Cefic-lri Programme | European Chemical Industry Council

CC2-UNBI: Determination of Human and Rodent Gene Expression Patterns in Response to Chemical Carcinogens: Facilitation of Knowledge-Based Human Risk Assessment From Molecular Mechanisms

Principal Investigator

Prof. Kevin Chipman
University of Birmingham
Edgbaston
Birmingham, B15 2TT
UK
Jk.chipman@bham.ac.uk
Tel: +44 121-414-5422
Fax: +44 121-414-3982

Collaborators

Dr. George Orphanides – Syngenta CTL
george.orphanides@syngenta.com

Description

Naturally-occurring and man-made chemicals are widespread in the environment. Predictions of human health risks are usually based on laboratory tests on animals such as rats and mice. Occasionally, cancer does occur in mice alone or in both rats and mice – particularly in the liver – without any evidence of the DNA damage normally associated with carcinogens. Regulators must then ask what the risk would be if humans were exposed. A conservative approach assumes that chemicals which cause cancer in laboratory animals are probable human carcinogens. However, this may be incorrect since studies of human populations with higher-than-normal exposure levels have failed to confirm predictions from mouse and rat tests. A reliable prediction of human responses is given by human liver cells (hepatocytes). Species differences between mouse, rat and human cell responses are commonplace. Confidence in predictions of safety to humans can only come from a better understanding of how such chemicals interact with cells.

Toxicogenomics has the potential to reveal the molecular pathways and cellular processes that mediate the adverse responses to a toxicant. However, the initial output of a toxicogenomic experiment often consists of large lists of genes whose expression is altered after toxicant exposure. To interpret gene expression changes in the context of underlying biological pathways and processes, new bioinformatics methods must be developed.

This study applied state-of-the-art genomic technology to improving understanding of interactions between chemicals and cells from humans and laboratory animals. Genomics allows rapid and simultaneous evaluation of hundreds to thousands of genes, allowing identification of multiple key molecular changes responsible for a toxicological response. Global gene expression profiling combined with an evaluation of Gene Ontology (GO) and pathway mapping tools were used as unbiased methods for identifying the molecular pathways and processes affected upon toxicant exposure.

Related Publications

RA Currie, V Bombail, JD Oliver, DJ Moore, FL Lim, V Gwilliam, I Kimber, K Chipman, JG Moggs, G Orphanides, Gene Ontology Mapping as an Unbiased Method for Identifying Molecular Pathways and Processes Affected by Toxicant Exposure: Application to Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate, Toxicological Sciences 2005, 86, 453-469.

Timeline: January 2001 > June 2004

LRI funding: €575,561

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