Abstract
Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance.
Highlights
Molecular endpoints are frequently monitored in tissues derived from in vivo studies
This study was designed to investigate the baseline gene expression changes in livers of rats subjected to common handling procedures in a standard short term multiple dose level preclinical study
Monte-Carlo methods exploring the dependency of signature size (Nsig) and false discovery rate (FDR) on the p-value cutoff (Pth) and number of replicates (n) in each group were employed to determine the Comparison Group 2 vs Group 1 Group 3 vs Group 1 Group 3 vs Group 2
Summary
Molecular endpoints are frequently monitored in tissues derived from in vivo studies. Numerous studies have reported gene expression changes in rat livers in response to various compound treatments [1]. During drug development in particular, the liver has been a major focus of toxicogenomics efforts with the goal of reducing hepatotoxicity which is a common cause for drug failure. These results are potentially affected by common handling procedures, including compound administration, restraint, and blood collection. Gene expression changes detected in toxicology studies can be viewed as a composition of effects resulting from handling of animals as well as treatment with compound and vehicle (Figure 1). While studies have documented the effects of handling on blood pressure, heart rate, and glucocorticoid concentrations in laboratory animals [4,5,6], no work has been reported far that has systematically examined the effects of common handling procedures on hepatic gene expression in rats
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