheal-bronchial epithelial cells transformation in radon-exposed rats. A good dose-effect relationship between changes in micronuclei and hprt mutation and doses exposed indicated that these two biological endpoints might be used as potential biomarkers of radon exposure.
2. The hprt mutation and micronuclei were two sensitive endpoints in reflecting genetic effects of the late fission products. A dose-response relationship was established at the low-dose region.
3. The dose-response relationship for radon and fission products were different due to their different entry route and radiation type, but they showed a common feature in that the hprt/MNR decreased with the dose suggesting more fragments loss of genetic material as doses going high.
方法:采用HD-3型多功能移动式氡室对24只Wistar大鼠动态吸入染毒,分为对照组和三个实验组,累积暴露剂量分别为60、90、120工作水平月(WLM)。链酶蛋白酶消化加细胞刷刷洗法提取大鼠气管-支气管上皮细胞,心脏穿刺取血以获得外周血淋巴细胞,同时取肺组织经甲醛固定。多核细胞法和胞松素阻滞微核法分别检测外周血淋巴细胞和气管-支气管上皮细胞的hprt突变和微核发生情况。气管-支气管上皮细胞在改良的F12培养基中培养,后进入转化细胞筛选,得到的转化细胞系在第8代时收集细胞用于RT-PCR检测,在传代结束时收集细胞用于Western Blot分析。采用链酶亲和素-过氧化物酶复合物免疫组织化学法测定肺组织p53和p16蛋白,链酶抗生物素蛋白-过氧化酶法测定cox-2的表达。48只Wistar大鼠用于晚期混合裂变产物染毒,随机分成1个对照组,4个不同累积剂量实验组和4个不同剂量率实验组。经大鼠尾静脉注入放射性比活度为(3.4023×105)Bq/ml的混合裂变产物,注入后间隔3,9,15,21d心脏穿刺取血;各剂量率组大鼠经尾静脉分别注入不同放射性比活度的混合裂变产物,注入后相应时间(累积剂量近于相等)心脏穿刺取血。以体细胞hprt突变和微核发生为效应终点,对氡和晚期混合裂变产物内照射的遗传毒效应进行比较毒理学研究。实验数据采用SPSS10.0统计软件包分析,并拟合剂量-效应曲线。
结果:随着氡累积暴露量的增加,外周血淋巴细胞和气管-支气管上皮细胞的hprt突变频率均相应增加,有明显的剂量-效应关系,拟合的函数方程为y=1.785×10-5x2+0.001174x+1.054和y=3.538×10-5x2+0.0008338x+1.032 ;微核率变化的函数方程分别为直线模型和直线平方模型:y = 0.1272x + 2.6546和y = 0.0006x2 - 0.0203x + 4.8598。气管-支气管上皮细胞经筛选培养,在90WLM和120WLM实验组大鼠各得到一个转化细胞系,命名为A和B。检测结果显示,p53和cox-2基因的mRNA和蛋白表达水平上调,而p16基因的mRNA和蛋白表达水平下调。肺组织免疫组化结果表明,p53蛋白的阳性表达率和cox-2的表达量均随暴露剂量的增加而增加,p16蛋白的阳性表达率在暴露剂量达90WLM后开始下降。随着混合裂变产物累积剂量和剂量率的增加, MNR随之增加,均可拟合为二次多项式,分别为y = 4.5407+1.3958x-0.0266x2和y = 4.5659+0.5167x-0.0034x2。对上述结果比较毒理学分析表明:晚期混合裂变产物作用时,单位剂量诱发的hprt突变频率和微核率的改变在低剂量区较明显;氡暴露时,单位剂量诱发的hprt突变频率和微核率随剂量改变不同,hprt突变频率有一明显的敏感剂量区间,而微核率则随剂量增加而明显升高。但同一剂量点hprt突变频率与微核率的比值随剂量增加而降低,氡和混合裂变产物有相同的变化趋势。
结论:
1.在氡诱发大鼠气管-支气管上皮细胞转化过程中,p53、p16和cox-2基因可能发挥了重要的作用。氡暴露后,hprt突变率和微核率均呈现良好的剂量-效应关系,有望成为氡暴露的生物剂量计和遗传毒性标志物。对两者的联合检测,应在敏感剂量区间进行。
2.微核、DNA损伤和hprt突变可作为晚期混合裂变产物内照射的敏感指标,并有明显的剂量效应关系,有可能成为晚期混合裂变产物遗传毒性评价和剂量估算的效应标志物,但在低剂量区较为适用。
3.氡和混合裂变产物内照射时,由于它们的进入途径和辐射类型不同,以外周血淋巴细胞hprt突变和微核发生为遗传损伤检测指标时,尽管具有不同的剂量-效应关系,但也有一些共性的辐射损伤特点,即hprt突变率/微核率均随剂量增加而减少,提示,随剂量增加有更多的遗传物质的片段性丢失。
Objective To compare differences in genetic effects and dose-effect relationship induced by different radionuclides to provide experimental date for evaluating on their genetic toxicity.
