TERATOGEN-INDUCED EYE DEFECTS MEDIATED BY P53-DEPENDENT APOPTOSIS

Background: Many birth defects are believed to involve gene-environmen t 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 tu mor 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 apopto sis and teratogenesis, we subjected day 8 mouse embryos with different p53 gene backgrounds to a genotoxic stress, 2-chloro-2'-deoxyadenosin e. Treatment rapidly stimulated nuclear p53 accumulation and triggered apoptosis in some (head-fold) but not other (primitive heart) develop ing structures. Induced cell death was p53 gene-dose dependent, as sho wn 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 d ay 11, particularly lens agenesis. Overall the incidences of these def ects at term were 73.3% for p53 wild-type fetuses, 52.5% for heterozyg ous mutants, and 2.2% for p53-null mutants. Statistical analysis indic ated that the interaction between teratogen and genotype was highly si gnificant (P less than or equal to 0.001) for cell death on day 8 and eye defects on day 17. Conclusions: We conclude that teratogen inducti on of p53-dependent apoptosis in the developing embryo is positively c oupled to the determination of congenital eye defects.