INDUCTION OF GENOMIC INSTABILITY IN NORMAL HUMAN BRONCHIAL EPITHELIAL-CELLS BY PU-238 ALPHA-PARTICLES

Pulmonary deposition of alpha-particle-emitting radon daughters is est imated to account for 10% of all lung cancer deaths in the USA, Howeve r, the nature and timing of early (preneoplastic) genetic alterations in radon-associated lung cancer are still relatively uncertain, The pu rpose of this investigation was to determine whether genomic instabili ty occurs after exposure of cultured normal human bronchial epithelial cells to six equal, fractionated doses of a-particles (total doses 2- 4 Gy), Two weeks after the final exposure, foci of phenotypically alte red cells (PACs) were detected in 0, 63 and 77% of control, low and hi gh dose cultures respectively, Of these, 18% exhibited extended life s pans relative to unexposed controls, Elevated frequencies of binucleat ed cells (BNCs), a marker of genomic instability, were observed in 60 and 38% of the PAC cultures from the low and high dose groups respecti vely, The micronucleus assay also showed evidence of genomic instabili ty in 40 and 38% of PAC cultures from the low dose and high dose group s 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 hemizy gous deletion at 9p13.3. Another PAC (H9), which exhibited the highest frequency of cells containing micronuclei (MN), exhibited a hemizygou s deletion at 7q31.3. Each loss may represent a stable mutation that r esulted either directly from irradiation or later in progeny of expose d cells because of a-particle-induced genomic instability, The fact th at elevated levels of BNCs and MN were present in the progeny many gen erations after irradiation indicates that the genetic alterations dete cted 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.