Sensitivity to cadmium-chloride-induced forelimb ectrodactyly is independent of the p53 gene-dosage in the C57BL/6J mouse.
BACKGROUND
The p53 pathway plays an important role in the regulation of apoptosis, osteoblast differentiation, skeletal development, and teratogenic sensitivity. The administration of cadmium chloride (CdCl(2)) on gestational day 9 in susceptible mouse strains causes postaxial forelimb ectrodactyly in a percentage of fetuses through unknown mechanisms. In this study, the hypothesis that the p53 gene dosage might affect the incidence or severity of CdCl(2)-induced forelimb ectrodactyly was examined.


METHODS
Heterozygous p53-null female mice, on the C57BL/6J background known to be sensitive to CdCl(2)-induced forelimb ectrodactyly, were mated with heterozygous males and then treated with a single intraperitoneal (ip) dose of CdCl(2) (4 mg x kg(-1)) at embryonic day (ED) 9. Embryos and fetuses, genotyped using DNA isolated from the yolk sacs, were collected at ED10 and examined for the pattern of cell death in the limb buds or collected at ED18 and examined for limb malformations.


RESULTS
In the wild type and heterozygous p53 embryonic limb buds, CdCl(2)-induced apoptosis involved mesenchymal cells as well as the apical ectodermal ridge (AER), whereas CdCl(2)-induced apoptosis was restricted mainly to the AER in the homozygous p53-null limb buds. No difference in the incidence or severity of forelimb ectrodactyly in the embryos of different p53 genotypes was observed.


CONCLUSIONS
Despite the fact that CdCl(2) induced both p53-dependent (in the mesenchyme) and p53-independent (in the AER) cell death in the developing limb bud, CdCl(2)-induced ectrodactyly was independent of the p53 gene dosage at the studied time point.
Elsaid
Ahmed F
AF
Molecular Toxicology Interdepartmental Program, University of California at Los Angeles, Los Angeles, California, USA.
Koriem
Khaled M M
KM
Collins
Michael D
MD
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000633:toxicity*; D004475:Ectoderm / Q000187:drug effects*; D004480:Ectromelia / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D005552:Forelimb / Q000196:embryology*; D018628:Gene Dosage; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D018878:Limb Buds / Q000187:drug effects* / Q000196:embryology; D008098:Litter Size / Q000187:drug effects; D008297:Male; D008648:Mesoderm / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011884:Radius / Q000002:abnormalities; D014034:Toes / Q000002:abnormalities; D014457:Ulna / Q000002:abnormalities; D038062:Upper Extremity Deformities, Congenital / Q000139:chemically induced / Q000235:genetics*
D019256:Cadmium Chloride