title: Resistance of CD-1 and ogg1 DNA repair-deficient mice to thalidomide and hydrolysis product embryopathies in embryo culture.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Crystal J J
authors.initials: CJ
authors.lastname: Lee
authors.forename: Luisa L
authors.initials: LL
authors.lastname: Gonçalves
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000473:pathology; D046149:Embryo Culture Techniques; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced* / Q000235:genetics; D005838:Genotype; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D011506:Proteins / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity*
chemical_list: D011506:Proteins; D013723:Teratogens; D013792:Thalidomide; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse