某铀矿工人痰细胞中p16和MGMT基因的甲基化状态

目的检测某铀矿氡职业暴露人群痰细胞中6-氧-甲基嘌呤-DNA甲基转移酶（MGMT）基因和p16基因的甲基化状态，为寻找氡致肺癌高危人群的分子标记物提供试验依据。方法91名氡职业暴露工人按氡子体累积暴露剂培工作水平月（WLM）分为高（〉120WLM）、中（60～120WIN）、低（30～60WLM）和较低（2～30WLM）4个剂量组，用聚合酶链反应-甲基化特异性（MSP）检测4组人群痰细胞中的p16和MGMT基因的异常甲基化状态。结果随着氡子体累积暴露剂量的增加，p16基因甲基化率（0．00％，20．00％）、MGMT基因甲基化率（0．00％～28．00％）、总甲基化率（0．00％～40．00％）均呈明昆上升趋势，差异有统计学意义（P〈0．01）。结论p16和MGMT基因甲基化与氡子体累积暴露剂量有关。     

氡对铀矿工MGMT基因甲基化及超氧化物歧化酶活力的影响

目的探讨氡及其子体对职业人群致肺癌的早期生物效应标志物。方法91名氡职业暴露工人按氡子体累积暴露剂量分为高[>120WLM(工作水平月)]、中(60~120WLM)、低(30~59WLM)和最低(2~29WLM)4个剂量组,用聚合酶链反应-甲基化特异性(MSP)检测4组人群痰细胞中的6-氧-甲基嘌呤-DNA甲基转移酶(MGMT)基因的异常甲基化状态,用黄嘌呤氧化酶法测定血浆超氧化物歧化酶(SOD)活力。结果随着氡子体累积暴露剂量增加,MGMT基因甲基化率呈上升趋势(0.00%~28.00%),且差异有统计学意义(P<0.01);在最低、低、中和高剂量职业氡暴露人群外周血中,SOD活力分别为(116.5±12.3)、(89.6±8.3)、(63.6±8.9)和(40.9±7.6)kU/L,组间差异有统计学意义(P<0.05),SOD活力呈逐渐下降趋势,线性回归方程y=138.78-16.32x(r=-0.96,P<0.05)。结论MGMT基因甲基化和SOD活力与氡子体累积暴露剂量有关。     

氡及其子体对大鼠肺组织的辐射损伤研究

目的研究氡及其子体对大鼠气管-支气管上皮细胞影响和肺组织病理学改变,从miR-34a(microRNA-34a)角度阐述肺损伤的机制。方法将SD大鼠置于多功能生态氡室,使其暴露于氡及其子体中,额外累积暴露剂量分别达90、120工作水平月(WLM)后,提取气管-支气管上皮细胞,分离收集肺组织,做病理学检查,检测肺组织中miR-34a的表达水平。结果与对照组大鼠比较,氡暴露组大鼠肺组织中出现类型、程度、范围多样性的病理学改变,主要表现为肺间质充血、水肿、炎症细胞浸润、纤维性蛋白增生、肺气肿等多种病变;氡暴露90 WLM组气管-支气管上皮细胞的存活率从100%降到73.2%,氡暴露120WLM组降到60.2%;氡暴露90 WLM组气管-支气管上皮细胞的集落形成率从100%降到74.3%,氡暴露120WLM组降到61.9%。90WLM组肺组织中miR-34a表达量为7.04,120WLM组表达量为6.26,均较对照组miR-34a表达量(6.03)升高。结论氡及其子体可造成SD大鼠肺组织的病理性损伤,气管-支气管上皮细胞存活率和集落形成率降低;miR-34a通路在氡暴露SD大鼠肺组织损伤中发挥一定作用。     

氡及其子体对大鼠肺及其支气管的损伤作用

[目的 ]研究大鼠吸入氡及其子体后肺及支气管组织的生物学变化。 [方法 ]雄性SD大鼠吸入氡及其子体的累积剂量分别达 66、111、174工作水平月 (workinglevelmonth ,WLM )后 ,收集支气管肺灌洗液 (bronchialveolarlavageflu ids ,BALF) ,观察BALF中细胞计数和分类的变化。采用SCGE技术 ,检测BALF和肺细胞的DNA链断裂情况。同时观察大鼠气管、支气管、细支气管和肺泡的病理组织学变化。 [结果 ]大鼠吸入氡及其子体后 ,各染毒组BALF中细胞总数有增加趋势 ,但仍在正常范围之内 ,淋巴细胞比例明显减少 ,而粒细胞增多 (P <0 0 5 )。各染毒组细胞DNA链断裂的迁移长度显著增加 ,且存在剂量 效应关系。病理结果观察到 174WLM剂量组肺组织慢性炎细胞浸润明显 ,部分区域浸及肌层 ,肺泡上皮大片脱落 ,出现灶性肺气肿。 [结论 ]在本实验的染毒剂量下 ,氡及其子体可降低BALF中淋巴细胞比例 ,增加粒细胞比例 ;能引起BALF和肺细胞的DNA链断裂的损伤     

