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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg097
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received January 26, 2003; accepted March 25, 2003
© 2003 Society of Toxicology

Reproductive and Developmental Toxicology

Genotoxic Stress Response Gene Expression in the Mid-Organogenesis Rat Conceptus

Robert K. Vinson 1 Barbara F. Hales 1*

1 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada, H3G 1Y6

* To whom correspondence should be addressed. E-mail: bhales{at}pharma.mcgill.ca.


  Abstract

The ability of the conceptus to respond to genotoxic stress may be critical for normal development, particularly after exposure to genotoxic teratogens. Members of the phosphatidylinositol 3-kinase (PI3K) superfamily are involved in controlling cell cycle activity and maintaining genomic stability. The expression of PI3K family members, ATM, ATR, and DNA-PKcs, and downstream genes, p53, GADD45, and p21, was examined in the mid-organogenesis rat conceptus in vivo on gestational days (GD) 10-12 and in vitro following exposure to genotoxic stress. ATM was the highest expressed PI3K family member in both yolk sac and embryo proper, with transcript levels increasing ~4-fold in the embryo from GD10 to GD12. Transcript concentrations for ATR, DNA-PKcs, and downstream genes were low in both tissues; all genes had increased transcript levels exclusively in the GD12 embryo. Transient oxidative stress, induced by short term in vitro embryo culture, had no effect on transcript levels in either tissue. Culture for 24 or 44 h significantly decreased ATM transcript levels in both embryo and yolk sac but downstream genes were unaffected compared to GD11 and 12 in vivo levels, respectively. Exposure to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated form of the nitrogen mustard cyclophosphamide (CPA), had no effect on transcript levels for any of the genes examined. Therefore, while transcripts for genotoxic stress response genes are present in the mid-organogenesis rat conceptus, their expression is not regulated by exposure in culture to either transient oxidative stress or a genotoxic alkylating agent. The inability of the conceptus to upregulate transcripts in response to insult may contribute to an increased susceptibility to stressors during organogenesis.

Key Words: DNA damage, oxidative stress, cyclophosphamide, phosphatidylinositol 3-kinase, gene expression, cell cycle checkpoint .


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