The impact of human superoxide dismutase 1 expression in a mouse model on the embryotoxicity of hydroxyurea

✍ Scribed by Geneviève Larouche; Barbara F. Hales

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 245 KB
• Volume: 85
• Category: Article
• ISSN: 1542-0752
• DOI: 10.1002/bdra.20595

✦ Synopsis

Abstract

BACKGROUND:

Oxidative stress is hypothesized to mediate embryotoxicity during organogenesis, yet the reactive oxygen species involved are not defined. The superoxide oxygen radical is converted to hydrogen peroxide, a less reactive species, by superoxide dismutases (SODs). If superoxide is important in mediating embryotoxicity, increased SOD expression should protect embryos against insult. Exposure to hydroxyurea during organogenesis causes brain defects, cleft palate, tail anomalies, and limb defects; administration of D‐mannitol, a free radical scavenger, ameliorates hydroxyurea embryotoxicity, suggesting that oxidative stress is important. To elucidate the role of superoxide in mediating hydroxyurea embryotoxicity, we assessed the impact of human SOD1 expression in a murine model.

METHODS:

hSOD1 hemizygous male mice, carrying the human SOD1 gene, were mated to wild‐type or hSOD1 hemizygous females. Dams were treated on gestation day (GD) 9 with saline (control) or 400 (low) or 600 (high) mg/kg hydroxyurea (n = 8–13/group). Mice were euthanized on GD 18 and developmental toxicity was assessed.

RESULTS:

Exposure to hydroxyurea caused a dose‐dependent increase in fetal deaths that was not affected by hSOD1 expression; hydroxyurea decreased fetal weights in litters from wild‐type but not hemizygous dams. Hydroxyurea increased the incidence of external and skeletal malformations; fetuses from hemizygous dams treated with high‐dose hydroxyurea had fewer malformations compared to wild‐type dams. There was no correlation between embryonic phenotype and genotype or SOD activity.

CONCLUSION:

Maternal hSOD1 expression protected fetuses against malformations induced by hydroxyurea, providing evidence that superoxide plays a role in mediating the response of organogenesis stage embryos to this teratogen. Birth Defects Research (Part A) 2009. © 2009 Wiley‐Liss, Inc.