Methods Twenty-four Wistar male rats were randomly divided into one control group and three radon inhaled groups(60, 90, and 120 working level month(WLM)), with each group of 6 rats. All the radon-exposed rats were exposed in the HD-3 multifunctional radon-room. The tracheal-bronchial epithelial(TBE) cells were isolated using pronase digestion and cell brushing, and the blood samples were obtained by cardiac puncture. Genetic toxicity of radon and late fussion products was detected by measuring the biological endpoints of hypoxanthine phosphoribosyl transferase (hprt) mutation and micronuclei(MN) rate and DNA damage. The micronuclei rate(MNR) was detected by cytokinesis-blocked(CB) micronuclei assay, and the hprt mutation was detected according to the multinucleated cells method, and DNA damage was detected by single cell gel electrophoresis(SCGE). The tracheal-bronchial epithelial cells were cultured in F12 media, and screened in selective F12 media. The transformed cell lines were collected at 8th generation for reversed transcript polymerase chain reaction(RT-PCR) , and confirmed with western blot assay. The p53 and p16 expression of lung tissue were detected according to strept actividin-biotin complex(SABC) method, and cox-2 expression was detected by the streptavidin-peroxidase(SP) method. SPSS 10.0 was used for statistical analysis on dose-effect and dose-rate-effect relationship.
Results About 1.30×106 tracheal-bronchial epithelial cells were obtained from each rat with a cell survival rate of 84.19 percent. The mutant frequency(y) of hprt in the lymphocytes and tracheal-bronchial epithelial cells increased with the accumulated doses(x), which could be described by the following functions: y = 4E-05x2 + 0.0008x + 1.0324; and y = 2E-05x2 + 0.0012x + 1.0538. The dose-effect relationship between the accumulated doses(x) and the MN rates (y) of the lymphocytes and the epithelial cells were given by the following functions: y = 0.1272x + 2.6546; and y = 0.0006x2 - 0.0203x + 4.8598. Two transformed cell lines from 90 and 120 WLM dose group rats were obtained and named as A and B. in which the expression of the p53 and cox-2 mRNA increased, while the expression of p16 decreased. The expression of p53 and cox-2 protein also increased and p16 decreased in a dose dependent manner. The relationships between MNR and accumulative doses or dose rate induced by late fission products could be described by y = 4.5407+1.3958x-0.0266x2 and y = 4.5659+0.5167x-0.0034x2 respectively. Comparative analysis revealed that the hprt mutation and MNR induced by unit dose fission products changed significantly at the low-dose region, while the effect induced by unit radon presented different features.The hprt/MNR of the same dose decreased for both radon and fission products.
Conclusions
1. p53, p16 and cox-2 gene may play an important role in tracheal-bronchial epithelial cells transformation in radon-exposed rats. A good dose-effect relationship between changes in micronuclei and hprt mutation and doses exposed indicated that these two biological endpoints might be used as potential biomarkers of radon exposure.
2. The hprt mutation and micronuclei were two sensitive endpoints in reflecting genetic effects of the late fission products. A dose-response relationship was established at the low-dose region.
3. The dose-response relationship for radon and fission products were different due to their different entry route and radiation type, but they showed a common feature in that the hprt/MNR decreased with the dose suggesting more fragments loss of genetic material as doses going high.
引文
1.印木泉,主编。遗传毒理学。北京:科学传版社,2002:2-3,402-409
2. Bowie C, Bowie SH. Radon and health. Lancet,1991, 337(8738):409-413
3. Steindorf K, Lubin J, Wichmann HE, et al. Lung cancer deaths attributable to indoor radon exposure in West Germany. Int J Epidemiol,1995, 24(3):485-492.
4.杨觉雄,王武芳,张福山。室内氡及其子体暴露研究近况。中华预防医学杂志,1999,33(2):125-126
5. Cross FT. A Review of Experimental Radon Health Effects Data. In Radiation Research: A Twentieth-Century Perspective, Vol II. Congress Proceedings. Academic Press Inc, 1992, 476-481.
6. Cross FT. Residential risks from the perspective of experimental animal studies. Am J Epidemiol 1994, 140:333-339.
7.朱寿彭,李章主编.放射毒理学.苏州:苏州大学出版社,2004:252-259
8. Thomassen DG, Saffiotti U, Kaighn ME. Clonal proliferation of rat tracheal epithelial cells in serum-free medium and their responses to hormones, growth factors and carcinogens. Carcinogen, 1986, 7(12):2033-2039
9.秦晓群,孙秀泓,张长青.联合应用酶消化和机械刷洗提取气道上皮细胞的实验技术.湖南医科大学学报,1999,24(1):74-76
10. Gray TE, Thomassen DG, Mass MJ, et al. Quantitation of cell proliferation, colony formation and carcinogen induced cytotoxicity of rat tracheal epithelial cells grown in culture on 3T3 feeder layers. In Vitro, 1983, 19(7):559-570
11.李红澜,周袁芬,张瑞稳,等.大鼠气管上皮细胞体外培养方法及生长条件.上海医科大学学报,1989,16(3):234-236
12. Thomas CB, Nelson DO, Pleshanov P, et al. Elevated frequencies of hypoxanthine phosphoribosyltransferase lymphocyte mutants are detected in Russian liquidators 6 to 10 years after exposure to radiation from the Chernobyl nuclear power plant accident. Mutat Res,1999,439:105-119
13.童建,洪承皎,王静,等.辐射研究与辐射工艺学报,2001, 19(3): 236-238
14.李冰燕,童建,洪承皎,等.大鼠吸入氡及其子体后的DNA损伤效应.辐射研究与辐射工艺学报,21(2):116-119
15. Yuko H,Yoichiro K Seishi K, et al. Mutant frequency at the hprt locus in peripheral blood T-lymphocytes of atomic bomb survivors.Mutat Res,1995,329:183-196.
16. Jianlin L, Jiliang H, Lifen J,et al. Measuring the genetic damage in cancer patients during radiotherapy with three genetic end-points. Mutagenesis. 2004,19(6):457-64.