氡及其子体吸入对大鼠外周血损伤的生物学效应

[目的 ]研究不同剂量氡暴露致大鼠外周血损伤的生物学效应。 [方法 ] 2 0 0 1年至 2 0 0 2年选用 2个月龄的雄性SD大鼠 ,吸入氡及子体的累积剂量分别为 66、111、174工作水平月 (WLM)后 ,观察外周血中白细胞计数与分类的变化 ,检测血清中LDH、GSH和总蛋白含量 ;用SCGE和RT PCR方法检测外周血单个核细胞 (PBMC)的DNA链断裂情况及IL 6mRNA的表达情况。 [结果 ]大鼠吸入氡及其子体后 ,66WLM组外周血中粒细胞的数量明显低于对照组 ;最高剂量组血清总蛋白明显低于对照组 ;各剂量组PBMC的DNA迁移长度与对照组相比显著增加 ,而且呈现剂量效应关系 ;IL 6mRNA的表达在 66和 174WLM剂量组均显著高于对照组。 [结论 ]在本实验的染毒剂量下 ,大鼠吸入氡及其子体后血清中总蛋白降低 ,PBMC的DNA损伤程度随着暴露剂量的升高而增加     

氡及其子体吸入对大鼠外周血损伤的生物学效应

[目的]研究不同剂量氡暴露致大鼠外周血损伤的生物学效应．[方法]2001年至2002年选用2个月龄的雄性SD大鼠，吸入氡及子体的累积剂量分别为66、111、174工作水平月(WLM)后，观察外周血中白细胞计数与分类的变化．检测血清中LDH、GSH和总蛋白含量；用SCGE和RT-PCR方法检测外周血单个核细胞(PBMC)的DNA链断裂情况及IL-6 mRNA的表达情况。[结果]大鼠吸入氡及其子体后，66WLM组外周血中粒细胞的数量明显低于对照组；最高剂量组血清总蛋白明显低于对照组；各剂量组PBMC的DNA迁移长度与对照组相比显著增加，而且呈现剂量效应关系；IL-6 mRNA的表达在66和174WLM剂量组均显著高于对照组。[结论]在本实验的染毒剂量下，大鼠吸入氡及其子体后血清中总蛋白降低，PBMC的DNA损伤程度随着暴露剂量的升高而增加．     

氡及其子体对职业人群和大鼠外周血SOD及MDA的影响

目的探讨长期氡及其子体吸入对职业氡暴露人群与大鼠的氧化损伤,寻找早期效应标志物。方法用固体核径迹法测定作业场所中氡浓度,利用1 Bq/m3=1.26×10-3WLM(工作水平月)的转换系数算出单位氡浓度氡子体年暴露量。职业氡暴露人群按照氡子体累积暴露剂量分为2,26和106 WLM即3个低、中、高剂量组。雄性Wistar大鼠15只,随机分成3组,低剂量组暴露于普通环境中,中、高剂量组整体暴露于多功能生态氡室,氡子体累积暴露剂量分别达1,27和105工作水平月。检测各组人群和各组大鼠外周血的超氧化物岐化酶(SOD)活力、丙二醛(MDA)含量。结果在低、中、高剂量职业氡暴露人群外周血中,SOD活力分别为(117.34±18.07)U/ml、(83.32±19.79)U/ml和(60.37±21.40)U/ml,MDA含量分别为(1.85±1.12)nmol/ml、(2.68±1.36)nmol/ml和(3.35±1.61)nmol/ml。随着氡子体累积暴露剂量的增加,SOD活力逐渐降低(P<0.05),MDA含量逐渐升高(P<0.05)。在低、中、高剂量吸入氡染毒大鼠外周血中,SOD活力分别为(1 393.40±88.30)U/ml、(1 198.60±132.44)U/ml和(1 098.60±50.90)U/ml,MDA含量分别为(0.53±0.13)nmol/ml、(1.89±0.13)nmol/ml和(2.18±0.18)nmol/ml。随着氡子体累积暴露剂量的增加,SOD活力逐渐降低(P<0.05),MDA含量逐渐升高(P<0.05)。结论SOD与MDA可作为氡及子体吸入引起氧化损伤的早期效应标志物。     

