Effects of hTERT on metal ion-induced genomic instability.

Abstract:

: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.

journal_name

Oncogene

journal_title

Oncogene

authors

Glaviano A,Nayak V,Cabuy E,Baird DM,Yin Z,Newson R,Ladon D,Rubio MA,Slijepcevic P,Lyng F,Mothersill C,Case CP

doi

10.1038/sj.onc.1209399

subject

Has Abstract

pub_date

2006-06-08 00:00:00

pages

3424-35

issue

24

eissn

0950-9232

issn

1476-5594

pii

1209399

journal_volume

25

pub_type

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