17. Zwingmann-IH,Welle-IJ,Engelen-JJ. Analysis of oxidative DNA damage and hprt mutant frequencies in cancer patients before and after radiotherapy[J]. Mutat Res,1997,431(2):361-369.
18. Schwartz-JL,Jordan-R,Sun-J, et al. Dose-dependent change in the spectrum of mutations induced by ionizing radiation. Mutat Res,1999,431(2):233-246.
19. Olsson G, Czene S, Jenssen D,et al. Induction of homologous recombination in the hprt gene of V79 Chinese hamster cells in response to low- and high-LET irradiation. Cytogenet Genome Res. 2004,104(1-4):227-31.
20. Mognato M, Bortoletto E, Ferraro P,et al. Genetic damage induced by in vitro irradiation of human G0 lymphocytes with low-energy protons (28 keV/microm): hprt mutations and chromosome aberrations. Radiat Res. 2003,160(1):52-60.
21. Tsuruoka C, Suzuki M, Fujitaka K. LET and ion-species dependence for mutation induction and mutation spectrum on hprt locus in normal human fibroblasts. Biol Sci Space. 2004,18(3):188-189.
22. O'neill P, Nicklas J, Hirsch B, et al. In vitro studies of the genotoxicity of ionizing radiation in human G(0) T lymphocytes. Environ Mol Mutagen. 2005,46(4):207-220.
23. Jostes RF, Fleck EW, Morgan TL, et al. Southern blot and polymerase chain reaction exon analyses of hprt-mutation induced by radon and radon progeny. Radiat Res, 1994,137(3):371-379
24. Satta L, Antonelli F, Belli M, et al. Influence of a low background radiation environment on biochemical and biological responses in V79 cells. Radiat Environ Biophys, 2002,41(3):217-224.
25. Shanahan EM, Peterson D, Roxby D, et al. Mutation rates at the glycophorin A and hprt loci in uranium miners exposed to radon progeny. Occup Environ Med, 1996,53(7):439-444
26. Ruttenber AJ, Harrison LT, Baron A, et al. hprt Mutant frequencies, nonpulmonary malignancies, and domestic radon exposure:“post mortem”analysis of an interesting hypothesis. Environ Mol Mutagen, 2001,37(1):7-16.
27.姚波,蒋本荣,贾蜀琼,等.胞浆分裂阻滞微核法对山东“10·21"辐射事故病人受照射剂量的估算.解放军医学杂志,2007,32(4):293-295
28. Muller wU,Rode A. The micronudeus assay in hurrmn lymphocytes after high radiation doses(5-15Gy).Mutat Res,2002,502(1-2):47-51
29.吕慧敏,董金婵,张翠兰,等.室内氡暴露居民外周血淋巴细胞DNA损伤及微核细胞发生率.中华放射医学与防护杂志,2002, 22(5):340-342
30. Marjan B,Janja V.Chromosome aberrations study of pupils in high radon level elementary schoo1.Health Phys,2001,80:157-163
31.胡勤芳.长期饮用高浓度含氡井水人员血液学、免疫学和遗传学指标观察.辐射防护,2003,23(4):242-252
32. ICRP. Publication 65. Protection against Radon-222 at Home and at Work. Annals of ICRP, 1993.
33. National Research Council. Health Effects of Exposure to Radon(BRIR-VI). Washington, DC: National Academy Press, 1999.
34.吴德昌.氡及子体辐射生物危害的研究.氡水平效应及危害评价专题讨论会论文摘要汇编,苏州,1995, 39-42.
35. Bruske-Hohlfeld I, Rosario AS, Wolke G, et al. Lung cancer risk among former uranium miners of the WISKUT Company in Germany. Health Phys. 2006, 90(3):208-216.
36. Leuraud K, Billon S, Bergot D, et al. Lung cancer risk associated to exposure to radon and smoking in a case-control study of French uranium miners. Health Phys. 2007, 92(4)371-378.
37. Kitamural H, Fitzgerald DJ, Li LA,et al. Morphological characterization of transformed colonies in rat tracheal epithelial cell cultures exposed to carcinogens. Cancer Research, 1986,46:4631-4641
38.刘国廉.细胞毒理学.北京:军事医学科学出版社,2000:367-370,287-311
39.鄂征.组织培养和分子细胞学技术.北京:北京出版社,1999:220
40.王虹,程书均,冯继农,等.菜油油烟冷凝物诱导大鼠气管上皮细胞转化的研究.肿瘤,1995,15(1):24-25
41. Ross JA, Rosen GD.The molecular biology of lung cancer. Curr Opin Pulm Med, 2002,8(4):265-269.
42.吴忧,白澎. p53与人类肺癌关系研究的进展.国际呼吸杂志,2006, 26(2):99-102
43.楼慧玲,张溪林,杜洪.肺癌组织中p53及pl6基因蛋白表达的检测.广东医学杂志,2004,25(6):648-649.
44. Yan G, Xing D, Tan S, et a1. Rapid and sensitive immunomagnetic -electrochemi luminescent detection of p53 antibodies in human serum.J Immunol M ethods,2004,288(1-2):47-54.
45. Gu CD,Osaki T,Oyama T,et a1.Detection of micrometastatictumor cells in PND lymph nodes of patients with completely resected nonsmall cell lung cancer:impact in recurrence and surviva1.Ann Surg,2002,235(I):133- I39.
46. Lutz W, Nowakowska-Swirta E. Gene p53 mutation, protein p53, and anti-p53 antibodies as biomarkers of cancer process. Int J Occup Med Environ Health, 2002,15(3):209-218.