铀矿工GSTP1基因多态与MGMT基因和p16基因甲基化的关系

目的探讨氡职业暴露人群谷胱甘肽S-转移酶P1(GSTP1)基因多态与痰细胞6-氧-甲基嘌呤-DNA甲基转移酶(MGMT)和p16基因甲基化的关系。方法用聚合酶链反应-限制性片段长度多态性法(PCR-RFLP)确定70例氡职业暴露人群GSTP1的基因型;用聚合酶链反应-甲基化特异性法(MSP)确定痰细胞中MGMT和p16基因的甲基化与非甲基化状态。结果在70名铀矿工中,GSTP1基因A105G位点的纯合子(Ile/Ile)42例,杂合子(Ile/Val)25例和纯合子(Val/Val)3例。MGMT、p16基因甲基化率和总甲基化率分别为14.2%、8.6%和18.6%。与携带Ile/Ile人群相比,携带异常等位基因(Ile/Val与Val/Val)的人群MGMT基因甲基化和总甲基化率增加[P=0.037,OR=4.8,95%CI(1.1~21.0);P=0.016,OR=5.1,95%CI(1.4~19.6)];p16基因甲基化率差异无统计学意义[P=0.057,OR=4.6,95%CI(0.8~29.2)]。结论GSTP1(A105G)基因多态性与氡致MGMT基因甲基化和总甲基化的易感性有关。     

氡及其子体诱发大鼠体细胞HPRT基因位点的突变

[目的]用多核细胞法研究氡及其子体诱发大鼠外周血淋巴细胞和气管-支气管上皮细胞的次黄嘌呤鸟嘌呤磷酸核糖转移酶(HPRT)基因位点突变情况。[方法]Wistar雄性大鼠24只,采用HD-3型多功能移动式氡室进行动态吸入染毒,按照氡染毒的累计暴露量,分为3个实验组和1个对照组;获取大鼠外周血淋巴细胞和气管-支气管上皮细胞,以多核细胞法检测该两种细胞的HPRT基因突变频率。[结果]大鼠外周血淋巴细胞和气管-支气管上皮细胞的HPRT基因突变频率均随氡累积暴露剂量的增加而相应增加,剂量-效应关系明显,拟合的函数分别为(?)=1.785×10~(-5)D~2 1.174×10~(-3)D 1.054和(?)=3.538×10~(-5)D~2 8.338×10~(-4)D 1.032。[结论]氡及其子体能诱发大鼠外周血淋巴细胞和气管-支气管上皮细胞的HPRT基因突变,呈现一定的剂量-效应关系。     

某铀矿的辐射水平和肺癌

袁丽云(中国辐射防护研究院)报道:贵州某铀汞共生矿矿井空气中氡和氡子体浓度偏高,1964～1976年平均氡浓度27.27×10~3Bqm~(-3),1976～1985年平均氡子体α潜能浓度62.75×10~(-6)Jm~(-3)(GB-J-8-74国家容许标准:氡3.7×10~3Bqm~(-3),氡子体α潜能6.4×10~(-6)Jm~(-3))。1960至1985年二十六年间主要工种氡子体潜能累积暴露量约为740WLM,辅助工种为400WLM。1971年以前下井的老工人中60%累积暴露量达200WLM以上,他们是观察辐射致癌效应的重点对象。1971～1986年间在1971年前下井的532名老工人中肺癌死亡2例,他们的累积暴露量分别为410和570WLM。用贵州省男性肺癌死亡作对照,肺     

Aberrant promoter methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase genes in workers at a Chinese uranium mine

To find the possible association of gene methylation of p16(INK4a) and O(6)-Methylguanine-DNA Methyltransferase (O(6)-MGMT) with occupational exposure to radon, 91 male miners from a uranium mine in China were divided into 4 groups according to the cumulative doses of radon exposure from 2 to 425 WLM (working-level months), and aberrant promoter methylation of p16(INK4a) and O(6)-MGMT genes in sputum samples was determined by a specific PCR assay. The results revealed that the methylated rates of 16(INK4a) gene (z=2.844, P=0.005) and O(6)-MGMT gene (z=3.034, P=0.002), and the total methylated rate of these two genes (z=3.859, P=0.0001) increased significantly with the cumulative doses of radon among the miners. This methylation could be applied as a potential marker for the detection of early DNA damage induced by occupational radon exposure.     

