Teratogen-induced eye defects mediated by p53-dependent apoptosis.
BACKGROUND
Many birth defects are believed to involve gene-environment interactions, although the mechanisms involved are poorly understood. Apoptosis is a common effect of many kinds of environmental stresses on the developing embryo; therefore, mechanisms of teratogenesis may be approached within the context of the cell death program. The p53 tumor suppressor gene encodes a transcription factor which functions as a critical regulator of apoptosis in response to environmental stress.


RESULTS
To investigate the relationship between p53-dependent apoptosis and teratogenesis, we subjected day 8 mouse embryos with different p53 gene backgrounds to a genotoxic stress, 2-chloro-2'-deoxyadenosine. Treatment rapidly stimulated nuclear p53 accumulation and triggered apoptosis in some (head-fold) but not other (primitive heart) developing structures. Induced cell death was p53 gene-dose dependent, as shown by the intermediate sensitivity of 4-5 somite stage embryos bearing only a single effective p53 allele and the lack of sensitivity of p53-null mutants. Abnormal development was manifested as eye defects by day 11, particularly lens agenesis. Overall the incidences of these defects at term were 73.3% for p53 wild-type fetuses, 52.5% for heterozygous mutants, and 2.2% for p53-null mutants. Statistical analysis indicated that the interaction between teratogen and genotype was highly significant (P < or = 0.001) for cell death on day 8 and eye defects on day 17.


CONCLUSIONS
We conclude that teratogen induction of p53-dependent apoptosis in the developing embryo is positively coupled to the determination of congenital eye defects.
Wubah
J A
JA
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Ibrahim
M M
MM
Gao
X
X
Nguyen
D
D
Pisano
M M
MM
Knudsen
T B
TB
D000014:Abnormalities, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D017338:Cladribine / Q000494:pharmacology*; D017931:DNA Primers; D003838:Deoxyadenine Nucleotides; D005124:Eye Abnormalities / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013723:Teratogens / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D003838:Deoxyadenine Nucleotides; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D017338:Cladribine; C012873:2'-deoxy-5'-adenosine monophosphate