47. Vahakangas KH, Bennett WP, Castren K, et al. p53 and K-ras mutation in lung cancers from former and never-smoking women. Cancer Res, 2001,61(11):4350-4356.
48. Taylor JA, Watson MA, Derereux TR, et al. p53 Mutation Hotpot in Radon Associated Lung Cancer. Lancet,1994, 343(8889):86-87.
49. Yngveson A, Williams C, Hjerpe A, et al. p53 Mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol Biomarkers Prev, 1999,8(5):433-438
50. Schneider J, Presek P, Braun A, et al. Serum levels of pantropic p53 protein and EGF-receptor, and detection of anti-p53 antibodies in former uraninm miners(SDAG Wismut). Am J Ind Med, 1999,36(6):602-609.
51. Petit B ,Leroy K,Kanavaros P ,et al . Expression of p53 protein in T and natural killer-2cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations . Hum Pathol ,2001 ,32 (2) :196～204.
52. Legros Y,Meyer A ,Ory K,et al . Mutations in p53 produce a commonconformational effect that can be detected with a panel of monoclonal antibodies directed toward the central part of the p53 protein . Oncogene ,1994 ,9 (12) :3689～3694.
53. William A, Palmisano, Keuin K. Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum. Cancer Research , 2000,60:5954-5958
54. Belinsky SA, Klinge DM, Liechty KC, et al. Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinama. Carcinogenesis, 2004,Jan 23[Epub ahead of print].
55. Esteban J, Robert D, Costanzo A, et al. Lung cancer and eyclooxygenase-2.Ann Thorac Surg,2003,76(4):1327-1335.
56.胡春宏,刘杨,邓婷,等.塞来昔布对不同cox-2表达肿瘤细胞株放射增敏作用及其机制研究。中华放射肿瘤学杂志,2007,16(1):62-67
57.胡立宽,王振波,宋轶鹏,等. cox-2抑制剂NS-398对肝癌细胞放射增敏作用的实验研究.中华放射肿瘤学杂志,2007,16(3):219-223
58. Liao Z,Milas L. cox-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer. Expert Rev Anticancer Ther. 2004, 4(4):543-60
59. Grimes KR, Warren GW,Fang F,et al. Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo. Oncol Rep. 2006,16(4):771-6
60. Hei TK。Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect。Mol Carcinog. 2006 Jun;45(6):455-60
61. Weaver DA, Hei TK, Hukku B, et al. Localization of tumor suppressor gene candidates by cytogenetic and short tandem repeat analyses in tumorigenic human bronchial epithelial cells. Carcinogenesis. 2000, 21(2): 201-211.
62. Kent CR , Eady JJ , Ross GM, et al. The comet moment as a measure of DNA damage in the comet assay. Int J Radiat Biol ,1995 ,67 :655 - 660.
63. Wojewodzka M, Kruszewski M, Iwanenko T, et al. Application of the comet assay for monitoring DNA damage in workers exposed to chronic low - dose irradiation. Ⅰ. Strand damage . Mutat Res , 1998 , 416 :21 - 35.
64. Kruszewski M, Wojewodzka M, Iwanenko T, et al. Application of the comet assay for monitoring DNA damage in workers exposed to chronic low - dose irradiation.Ⅱ.Base damage . Mutat Res ,1998 ,416 :37 - 57.
65.朱寿彭著.不同辐射体核素的生殖毒性.原子能出版社:2002,北京
66.闵锐.电离辐射生物剂量研究现状.国外医学放射医学核医学分册2004,28(3):121-127
67. Henshaw DL. Radon and childhood cancer. Br J Cancer. 2002,87(11):1336-1337
68. Charles MW. Radon exposure of the skin:Ⅱ. Estimation of the attributable risk for skin cancer incidence. J Radiol Prot. 2007, 27(3):253-274
69. Villeneuve PJ, Lane RSD and Morrison HI. Coronary heart disease mortality and radon exposure in the Newfoundland Xuorspar miners’cohort, 1950–2001. Radiat Environ Biophys, 2007, 46(3):291-296
70.赵经涌,崔凤梅,劳勤华,等.多核细胞法和5-BrdU法检测辐射诱发体细胞hprt基因突变的比较研究.工业卫生与职业病29(2):72-74
71.崔凤梅,赵经涌,劳勤华,王六一,杨淑琴,胡明江.放射性核素内照射诱发大鼠外周血淋巴细胞hprt基因突变.中华放射医学与防护,2004,24(6):538-540
72.徐永忠,赵经涌,劳勤华.晚期混合裂变产物内照射诱发大鼠外周血淋巴细胞HPRT基因位点突变与微核的比较研究.中华放射医学与防护.1999,19(5):337-340
73. Thierens H, Vral A, Barbe M,et al. A cytogenetic study of nuclear power plant workers using the micronucleus-centromere assay. Mutat Res, 1999,445(1):105-111
74. Mill AJ, Wells J, Hall SC,et al.A micronucleus induced in human lymphocytes:Comparative effects of X rays, alpha particles, beta particles and neutrons and implications for biological dosimetry. Radiat Res, 1996,145(5):575-585
[1] UNSCEAR.2000 Report to the General Assembly with Scientific Annexes[M],UN.New York,2000:97-105.
[2] Popp W, Plappert U, Muller MU, et al. Biomarkers of genetic damage and inflammation in blood and branchoalveolar lavage fluid among former German Uranium miners: a pilot study[J]. Radiat Environ Biophys, 2000,39(4):275-282.
