Kennedy C H, Mitchell C E, Fukushima N H, Neft R E, Lechner J F
Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM 87185, USA.
Carcinogenesis. 1996 Aug;17(8):1671-6. doi: 10.1093/carcin/17.8.1671.
Pulmonary deposition of alpha-particle-emitting radon daughters is estimated to account for 10% of all lung cancer deaths in the USA. However, the nature and timing of early (preneoplastic) genetic alterations in radon-associated lung cancer are still relatively uncertain. The purpose of this investigation was to determine whether genomic instability occurs after exposure of cultured normal human bronchial epithelial cells to six equal, fractionated doses of alpha-particles (total doses 2-4 Gy). Two weeks after the final exposure, foci of phenotypically altered cells (PACs) were detected in 0, 63 and 77% of control, low and high dose cultures respectively. Of these, 18% exhibited extended life spans relative to unexposed controls. Elevated frequencies of binucleated cells (BNCs), a marker of genomic instability, were observed in 60 and 38% of the PAC cultures from the low and high dose groups respectively. The micronucleus assay also showed evidence of genomic instability in 40 and 38% of PAC cultures from the low dose and high dose groups respectively. No changes in microsatellite length, another marker of genomic instability, were detected in any of the PAC samples with the 28 markers used for this assay. However, one PAC (L2) showed a hemizygous deletion at 9p13.3. Another PAC (H9), which exhibited the highest frequency of cells containing micronuclei (MN), exhibited a hemizygous deletion at 7q31.3. Each loss may represent a stable mutation that resulted either directly from irradiation or later in progeny of exposed cells because of alpha-particle-induced genomic instability. The fact that elevated levels of BNCs and MN were present in the progeny many generations after irradiation indicates that the genetic alterations detected with these two markers were not a direct consequence of radiation exposure, but of resulting genomic instability, which may be an early change after exposure to alpha-particles.
据估计，在美国，发射α粒子的氡子体在肺部的沉积导致的肺癌死亡占所有肺癌死亡病例的10%。然而，氡相关肺癌早期（癌前）基因改变的性质和时间仍相对不确定。本研究的目的是确定培养的正常人支气管上皮细胞在接受六次等量分次的α粒子照射（总剂量2 - 4 Gy）后是否会发生基因组不稳定。末次照射两周后，在对照、低剂量和高剂量培养组中，分别有0%、63%和77%检测到表型改变细胞（PAC）灶。其中，18%的PAC相对于未照射的对照表现出延长的寿命。作为基因组不稳定标志物的双核细胞（BNC）频率升高，在低剂量组和高剂量组的PAC培养物中分别有60%和38%观察到。微核试验也显示，低剂量组和高剂量组的PAC培养物中分别有40%和38%存在基因组不稳定的证据。使用本试验的28个标志物，在任何PAC样本中均未检测到作为基因组不稳定另一标志物的微卫星长度变化。然而，一个PAC（L2）在9p13.3处出现半合子缺失。另一个PAC（H9），其含有微核（MN）的细胞频率最高，在7q31.3处出现半合子缺失。每一次缺失可能代表一个稳定的突变，该突变要么直接由辐射导致，要么在照射细胞的后代中由于α粒子诱导的基因组不稳定而产生。照射后许多代的后代中BNC和MN水平升高这一事实表明，用这两种标志物检测到的基因改变不是辐射暴露的直接后果，而是基因组不稳定的结果，这可能是暴露于α粒子后的早期变化。
