We conclude that teratogen induction of p53-dependent apoptosis in the developing embryo is positively coupled to the determination of congenital eye defects.

Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered teratogenicity in early embryos. To gain insight into the function of p53 during early embryogenesis, RNA profiles of wild-type p53(+/+) and p53(-/-) null mutant mouse embryos were compared at the head-fold stage (day 8 post coitum) using HPLC-based mRNA differential display. The results of this screen revealed a deficiency of mitochondrial 16S ribosomal RNA in p53(-/-) embryos. RT-PCR showed abnormalities in 16S rRNA levels relative to some representative nuclear (COIV, beta-actin) and mitochondrial (COIII) transcripts in p53(-/-) embryos, and that 16S rRNA expression increased with development of p53(+/+) embryos during neurulation. Embryos that lack p53 also displayed weakened cytochrome c oxidase staining and reduced ATP content. During neurulation, the mouse embryo switches from an anaerobic (glycolytic) to an aerobic (oxidative) metabolism. The preliminary results of the present study suggest that p53 may be involved, directly or indirectly, in this transition.

Microphthalmia represented the critical effect malformation of 2CdA. The findings suggest a mitochondrial mechanism for 2CdA bioactivation, leading to an embryonic p53 response only after 2CdA elimination and implying pharmacodynamic coupling to the exposure-disease continuum. Published 2001 Wiley-Liss, Inc.

2-CdA produced similar ocular defects in the rat and mouse, although the incidence was much lower in the former species. In contrast, the drug-induced lumbar hernia was only seen in the rat. These apparent disparities were not readily explained by species differences in pharmacokinetic parameters. the similarities between the teratological features of 2-CdA-induced lumbar hernia in the rat and the clinical description of lumbocostovertebral syndrome, however, may provide a key to unlock the etiology of this rare birth defect in humans.

The spatial distribution and early postnatal onset of Vpp1 expression is consistent with a role for this gene in prostate regionalization. The absolute prostate specificity of Vpp1 expression may allow this gene to serve as a paradigm to study the molecular basis of gene expression that is restricted exclusively to the prostate gland.