[3] Dano Laurent, Marie-Noelle Guilly, Bernard Dutrillaux, et al. Clonal evolution of a radon-induced rat lung tumor[J]. Cancer Genetics and Cytogenetics, 2001,125(1):52-58.
[4] Lutz W, Nowakowska-Swirta E. Gene p53 mutation, protein p53, and anti-p53 antibodies as biomarkers of cancer process[J]. Int J Occup Med Environ Health, 2002,15(3):209-218.
[5] Vahakangas KH, Bennett WP, Castren K, et al. p53 and K-ras mutation in lung cancers from former and never-smoking women[J]. Cancer Res, 2001,61(11):4350-4356.
[6] Vahakangas KH, Samet JM, Metcalf RA, et al. Mutation of p53 and Ras Gene in Radon Associated Lung Cancer from Uranium Miners[J]. Lanat, 1992,339(8793):576-580.
[7] Taylor JA, Watson MA, Derereux TR, et al. p53 Mutation Hotpot in Radon Associated Lung Cancer[J]. Lancet,1994, 343(8889):86-87.
[8] Yang Q, Wesch H, Mueller KM, et al. Analysis of radon-associated squamous cellcarcinomas of the lung for a p53 gene hotspot mutation[J]. Br J Cancer, 2000,82(4):763-766.
[9] Wiethege T, Wesch H, Wegener K, et al. German uranium miner study-pathological and molecular genetic findings[J].German Uranium Miner Study, Research Group Pathology. Radiat Res, 1999,152(6 suppl):S52-55.
[10] Schneider J, Presek P, Braun A, et al. Serum levels of pantropic p53 protein and EGF-receptor, and detection of anti-p53 antibodies in former uraninm miners(SDAG Wismut)[J]. Am J Ind Med, 1999,36(6):602-609.
[11] Yngveson A, Williams C, Hjerpe A, et al. p53 Mutations in lung cancer associated with residential radon exposure[J]. Cancer Epidemiol Biomarkers Prev, 1999,8(5):433-438.
[12] William A, Palmisano, Keuin K. Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum[J]. Cancer Research , 2000,60:5954-5958.
[13] Gilliland FD, Harms HJ, Crowell RE, et al. Glutathione S-transferase p1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum[J]. Cancer Res, 2002,62(8):2248-2252.
[14] Belinsky SA, Klinge DM, Liechty KC, et al. Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinama[J]. Carcinogenesis, 2004,Jan 23[Epub ahead of print].
[15] McDonald JW, Taylor JA, Watson MA, et al. p53 and K-ras in radon-associated lung adenocarcinama[J]. Cancer Epidemiol Biomarkers Prev, 1995,4(7):791-793.
[16] Schneider J, Presek P, Braun A, et al. Serum ras(p21) as a marker for occupationally derived lung cancer[J]? Clin Chem Lab Med, 2000,38(4):301-305.
[17] Pulling LC, Divine KK, Klinge DM, et al. Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression[J]. Cancer Res, 2003,63(16):4842-4848.
[18] Jostes RF, Fleck EW, Morgan TL, et al. Southern blot and polymerase chain reaction exon analyses of hprt-mutation induced by radon and radon progeny[J].Radiat Res, 1994,137(3):371-379.
[19] Satta L, Antonelli F, Belli M, et al. Influence of a low background radiation environment on biochemical and biological responses in V79 cells[J]. Radiat Environ Biophys, 2002,41(3):217-224.
[20] Shanahan EM, Peterson D, Roxby D, et al. Mutation rates at the glycophorin A and hprt loci in uranium miners exposed to radon progeny[J]. Occup Environ Med, 1996,53(7):439-444.
[21] Ruttenber AJ, Harrison LT, Baron A, et al. hprt Mutant frequencies, nonpulmonary malignancies, and domestic radon exposure:“post mortem”analysis of an interesting hypothesis[J]. Environ Mol Mutagen, 2001,37(1):7-16.
[22] Liu Y, Cortopassi G, Steingrimsdotlir H, et al. Correlated metagenesis of bcl2 and hprt loci in blood lymphocytes[J]. Environ Mol Mutagen, 1997,29(1):36-45.
2. Bowie C, Bowie SH. Radon and health. Lancet,1991, 337(8738):409-413
3. Steindorf K, Lubin J, Wichmann HE, et al. Lung cancer deaths attributable to indoor radon exposure in West Germany. Int J Epidemiol,1995, 24(3):485-492.
4.杨觉雄,王武芳,张福山。室内氡及其子体暴露研究近况。中华预防医学杂志,1999,33(2):125-126
5. Cross FT. A Review of Experimental Radon Health Effects Data. In Radiation Research: A Twentieth-Century Perspective, Vol II. Congress Proceedings. Academic Press Inc, 1992, 476-481.
