Glaviano A, Nayak V, Cabuy E, Baird D M, Yin Z, Newson R, Ladon D, Rubio M A, Slijepcevic P, Lyng F, Mothersill C, Case C P
Bristol Implant Research Centre, University of Bristol, Bristol, UK.
Oncogene. 2006 Jun 8;25(24):3424-35. doi: 10.1038/sj.onc.1209399. Epub 2006 Jan 30.
There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longer-term genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERT- cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased beta-galactosidase staining and apoptosis. This instability was not present in telomerase-positive hTERT+ cells. In contrast, in hTERT+ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERT- cells. The growth and survival of both metal-exposed hTERT+ and hTERT- cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.
目前，人们对低剂量接触各种污染物所产生的延迟性染色体及其他损害效应极为关注，这些污染物似乎共同通过诱导与氧化应激和衰老相关的应激反应途径发挥作用。这些效应大多在辐射领域进行了研究，但越来越多的证据表明，化学物质，尤其是重金属，也能触发这些机制。人类通过环境、工业和外科植入物接触包括铬（Cr）（VI）和钒（V）（V）在内的金属。因此，低剂量应激反应的影响可能比个体毒性预测所预期的要大。在本研究中，人类成纤维细胞短期（24小时）暴露于低剂量的Cr（VI）和V（V），在暴露后至少30天内，导致暴露细胞后代出现急性染色体损伤和基因组不稳定。急性情况下，Cr（VI）导致染色单体断裂但无非整倍体，而V（V）导致非整倍体但无染色单体断裂。长期的基因组不稳定情况相似，但取决于hTERT的阳性状态。在端粒酶阴性的hTERT -细胞中，Cr（VI）和V（V）导致双着丝粒染色体、核质桥、微核和非整倍体的长期持续诱导。克隆形成存活率也出现长期且可遗传的降低，同时β -半乳糖苷酶染色增加和细胞凋亡。这种不稳定性在端粒酶阳性的hTERT +细胞中不存在。相反，在hTERT +细胞中，这些金属导致四倍体的持续诱导，而在hTERT -细胞中未观察到这种情况。如果将暴露于金属的hTERT +和hTERT -细胞以亚汇合水平培养或接种成集落，它们的生长和存活情况会有所不同。基因组不稳定被认为是癌症发展的驱动力。这项研究表明，人类细胞中基因组不稳定的类型可能严重取决于它们是端粒酶阳性还是阴性，并且它们对金属的敏感性可能取决于它们是聚集的还是分散的。
