PMID- 7536356
OWN - NLM
STAT- MEDLINE
DCOM- 19950517
LR  - 20181130
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 50
IP  - 5
DP  - 1994 Nov
TI  - Cell death and cell cycle perturbation in the developmental toxicity of the 
      demethylating agent, 5-aza-2'-deoxycytidine.
PG  - 332-9
AB  - DNA methylation is a probable mechanism for regulating gene expression, and 
      alterations in methylation may significantly affect embryonic development. We 
      administered the cytidine analogue 5-aza-2'-deoxycytidine (dAZA), a specific and 
      potent demethylator of DNA, to pregnant mice to determine its teratogenicity and 
      effects on embryonic cell death and cell cycle. Groups of females were dosed 
      intraperitoneally on gestation day 10 with doses of 0.05-3 mg/kg dAZA and killed 
      at 4, 8, or 28 hr later. Two embryos per litter were immediately stained with 
      Nile blue sulfate (NBS) to identify areas of cell death; the remaining embryos 
      were frozen and stored for subsequent flow cytometric (FCM) analysis of the 
      cellular DNA synthetic cycle in limb buds. A dose-related accumulation of cells 
      in the S and G2/M phases was observed at 4 and 8 hr after maternal dosing. 
      S-phase accumulation was the most sensitive indicator of effect; a dose-related 
      increase in the percentage of hindlimb bud cells in S-phase was evident at all 
      dosages 4 hr after maternal dosing. By 28 hr postdosing, a normal cell cycle 
      phase distribution was observed at doses of < 0.3 mg/kg. However, cell cycle 
      perturbations persisted at higher dosages. NBS staining demonstrated increased 
      cell death in areas of rapid cell division, indicative of replication-associated 
      cytotoxicity, at doses of > or = 0.1 mg/kg. Observation of litters from 
      additional dams killed at term revealed that at dosages of > or = 0.3 mg/kg, 
      cleft palate and hindlimb defects were significantly elevated. In addition, above 
      0.3 mg/kg, fetal weight was significantly decreased.(ABSTRACT TRUNCATED AT 250 
      WORDS)
FAU - Rogers, J M
AU  - Rogers JM
AD  - Developmental Toxicology Division, Environmental Protection Agency, Research 
      Triangle Park, North Carolina 27711, USA.
FAU - Francis, B M
AU  - Francis BM
FAU - Sulik, K K
AU  - Sulik KK
FAU - Alles, A J
AU  - Alles AJ
FAU - Massaro, E J
AU  - Massaro EJ
FAU - Zucker, R M
AU  - Zucker RM
FAU - Elstein, K H
AU  - Elstein KH
FAU - Rosen, M B
AU  - Rosen MB
FAU - Chernoff, N
AU  - Chernoff N
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Teratogens)
RN  - 776B62CQ27 (Decitabine)
RN  - 9007-49-2 (DNA)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Animals
MH  - Azacitidine/*analogs & derivatives/toxicity
MH  - Cell Cycle/drug effects
MH  - Cell Death
MH  - DNA/drug effects
MH  - Decitabine
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Flow Cytometry
MH  - Limb Deformities, Congenital
MH  - Mice
MH  - Pregnancy
MH  - Teratogens/*toxicity
EDAT- 1994/11/01 00:00
MHDA- 1994/11/01 00:01
CRDT- 1994/11/01 00:00
PHST- 1994/11/01 00:00 [pubmed]
PHST- 1994/11/01 00:01 [medline]
PHST- 1994/11/01 00:00 [entrez]
AID - 10.1002/tera.1420500504 [doi]
PST - ppublish
SO  - Teratology. 1994 Nov;50(5):332-9. doi: 10.1002/tera.1420500504.