6. Cross FT. Residential risks from the perspective of experimental animal studies. Am J Epidemiol 1994, 140:333-339.
7.朱寿彭,李章主编.放射毒理学.苏州:苏州大学出版社,2004:252-259
8. Thomassen DG, Saffiotti U, Kaighn ME. Clonal proliferation of rat tracheal epithelial cells in serum-free medium and their responses to hormones, growth factors and carcinogens. Carcinogen, 1986, 7(12):2033-2039
9.秦晓群,孙秀泓,张长青.联合应用酶消化和机械刷洗提取气道上皮细胞的实验技术.湖南医科大学学报,1999,24(1):74-76
10. Gray TE, Thomassen DG, Mass MJ, et al. Quantitation of cell proliferation, colony formation and carcinogen induced cytotoxicity of rat tracheal epithelial cells grown in culture on 3T3 feeder layers. In Vitro, 1983, 19(7):559-570
11.李红澜,周袁芬,张瑞稳,等.大鼠气管上皮细胞体外培养方法及生长条件.上海医科大学学报,1989,16(3):234-236
12. Thomas CB, Nelson DO, Pleshanov P, et al. Elevated frequencies of hypoxanthine phosphoribosyltransferase lymphocyte mutants are detected in Russian liquidators 6 to 10 years after exposure to radiation from the Chernobyl nuclear power plant accident. Mutat Res,1999,439:105-119
13.童建,洪承皎,王静,等.辐射研究与辐射工艺学报,2001, 19(3): 236-238
14.李冰燕,童建,洪承皎,等.大鼠吸入氡及其子体后的DNA损伤效应.辐射研究与辐射工艺学报,21(2):116-119
15. Yuko H,Yoichiro K Seishi K, et al. Mutant frequency at the hprt locus in peripheral blood T-lymphocytes of atomic bomb survivors.Mutat Res,1995,329:183-196.
16. Jianlin L, Jiliang H, Lifen J,et al. Measuring the genetic damage in cancer patients during radiotherapy with three genetic end-points. Mutagenesis. 2004,19(6):457-64.
17. Zwingmann-IH,Welle-IJ,Engelen-JJ. Analysis of oxidative DNA damage and hprt mutant frequencies in cancer patients before and after radiotherapy[J]. Mutat Res,1997,431(2):361-369.
18. Schwartz-JL,Jordan-R,Sun-J, et al. Dose-dependent change in the spectrum of mutations induced by ionizing radiation. Mutat Res,1999,431(2):233-246.
19. Olsson G, Czene S, Jenssen D,et al. Induction of homologous recombination in the hprt gene of V79 Chinese hamster cells in response to low- and high-LET irradiation. Cytogenet Genome Res. 2004,104(1-4):227-31.
20. Mognato M, Bortoletto E, Ferraro P,et al. Genetic damage induced by in vitro irradiation of human G0 lymphocytes with low-energy protons (28 keV/microm): hprt mutations and chromosome aberrations. Radiat Res. 2003,160(1):52-60.
21. Tsuruoka C, Suzuki M, Fujitaka K. LET and ion-species dependence for mutation induction and mutation spectrum on hprt locus in normal human fibroblasts. Biol Sci Space. 2004,18(3):188-189.
22. O'neill P, Nicklas J, Hirsch B, et al. In vitro studies of the genotoxicity of ionizing radiation in human G(0) T lymphocytes. Environ Mol Mutagen. 2005,46(4):207-220.
23. Jostes RF, Fleck EW, Morgan TL, et al. Southern blot and polymerase chain reaction exon analyses of hprt-mutation induced by radon and radon progeny. Radiat Res, 1994,137(3):371-379
24. Satta L, Antonelli F, Belli M, et al. Influence of a low background radiation environment on biochemical and biological responses in V79 cells. Radiat Environ Biophys, 2002,41(3):217-224.
25. Shanahan EM, Peterson D, Roxby D, et al. Mutation rates at the glycophorin A and hprt loci in uranium miners exposed to radon progeny. Occup Environ Med, 1996,53(7):439-444
26. Ruttenber AJ, Harrison LT, Baron A, et al. hprt Mutant frequencies, nonpulmonary malignancies, and domestic radon exposure:“post mortem”analysis of an interesting hypothesis. Environ Mol Mutagen, 2001,37(1):7-16.
27.姚波,蒋本荣,贾蜀琼,等.胞浆分裂阻滞微核法对山东“10·21"辐射事故病人受照射剂量的估算.解放军医学杂志,2007,32(4):293-295
28. Muller wU,Rode A. The micronudeus assay in hurrmn lymphocytes after high radiation doses(5-15Gy).Mutat Res,2002,502(1-2):47-51
29.吕慧敏,董金婵,张翠兰,等.室内氡暴露居民外周血淋巴细胞DNA损伤及微核细胞发生率.中华放射医学与防护杂志,2002, 22(5):340-342
30. Marjan B,Janja V.Chromosome aberrations study of pupils in high radon level elementary schoo1.Health Phys,2001,80:157-163
31.胡勤芳.长期饮用高浓度含氡井水人员血液学、免疫学和遗传学指标观察.辐射防护,2003,23(4):242-252
32. ICRP. Publication 65. Protection against Radon-222 at Home and at Work. Annals of ICRP, 1993.
33. National Research Council. Health Effects of Exposure to Radon(BRIR-VI). Washington, DC: National Academy Press, 1999.
34.吴德昌.氡及子体辐射生物危害的研究.氡水平效应及危害评价专题讨论会论文摘要汇编,苏州,1995, 39-42.
35. Bruske-Hohlfeld I, Rosario AS, Wolke G, et al. Lung cancer risk among former uranium miners of the WISKUT Company in Germany. Health Phys. 2006, 90(3):208-216.
36. Leuraud K, Billon S, Bergot D, et al. Lung cancer risk associated to exposure to radon and smoking in a case-control study of French uranium miners. Health Phys. 2007, 92(4)371-378.
