Teratogenic effects of the demethylating agent 5-aza-2'-deoxycytidine in the Swiss Webster mouse.
5-Aza-2'-deoxycytidine (d-AZA) replaces cytidine in DNA thereby altering gene expression by passively removing methyl groups. This study determined the temporal patterns of morphological defects induced by d-AZA in mice. The dosages (0, 0.3, or 1.0 mg/kg) were administered by a single i.p. injection on gestational days (GD) 8, 9, 10, or 11. Mice were killed on GD 17 and fetal skeletons examined. The 1.0 mg/kg dose elicited characteristic defects for each treatment day: GD 8, supernumerary ribs, (significantly above background), fused vertebrae and ribs; GD 9, cleft palate and vertebral variations; GD 10, hind limb defects (especially phocomelia); GD 11, digital defects of fore and hindlimbs. The 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.
Branch
S
S
North Carolina State University, Department of Toxicology, Raleigh 27695, USA.
Francis
B M
BM
Brownie
C F
CF
Chernoff
N
N
D000704:Analysis of Variance; D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002972:Cleft Palate / Q000139:chemically induced / Q000196:embryology; D004249:DNA Damage / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D005865:Gestational Age; D006614:Hindlimb / Q000187:drug effects / Q000196:embryology; D007274:Injections, Intraperitoneal; D051379:Mice; D011247:Pregnancy; D012272:Ribs / Q000187:drug effects / Q000196:embryology; D013131:Spine / Q000187:drug effects / Q000196:embryology; D013723:Teratogens / Q000633:toxicity*
D004791:Enzyme Inhibitors; D013723:Teratogens; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine