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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh080
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received September 17, 2003; accepted January 20, 2004
© 2004 Society of Toxicology

Reproductive and Developmental Toxicology

Alterations in Gene Expression Induced in Day 9 Mouse Embryos Exposed to Hyperthermia (HS) or 4-Hydroperoxycyclophosphamide (4CP): Analysis Using cDNA Microarrays

Svetlana Mikheeva 1, Marianne Barrier 1, Sally A. Little 1, Richard Beyer 2, Andrei M. Mikheev 3, M. Kathleen Kerr 4, and Philip E. Mirkes 1*

1 Birth Defects Research Laboratory, Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195
2 Department of Environmental Health, University of Washington, Seattle, WA 98195
3 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195
4 Department of Biostatistics, University of Washington, Seattle, WA 98195

* To whom correspondence should be addressed. E-mail: pemst{at}u.washington.edu.


  Abstract

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 hours 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 9,000 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 up-regulated by HS but not 4CP. Among genes whose expression is altered by both HS and 4CP, cluster analysis identified 3 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 down-regulation 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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H. Hosako, S. A. Little, M. Barrier, and P. E. Mirkes
Teratogen-Induced Activation of p53 in Early Postimplantation Mouse Embryos
Toxicol. Sci., January 1, 2007; 95(1): 257 - 269.
[Abstract] [Full Text] [PDF]


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