37. Kitamural H, Fitzgerald DJ, Li LA,et al. Morphological characterization of transformed colonies in rat tracheal epithelial cell cultures exposed to carcinogens. Cancer Research, 1986,46:4631-4641
38.刘国廉.细胞毒理学.北京:军事医学科学出版社,2000:367-370,287-311
39.鄂征.组织培养和分子细胞学技术.北京:北京出版社,1999:220
40.王虹,程书均,冯继农,等.菜油油烟冷凝物诱导大鼠气管上皮细胞转化的研究.肿瘤,1995,15(1):24-25
41. Ross JA, Rosen GD.The molecular biology of lung cancer. Curr Opin Pulm Med, 2002,8(4):265-269.
42.吴忧,白澎. p53与人类肺癌关系研究的进展.国际呼吸杂志,2006, 26(2):99-102
43.楼慧玲,张溪林,杜洪.肺癌组织中p53及pl6基因蛋白表达的检测.广东医学杂志,2004,25(6):648-649.
44. Yan G, Xing D, Tan S, et a1. Rapid and sensitive immunomagnetic -electrochemi luminescent detection of p53 antibodies in human serum.J Immunol M ethods,2004,288(1-2):47-54.
45. Gu CD,Osaki T,Oyama T,et a1.Detection of micrometastatictumor cells in PND lymph nodes of patients with completely resected nonsmall cell lung cancer:impact in recurrence and surviva1.Ann Surg,2002,235(I):133- I39.
46. Lutz W, Nowakowska-Swirta E. Gene p53 mutation, protein p53, and anti-p53 antibodies as biomarkers of cancer process. Int J Occup Med Environ Health, 2002,15(3):209-218.
47. Vahakangas KH, Bennett WP, Castren K, et al. p53 and K-ras mutation in lung cancers from former and never-smoking women. Cancer Res, 2001,61(11):4350-4356.
48. Taylor JA, Watson MA, Derereux TR, et al. p53 Mutation Hotpot in Radon Associated Lung Cancer. Lancet,1994, 343(8889):86-87.
49. Yngveson A, Williams C, Hjerpe A, et al. p53 Mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol Biomarkers Prev, 1999,8(5):433-438
50. Schneider J, Presek P, Braun A, et al. Serum levels of pantropic p53 protein and EGF-receptor, and detection of anti-p53 antibodies in former uraninm miners(SDAG Wismut). Am J Ind Med, 1999,36(6):602-609.
51. Petit B ,Leroy K,Kanavaros P ,et al . Expression of p53 protein in T and natural killer-2cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations . Hum Pathol ,2001 ,32 (2) :196～204.
52. Legros Y,Meyer A ,Ory K,et al . Mutations in p53 produce a commonconformational effect that can be detected with a panel of monoclonal antibodies directed toward the central part of the p53 protein . Oncogene ,1994 ,9 (12) :3689～3694.
53. William A, Palmisano, Keuin K. Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum. Cancer Research , 2000,60:5954-5958
54. Belinsky SA, Klinge DM, Liechty KC, et al. Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinama. Carcinogenesis, 2004,Jan 23[Epub ahead of print].
55. Esteban J, Robert D, Costanzo A, et al. Lung cancer and eyclooxygenase-2.Ann Thorac Surg,2003,76(4):1327-1335.
56.胡春宏,刘杨,邓婷,等.塞来昔布对不同cox-2表达肿瘤细胞株放射增敏作用及其机制研究。中华放射肿瘤学杂志,2007,16(1):62-67
57.胡立宽,王振波,宋轶鹏,等. cox-2抑制剂NS-398对肝癌细胞放射增敏作用的实验研究.中华放射肿瘤学杂志,2007,16(3):219-223
58. Liao Z,Milas L. cox-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer. Expert Rev Anticancer Ther. 2004, 4(4):543-60
59. Grimes KR, Warren GW,Fang F,et al. Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo. Oncol Rep. 2006,16(4):771-6
60. Hei TK。Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect。Mol Carcinog. 2006 Jun;45(6):455-60
61. Weaver DA, Hei TK, Hukku B, et al. Localization of tumor suppressor gene candidates by cytogenetic and short tandem repeat analyses in tumorigenic human bronchial epithelial cells. Carcinogenesis. 2000, 21(2): 201-211.
62. Kent CR , Eady JJ , Ross GM, et al. The comet moment as a measure of DNA damage in the comet assay. Int J Radiat Biol ,1995 ,67 :655 - 660.
63. Wojewodzka M, Kruszewski M, Iwanenko T, et al. Application of the comet assay for monitoring DNA damage in workers exposed to chronic low - dose irradiation. Ⅰ. Strand damage . Mutat Res , 1998 , 416 :21 - 35.
64. Kruszewski M, Wojewodzka M, Iwanenko T, et al. Application of the comet assay for monitoring DNA damage in workers exposed to chronic low - dose irradiation.Ⅱ.Base damage . Mutat Res ,1998 ,416 :37 - 57.
