Branch S, Francis B M, Brownie C F, Chernoff N
North Carolina State University, Department of Toxicology, Raleigh 27695, USA.
Toxicology. 1996 Aug 1;112(1):37-43. doi: 10.1016/0300-483x(96)88183-2.
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.
5-氮杂-2'-脱氧胞苷（d-AZA）可取代DNA中的胞苷，从而通过被动去除甲基来改变基因表达。本研究确定了d-AZA在小鼠中诱导形态缺陷的时间模式。在妊娠第8、9、10或11天通过单次腹腔注射给予剂量（0、0.3或1.0 mg/kg）。在妊娠第17天处死小鼠并检查胎儿骨骼。1.0 mg/kg剂量在每个治疗日都引发了特征性缺陷：妊娠第8天，肋骨多余（显著高于背景水平）、椎骨和肋骨融合；妊娠第9天，腭裂和椎体变异；妊娠第10天，后肢缺陷（尤其是短肢畸形）；妊娠第11天，前肢和后肢的指（趾）缺陷。d-AZA已知的去甲基化能力以及仅在后肢诱导长骨缺陷表明，d-AZA可能通过DNA低甲基化破坏特定的后肢基因功能而起作用。
