Miller Alexandra C, Brooks Kia, Stewart Michael, Anderson Blake, Shi Lin, McClain David, Page Natalie
Applied Cellular Radiobiology Department Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA.
J Environ Radioact. 2003;64(2-3):247-59. doi: 10.1016/s0265-931x(02)00053-x.
It is known that radiation can induce a transmissible persistent destabilization of the genome. We have established an in vitro cellular model using HOS cells to investigate whether genomic instability plays a role in depleted uranium (DU)-induced effects. Transmissible genomic instability, manifested in the progeny of cells exposed to ionizing radiation, has been characterized by de novo chromosomal aberrations, gene mutations, and an enhanced death rate. Cell lethality and micronuclei formation were measured at various times after exposure to DU, Ni, or gamma radiation. Following a prompt, concentration-dependent acute response for both endpoints, there was de novo genomic instability in progeny cells. Delayed reproductive death was observed for many generations (36 days, 30 population doublings) following exposure to DU, Ni, or gamma radiation. While DU stimulated delayed production of micronuclei up to 36 days after exposure, levels in cells exposed to gamma-radiation or Ni returned to normal after 12 days. There was also a persistent increase in micronuclei in all clones isolated from cells that had been exposed to nontoxic concentrations of DU. While clones isolated from gamma-irradiated cells (at doses equitoxic to metal exposure) generally demonstrated an increase in micronuclei, most clonal progeny of Ni-exposed cells did not. These studies demonstrate that DU exposure in vitro results in genomic instability manifested as delayed reproductive death and micronuclei formation.
众所周知，辐射可诱发基因组的可传递性持续不稳定。我们利用人骨肉瘤细胞（HOS细胞）建立了一个体外细胞模型，以研究基因组不稳定是否在贫铀（DU）诱导的效应中发挥作用。可传递的基因组不稳定表现为暴露于电离辐射的细胞后代出现的从头染色体畸变、基因突变和死亡率增加。在暴露于DU、镍（Ni）或γ辐射后的不同时间测量细胞杀伤力和微核形成情况。对于这两个终点，在出现迅速的、浓度依赖性急性反应后，子代细胞中出现了从头基因组不稳定。在暴露于DU、Ni或γ辐射后的许多代（36天，30次群体倍增）中都观察到了延迟性生殖死亡。虽然DU在暴露后长达36天刺激了微核的延迟产生，但暴露于γ辐射或Ni的细胞中的微核水平在12天后恢复正常。从暴露于无毒浓度DU的细胞中分离出的所有克隆中，微核也持续增加。虽然从γ辐射细胞（剂量与金属暴露等效毒性）中分离出的克隆通常显示微核增加，但暴露于Ni的细胞的大多数克隆后代并非如此。这些研究表明，体外暴露于DU会导致基因组不稳定，表现为延迟性生殖死亡和微核形成。