氡暴露对大鼠淋巴细胞的免疫毒性

[目的]通过研究氡暴露对大鼠胸腺、脾脏、外周血及骨髓淋巴细胞的损伤作用,探讨氡对大鼠免疫功能的影响,为探索氡致机体免疫损伤的可能机制提供实验资料。[方法]将15只健康雄性Wistar大鼠随机分成3组,每组5只,动物整体暴露于HD-3型多功能生态氡室,累积受照剂量分别达200工作水平月（WLM）和400WLM后,腹主动脉采血,胸腺、脾脏制成单细胞悬液,分离股骨取骨髓。采用五分类血液分析仪进行骨髓、外周血细胞计数及分类。采用荧光探针检测不同剂量氡暴露组淋巴细胞内活性氧（ROS）、游离钙离子浓度、线粒体膜电位（MMP）水平的变化。采用碘化丙啶（PI）染色后,观察脾脏、胸腺淋巴细胞周期及凋亡率。[结果]200WLM氡暴露组大鼠外周血淋巴细胞数为（6．84土1．40）×10-9／L,高于对照组的（3．34±1．10）×10-9／L（P〈0．01）,2剂量组骨髓淋巴细胞计数均明显增加（P〈0．01）;200WLM组胸腺淋巴细胞ROS高于对照组（P〈0．01）,骨髓、外周血淋巴细胞MMP低于对照组（P〈0．01）,脾脏、胸腺淋巴细胞钙离子浓度明显升高（P〈0．01）;与对照组比较,胸腺细胞Go／G,期细胞比例明显降低,而s期细胞比例显著升高,脾脏细胞则相反;200WLM氡暴露组胸腺细胞凋亡率为（1．63±0．46）％,高于对照组的（0．69±0．64）％（P〈0．05）,而400WLM氡暴露组未见明显改变。[结论]氡及其子体可暴露对大鼠免疫细胞和免疫功能产生毒性作用。     

Carcinogenic and Cocarcinogenic Effects of Radon and Radon Daughters in Rats.

It has been previously established that lung cancer could be induced in rats by exposure to radon and radon daughters. Although the oat-cell carcinomas that are common in humans were not found in rats, other histological types of lung carcinomas, especially squamous cell carcinomas and primitive lung adenocarcinomas, were similar to those observed in humans. A dose-effect relationship was established for cumulative doses varying from 25 to 3000 working-level-months (WLM), which was similar for medium and high cumulative doses to that observed in uranium miners. This experimental protocol was also used to study the potential cocarcinogenic effects of other environmental or industrial airborne pollutants such as tobacco smoke, mineral fibers, diesel exhausts, or minerals from metallic mine ores that may act synergistically with radon exposure. In rats exposed to radon and tobacco smoke combined, the incidence of lung cancers was higher by a factor of 2-4 according to the cumulative radon exposure and the duration of tobacco smoke exposure. When mineral fibers were injected intrapleurally, an increased incidence of malignant thoracic tumors was observed in rats exposed to radon and fibers combined, but synergistic effects resulted in additivity. With diesel exhausts or minerals from metallic ores, a slight, nonsignificant increase in the incidence of lung carcinomas was observed compared with rats exposed to radon alone. These results demonstrated that it is possible to establish the potential cocarcinogenic action, showing either multiplicative, additive, or no effect of various environmental or industrial airborne pollutants combined with radon exposure. This radon model is valid for investigating possible interactions between two occupational exposures.     

Clinical measures, smoking, radon exposure, and risk of lung cancer in uranium miners.

OBJECTIVES: Exposure to the radioactive daughters of radon is associated with increased risk of lung cancer in mining populations. An investigation of incidence of lung cancer following a clinical survey of Ontario uranium miners was undertaken to explore whether risk associated with radon is modified by factors including smoking, radiographic silicosis, clinical symptoms, the results of lung function testing, and the temporal pattern of radon exposure. METHODS: Miners were examined in 1974 by a respiratory questionnaire, tests of lung function, and chest radiography. A random selection of 733 (75%) of the original 973 participants was followed up by linkage to the Ontario Mortality and Cancer Registries. RESULTS: Incidence of lung cancer was increased threefold. Risk of lung cancer among miners who had stopped smoking was half that of men who continued to smoke. There was no interaction between smoking and radon exposure. Men with lung function test results consistent with airways obstruction had an increased risk of lung cancer, even after adjustment for cigarette smoking. There was no association between radiographic silicosis and risk of lung cancer. Lung cancer was associated with exposures to radon daughters accumulated in a time window four to 14 years before diagnosis, but there was little association with exposures incurred earlier than 14 years before diagnosis. Among the men diagnosed with lung cancer, the mean and median dose rates were 2.6 working level months (WLM) a year and 1.8 WLM/year in the four to 14 year exposure window. CONCLUSIONS: Risk of lung cancer associated with radon is modified by dose and time from exposure. Risk can be substantially decreased by stopping smoking.     

