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ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg142
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 17, 2003; accepted April 22, 2003
© 2003 Society of Toxicology

Systems Toxicology

Gene Expression Analysis of the Acute Phase Response Using a Canine Microarray

M.A. Higgins 1, B.R. Berridge 2, B.J. Mills 3, A.E. Schultze 2, H. Gao 1, G.H. Searfoss 1, T.K. Baker 1, T.P. Ryan 1*

1 Department of Lead Optimization Toxicology, Lilly Research Laboratories, Divisions of Eli Lilly and Company, Greenfield, IN 46140
2 Department of Pathology, Lilly Research Laboratories, Divisions of Eli Lilly and Company, Greenfield, IN 46140
3 Elanco Animal Health, Divisions of Eli Lilly and Company, Greenfield, IN 46140

* To whom correspondence should be addressed. E-mail: timryan{at}lilly.com.


  Abstract

The safety of pharmaceuticals is typically assessed in the dog and rat prior to investigation in humans. As a result, a greater understanding of adverse effects in these pre-clinical testing species would improve safety assessment. Despite this need, there is a lack of tools to examine mechanisms and identify biomarkers in the dog. To address this issue, we developed an Affymetrix-based oligonucleotide microarray capable of monitoring the expression of thousands of canine genes in parallel. The custom canine array contains 22,774 probe sets, consisting of 13,729 canine and 9,045 human-derived probe sets. To improve cross-species hybridization with human-derived probes, the detection region was moved from the variable 3' UTR to the more homologous coding region. Testing of this strategy was accomplished by comparing hybridization of naïve dog liver RNA to the canine array (coding region design) and human U133A array (standard 3' design). Although raw signal intensity was greater with canine-specific probe sets, human-derived probes detected the expression of additional liver transcripts. To assess the ability of this tool to detect differential gene expression, the acute phase response was examined in beagle dogs given lipopolysaccharide (LPS). Hepatic gene expression 4 and 24 hours post-LPS administration was compared to gene expression profiles of vehicle-treated dogs (n=3/group). Array data was consistent with an acute inflammatory response, with transcripts for multiple cytokines and acute phase proteins markedly induced 4 hours after LPS challenge. Robust changes in the expression of transcripts involved with glucose homeostasis, biotransformation, and extracellular matrix remodeling were observed 24 hours post-dose. Strong correlations were found between gene expression data and alterations in clinical chemistry parameters such as serum amyloid A (SAA), albumin, and alkaline phosphatase (ALP). In addition, the canine array identified several potential biomarkers of hepatic inflammation. In summary, this new genomic tool successfully detected basal canine gene expression and identified novel aspects of the acute phase response in dog that shed new light on mechanisms underlying inflammatory processes.

Key Words: acute phase response, canine genomics, dog, gene expression, inflammation, lipopolysaccharide (LPS), liver, microarray, toxicogenomics .


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