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Listen to this siteWednesday 24 March 2004
This research project seeks to develop biomarkers that are predictive of subsequent tumour formation by non-genotoxic chemicals.
Study Duration : April 2000 to January 2006
Contractor : BIBRA International Ltd and CXR Biosciences Ltd, University of Dundee
A large number of food and environmental chemicals have been shown to produce tumours in experimental animals. Such chemicals can be broadly divided into genotoxic (substances that damage DNA) and non-genotoxic agents. While screening tests are available for DNA reactive (genotoxic) agents, non-genotoxic carcinogens are only normally identified by performing chronic rodent bioassay studies. The objective of this project is to develop biomarkers that are predictive of subsequent tumour formation by non-genotoxic chemicals in experimental animals. Such biomarkers could be employed in conjunction with biomarkers of exposure, to provide a better assessment of the hazard of food chemicals to humans.
Three different approaches are being employed to identify novel biomarkers:
The proteomics studies showed that compared to the controls, treatment with either furan, chloroform, di-(2-ethylhexyl) phthalate or oxazepam resulted in alterations in the pattern of expression of liver proteins and identified some potentially useful biomarkers of non-genotoxic mouse liver carcinogenesis. These studies also demonstrated effects of the test compounds on some GSH S-transferase forms.
Examination of the gene expression data obtained demonstrated that there was no single gene whose expression discriminated between carcinogenic and non-carcinogenic doses of all four test compounds at all time points examined. However, a number of genes were identified as potentially useful biomarkers when used in combination. The genes identified as potentially useful biomarkers were not necessarily selective for either the two cytotoxic or the two mitogenic agents studied. From the data obtained in this study the best potential biomarkers used in combination were Gadd45, c-myc, Igfbp1 and GSTM1. For effects after 1 day only, TGF also appeared to be a useful biomarker.
It was concluded that effects on the p53 pathway were unlikely to result in the identification of novel biomarkers of non-genotoxic mouse liver tumour formation, however, the results of the proteomics and molecular analysis studies conducted in this project identified some potentially useful biomarkers of non-genotoxic mouse liver tumour formation. The biomarkers identified in these studies appear to be associated with cell cycling and proliferation and other genes.
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