5-AZA-2 '-deoxycytidine-induced dysmorphogenesis in the rat

5-aza-2'-deoxycytidine (d-AZA) causes temporally related defects in the dev eloping mouse. Treatment of 1.0 mg/kg on gestation day (GD) 8 results in ax ial skeletal defects; on GD9, cleft palate and vertebral defects; on GD10, hindlimb phocomelia; and on GD11, digital defects. An unusual aspect of d-A ZA teratogenicity in mice is that the phocomelia appears to be specific to the hindlimb, and the forelimb is not similarly affected regardless of trea tment day. The current study was initiated to evaluate the embryonic respon se of another species, the rat, to this unique teratogen. Pregnant Sprague Dawley (CD) rats were treated with d-AZA or vehicle control. The compound w as administered i.p. on GD9, 10, 11, or 12 to parallel developmental stagin g of the mouse. The highest dose (1.0 mg/kg) elicited effects indicating in creased sensitivity to the compound in the rat as compared to the mouse. GD 9 treatment was characterized by massive resorptions; GD10, by a predominan ce of axial skeletal defects and cleft palate; GD11, by a predominance of f orelimb phocomelia and missing ribs; and GD12 by hindlimb phocomelia and fo relimb digit defects. These data indicate significant differences in the de velopmental responses to d-AZA of the mouse and the rat. This may reflect i nterspecies differences in the temporal expression of genes involved in mor phogenesis and/or the methylation patterns of such genes. Molecular data ge nerated in the mouse will be compared to that of the rat to further charact erize the developmental dynamics responsible for the interspecies differenc es. Teratogenesis Carcinog. Mutagen. 19:329-338, 1999. (C) 1999 Wiley-Liss, Inc.