Journal Article

Resistance of CD-1 and <i>ogg1</i> DNA Repair–Deficient Mice to Thalidomide and Hydrolysis Product Embryopathies in Embryo Culture

Crystal J. J. Lee, Luisa L. Gonçalves and Peter G. Wells

in Toxicological Sciences

Volume 122, issue 1, pages 146-156
Published in print July 2011 | ISSN: 1096-6080
Published online April 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr084
Resistance of CD-1 and ogg1 DNA Repair–Deficient Mice to Thalidomide and Hydrolysis Product Embryopathies in Embryo Culture

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Thalidomide (TD) displays remarkable species specificity, causing birth defects (teratogenesis) in humans and rabbits, but not rats or mice; yet, few determinants of species susceptibility have been identified. Also, certain mouse strains are susceptible to the embryopathic effects of some teratogens in embryo culture despite their resistance in vivo. Herein we show that CD-1 mouse embryos in culture are resistant to limb embryopathies caused by TD and two of its hydrolysis products, 2-phthalimidoglutaramic acid and 2-phthalimidoglutaric acid, although all three compounds cause these embryopathies in rabbit embryo culture. These results show that the resistance of CD-1 mice to TD teratogenesis is inherent to the embryo and is not dependent upon maternal factors, including differential in vivo exposure to the many hydrolysis products of TD. In utero TD exposure of rabbit but not mouse embryos elevates levels of the teratogenic oxidative DNA lesion 8-oxoguanine, which is repaired by oxoguanine glycosylase 1 (OGG1). However, DNA repair–deficient ogg1 knockout mice proved resistant to TD-initiated embryopathies in culture and teratogenesis in vivo, indicating that the resistance of mice is not due to a higher level of DNA repair.

Keywords: thalidomide; hydrolysis products; embryopathies; mouse embryo culture; DNA repair; oxoguanine glycosylase 1

Journal Article.  6585 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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