ToxSci Advance Access published online on March 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi148
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1 Department of Pharmacology and Therapeutics McGill University, Montreal, QC, Canada
* To whom correspondence should be addressed. Hydroxyurea is a potent teratogen; free radical scavengers or antioxidants reduce its teratogenicity. Activator Protein-1 (AP-1) and NF-
Received December 12, 2004
Accepted March 3, 2005
Reproductive and Developmental Toxicology
Activator Protein-1 (AP-1) DNA Binding Activity Is Induced By Hydroxyurea In Organogenesis Stage Mouse Embryos
Barbara F. Hales, E-mail: barbara.hales{at}mcgill.ca
Abstract 
B are redox sensitive transcription factors with important roles in normal development and the stress response. This study determined if exposure to teratogenic doses of hydroxyurea induces oxidative stress and alters gene expression by activating these transcription factors. Pregnant mice were treated with saline or hydroxyurea (400, 500, or 600 mg/kg) on gestation day 9 (GD9) and killed either on GD9, 0.5, 3 or 6 hrs after treatment, to assess oxidative stress and transcription factor activities, or on GD18, to assess fetal development. Exposure to 400 mg/kg hydroxyurea did not affect the progeny, while exposure to 500 or 600 mg/kg resulted in dose-dependent increases in fetal resorptions and malformations, including curly tails, abnormal limbs (oligodactyly, hemimelia, and amelia), and short ribs. Hydroxyurea did not induce oxidative stress, as assessed by the ratio of oxidized to reduced glutathione, or alter NF-B DNA binding activity in the GD9 conceptus. In contrast, exposure to hydroxyurea at any dose increased AP-1 DNA binding activity in embryos and yolk sacs 0.5 or 3 hrs after treatment. Hydroxyurea-induced c-Fos heterodimer activity in the embryo peaked 3-4 fold above control at 3 hrs and remained elevated by 6 hrs; in contrast, the activity of c- Jun dimers was not altered by drug exposure. A dramatic and region-specific increase in c-Fos immunoreactivity was found in hydroxyurea-treated embryos. The induction of AP-1 DNA binding activity by hydroxyurea represents an early, sensitive marker of the embryonic response to insult.
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