ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 345-359 (2004)
Toxicological Sciences vol. 79 no. 2 © Society of Toxicology; all rights reserved.
Alterations in Gene Expression Induced in Day-9 Mouse Embryos Exposed to Hyperthermia (HS) or 4-Hydroperoxycyclophosphamide (4CP): Analysis Using cDNA Microarrays
* Birth Defects Research Laboratory, Division of Genetics and Developmental Medicine, Departments of Pediatrics and Environmental Health; Fred Hutchinson Cancer Research Center; and Department of Biostatistics; University of Washington, Seattle, Washington 98195
Received September 17, 2003; accepted January 20, 2004
Teratogen-induced alterations in gene expression play an important role in the genesis of malformations in animals. The recent development of DNA microarrays now offers the opportunity to monitor global changes in gene expression and therefore the potential to obtain significant new information concerning both normal and abnormal development. RNA was isolated from day-9 mouse embryos at 1 and 5 h after exposure to hyperthermia (HS) or 4-hydroperoxycyclophosphamide (4CP) and compared to RNA isolated from concurrent controls using mouse cDNA microarrays. Cy5/Cy3 intensity data were extracted using Spot-on Image software and then normalized using the statistical software program R/maanova. Differentially expressed genes were identified using a linear mixed-effects model and p values derived from t-test statistics. Approximately 9000 genes show statistically significant alterations in expression in day-9 mouse embryos exposed to HS or 4CP. HS and 4CP also induce alterations in the expression of distinct sets of genes, e.g., DNA replication/repair, cell cycle, signal transduction, and transcription-related genes. As expected, a variety of heat shock genes are upregulated by HS but not 4CP. Among genes whose expression is altered by both HS and 4CP, cluster analysis identified three p53 target genes (Cyclin G1, Gtse1, and Mdm2), and follow up studies confirmed that p53 is activated in embryos exposed to these two teratogens. In addition, cluster analyses also revealed that HS but not 4CP induces the downregulation of genes encoding key enzymes in the cholesterol biosynthesis pathway. Thus, our microarray data have identified one potentially important pathway (p53) common to both HS- and 4CP-induced teratogenesis and another pathway (cholesterol biosynthesis) potentially important, but specific to HS-induced teratogenesis.
Key Words: day-9 mouse embryos; hyperthermia; 4-hydroperoxycyclophosphamide; cDNA microarrays; gene expression profiling.
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