Document Type

Theses, Ph.D

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

1.6 BIOLOGICAL SCIENCES

Publication Details

Thesis successfully submitted for the award of Doctor of Philosophy to the Dublin Institute of Technology, September, 2009.

Abstract

The radiation-induced bystander effect is a phenomenon known to occur post irradiation, characterised by the induction of biological effects in unirradiated cells as a result of receiving signals from irradiated cells or their culture medium. Chemicalinduced bystander effects are poorly characterised and there are no reports of a bystander effect induced by metals. Heavy metals and in particular chromium (VI) are known to cause persistent genomic instability. For the first time, this study provides evidence that a short, low-dose exposure of human fibroblasts to chromium (VI) causes a bystander effect in human fibroblasts that persists for at least thirty days post metal treatment. The biological effects induced in these bystander cells include induction of micronuclei, nucleoplasmic bridges, cytogenetic abnormalities and DNA Crucially, this effect depends on whether the bystander cells are telomerase positive or negative. Telomerase negative human fibroblasts respond to a mediumtransmissible bystander signal from all ‘donor’ cell types; but telomerase positive cells, whether they express ectopic hTERT or physiological telomerase as is the case for the immortalized k1 thyroid carcinoma cell line and human embryonic stem cells, are resistant to a signal from other telomerase positive cells. Treatment of cells with ascorbic acid revealed that the role of oxidative stress in transmission of bystander responses is more important for telomerase positive cells than telomerase negative cells. The role of TNF-alpha was also explored. In telomerase negative cells, addition of a neutralizing antibody to TNF-alpha to conditioned medium from either cell type caused a significant reduction in bystander γ-H2AX foci. In contrast, there was a significant reduction in γ-H2AX foci in bystander telomerase positive cells exposed to conditioned medium from telomerase negative but not telomerase positive donor cells. Inhibition of p38MAP Kinase by SB203580 had no effect on bystander signalling. This study highlights novel considerations for predicting the outcome of metal exposure and the importance of the indirect biological effects of heavy metals in cancer risk assessment, which has implications for cancer therapy.

DOI

10.21427/D7RW2R

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