TERATOGENIC EFFECTS OF THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINEIN THE SWISS WEBSTER MOUSE

5-Aza-2'-deoxycytidine (d-AZA) replaces cytidine in DNA thereby alteri ng gene expression by passively removing methyl groups. This study det ermined the temporal patterns of morphological defects induced by d-AZ A in mice. The dosages (0, 0.3, or 1.0 mg/kg) were administered by a s ingle i.p. injection on gestational days (GD) 8, 9, 10, or 11. Mice we re killed on GD 17 and fetal skeletons examined. The 1.0 mg/kg dose el icited characteristic defects for each treatment day: GD 8, supernumer ary ribs, (significantly above background),fused vertebrae and ribs; G D 9, cleft palate and vertebral variations; GD 10 hind limb defects (e specially phocomelia); GD 11, digital defects of fore and hindlimbs. T he known demethylating ability of d-AZA coupled with the induction of longbone defects only in the hindlimbs suggests that d-AZA may act by disrupting specific hindlimb gene function through DNA hypomethylation .