65.朱寿彭著.不同辐射体核素的生殖毒性.原子能出版社:2002,北京
66.闵锐.电离辐射生物剂量研究现状.国外医学放射医学核医学分册2004,28(3):121-127
67. Henshaw DL. Radon and childhood cancer. Br J Cancer. 2002,87(11):1336-1337
68. Charles MW. Radon exposure of the skin:Ⅱ. Estimation of the attributable risk for skin cancer incidence. J Radiol Prot. 2007, 27(3):253-274
69. Villeneuve PJ, Lane RSD and Morrison HI. Coronary heart disease mortality and radon exposure in the Newfoundland Xuorspar miners’cohort, 1950–2001. Radiat Environ Biophys, 2007, 46(3):291-296
70.赵经涌,崔凤梅,劳勤华,等.多核细胞法和5-BrdU法检测辐射诱发体细胞hprt基因突变的比较研究.工业卫生与职业病29(2):72-74
71.崔凤梅,赵经涌,劳勤华,王六一,杨淑琴,胡明江.放射性核素内照射诱发大鼠外周血淋巴细胞hprt基因突变.中华放射医学与防护,2004,24(6):538-540
72.徐永忠,赵经涌,劳勤华.晚期混合裂变产物内照射诱发大鼠外周血淋巴细胞HPRT基因位点突变与微核的比较研究.中华放射医学与防护.1999,19(5):337-340
73. Thierens H, Vral A, Barbe M,et al. A cytogenetic study of nuclear power plant workers using the micronucleus-centromere assay. Mutat Res, 1999,445(1):105-111
74. Mill AJ, Wells J, Hall SC,et al.A micronucleus induced in human lymphocytes:Comparative effects of X rays, alpha particles, beta particles and neutrons and implications for biological dosimetry. Radiat Res, 1996,145(5):575-585
[1] UNSCEAR.2000 Report to the General Assembly with Scientific Annexes[M],UN.New York,2000:97-105.
[2] Popp W, Plappert U, Muller MU, et al. Biomarkers of genetic damage and inflammation in blood and branchoalveolar lavage fluid among former German Uranium miners: a pilot study[J]. Radiat Environ Biophys, 2000,39(4):275-282.
[3] Dano Laurent, Marie-Noelle Guilly, Bernard Dutrillaux, et al. Clonal evolution of a radon-induced rat lung tumor[J]. Cancer Genetics and Cytogenetics, 2001,125(1):52-58.
[4] Lutz W, Nowakowska-Swirta E. Gene p53 mutation, protein p53, and anti-p53 antibodies as biomarkers of cancer process[J]. Int J Occup Med Environ Health, 2002,15(3):209-218.
[5] Vahakangas KH, Bennett WP, Castren K, et al. p53 and K-ras mutation in lung cancers from former and never-smoking women[J]. Cancer Res, 2001,61(11):4350-4356.
[6] Vahakangas KH, Samet JM, Metcalf RA, et al. Mutation of p53 and Ras Gene in Radon Associated Lung Cancer from Uranium Miners[J]. Lanat, 1992,339(8793):576-580.
[7] Taylor JA, Watson MA, Derereux TR, et al. p53 Mutation Hotpot in Radon Associated Lung Cancer[J]. Lancet,1994, 343(8889):86-87.
[8] Yang Q, Wesch H, Mueller KM, et al. Analysis of radon-associated squamous cellcarcinomas of the lung for a p53 gene hotspot mutation[J]. Br J Cancer, 2000,82(4):763-766.
[9] Wiethege T, Wesch H, Wegener K, et al. German uranium miner study-pathological and molecular genetic findings[J].German Uranium Miner Study, Research Group Pathology. Radiat Res, 1999,152(6 suppl):S52-55.
[10] Schneider J, Presek P, Braun A, et al. Serum levels of pantropic p53 protein and EGF-receptor, and detection of anti-p53 antibodies in former uraninm miners(SDAG Wismut)[J]. Am J Ind Med, 1999,36(6):602-609.
[11] Yngveson A, Williams C, Hjerpe A, et al. p53 Mutations in lung cancer associated with residential radon exposure[J]. Cancer Epidemiol Biomarkers Prev, 1999,8(5):433-438.
[12] William A, Palmisano, Keuin K. Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum[J]. Cancer Research , 2000,60:5954-5958.
[13] Gilliland FD, Harms HJ, Crowell RE, et al. Glutathione S-transferase p1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum[J]. Cancer Res, 2002,62(8):2248-2252.
[14] Belinsky SA, Klinge DM, Liechty KC, et al. Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinama[J]. Carcinogenesis, 2004,Jan 23[Epub ahead of print].
[15] McDonald JW, Taylor JA, Watson MA, et al. p53 and K-ras in radon-associated lung adenocarcinama[J]. Cancer Epidemiol Biomarkers Prev, 1995,4(7):791-793.
[16] Schneider J, Presek P, Braun A, et al. Serum ras(p21) as a marker for occupationally derived lung cancer[J]? Clin Chem Lab Med, 2000,38(4):301-305.
[17] Pulling LC, Divine KK, Klinge DM, et al. Promoter hypermethylation of the O6-methylguanine-DNA methyltransferase gene: more common in lung adenocarcinomas from never-smokers than smokers and associated with tumor progression[J]. Cancer Res, 2003,63(16):4842-4848.
[18] Jostes RF, Fleck EW, Morgan TL, et al. Southern blot and polymerase chain reaction exon analyses of hprt-mutation induced by radon and radon progeny[J].Radiat Res, 1994,137(3):371-379.
[19] Satta L, Antonelli F, Belli M, et al. Influence of a low background radiation environment on biochemical and biological responses in V79 cells[J]. Radiat Environ Biophys, 2002,41(3):217-224.
[20] Shanahan EM, Peterson D, Roxby D, et al. Mutation rates at the glycophorin A and hprt loci in uranium miners exposed to radon progeny[J]. Occup Environ Med, 1996,53(7):439-444.
[21] Ruttenber AJ, Harrison LT, Baron A, et al. hprt Mutant frequencies, nonpulmonary malignancies, and domestic radon exposure:“post mortem”analysis of an interesting hypothesis[J]. Environ Mol Mutagen, 2001,37(1):7-16.
[22] Liu Y, Cortopassi G, Steingrimsdotlir H, et al. Correlated metagenesis of bcl2 and hprt loci in blood lymphocytes[J]. Environ Mol Mutagen, 1997,29(1):36-45.