Radon daughter exposure to uranium miners

Radon exposures to U.S. uranium miners under present conditions average about 1.3 WLM per year approximately or equal to 60 WLM per full working lifetime. This is intermediate between (a) the lowest exposures for which there have been excess lung cancers reported among U.S. miners (120-240 WLM) and (b) average environmental radon exposures (16 WLM), so models based on these two situations are used to estimate expected effects on present uranium miners. In Model A, the loss of life expectancy is 45 days, the SMR (standardized mortality ratio) for lung cancer is 1.10, and the SMR for all causes between ages 18 and 65 is 1.013. In Model B these are 10 days, 1.03 and 1.002 respectively. It is shown that the radon exposures to miners are similar to those to millions of Americans from environmental exposure, and that miner health risks are comparable to those of other radiation workers. Their lung cancer risk from radon is 7-50 times less than their job-related accident mortality risk, and represents 0.7-4% of their total risk in mining. Miners suffer from many diseases with SMR very much larger than that for radon-induced lung cancer, and there are many other occupations and industries with far higher SMR for lung cancer than that from radon exposure to miners.     

Dose conversion factors for radon daughters in underground and open-cut mine atmospheres

As uranium will be mined in Australia by open-cut methods, previous work on calculating dose conversion factors for radon daughters has been re-examined. The fractions of radon daughters deposited on lung airways and the factors for converting from equilibrium activity of radon daughters on airways to dose to basal cells are re-calculated. The variation around these estimates through variability of lung morphology and the depth of the basal cells is discussed. Average dose conversion factors calculated for atmospheres which may be typical of underground mines range from 12 mGy/WLM to 33 mGy/WLM. Use has been made of measurement results on unattached fraction at an open-cut mine in the Northern Territory, Australia, to derive dose conversion factors, ranging from 50 mGy/WLM to 135 mGy/WLM which are applicable to this environment.     

Relationship between the 210Pb content of teeth and exposure to Rn and Rn daughters

Existing data on 210Pb in human teeth are reviewed for various countries. The mean value of 210Pb in the teeth of population groups exposed to "normal" levels of radon-daughter exposure is about 2 mBq/g. A detailed analysis of 48 samples from a "normal" Italian population group revealed that smoking habits and age may have some influence on 210Pb content of teeth, while this is not the case for differences in sex. A group of 45 Austrians exposed to elevated levels of radon and radon daughters is compared with the Italian group. After subtraction of background levels of 210Pb as found for the normal Italian population, the incremental 210Pb tooth content due to excessive radon-daughter exposure has been correlated with the individual cumulative exposure corrected for background radon-daughter exposure. A statistical analysis shows the significance of the linear correlation at the alpha = 0.01 level. For the incremental increase of 210Pb in teeth, a value of 1.2 mBq/g has been used for a lifetime exposure to 1 WLM. This result is compared to corresponding data published in the literature, which are predominantly related to the 210Pb content of bone after short-time exposure at high levels, e.g. in uranium mines. The comparison seems to indicate the influence of the exposure rate and the need for a comprehensive model, which takes into account radon-daughter inhalation, radon dissolved in body fluids and 210Pb metabolism.     

Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: a case-cohort study

OBJECTIVE: Uranium miners are chronically exposed to low levels of radon and its progeny. We investigated whether radon exposure is associated with increased incidence of leukemia, lymphoma, or multiple myeloma in this population. DESIGN: We conducted a retrospective case-cohort study in 23,043 uranium miners and identified a total of 177 incident cases of leukemia, lymphoma, and myeloma. Detailed information on occupational radon exposure was obtained for the cases and a randomly selected subcohort of 2,393 subjects. We used the proportional hazards model with power relative risk (RR) function to estimate and test the effects of cumulative radon exposures on incidence rates. RESULTS: Incidence of all leukemia combined and chronic lymphocytic leukemia (CLL) alone was positively associated with cumulative radon exposure. The RR comparing high radon exposure [110 working level months (WLM) ; 80th percentile] to low radon exposure (3 WLM ; 20th percentile) was 1.75 [95% confidence interval (CI) , 1.10-2.78 ; p = 0.014] for all leukemia combined and 1.98 (95% CI, 1.10-3.59 ; p = 0.016) for CLL. Myeloid leukemia and Hodgkin lymphoma were also associated with radon, but RRs were not statistically significant. There was no apparent association of radon with either non-Hodgkin lymphoma or multiple myeloma. Exposure to radon and its progeny was associated with an increased risk of developing leukemia in underground uranium miners. CLL, not previously believed to be radiogenic, was linked to radon exposure.