PMID- 12797458
OWN - NLM
STAT- MEDLINE
DCOM- 20031027
LR  - 20131121
IS  - 1542-0752 (Print)
IS  - 1542-0752 (Linking)
VI  - 67
IP  - 3
DP  - 2003 Mar
TI  - Combination therapy with folic acid and methionine in the prevention of retinoic 
      acid-induced cleft palate in mice.
PG  - 168-73
AB  - BACKGROUND: During formation of the secondary palate, clefting may result when 
      critical developmental events are altered. The purpose of this study was to 
      reduce the incidence of retinoic acid (RA)-induced cleft palate (CP) in mice by 
      the co-administration of folic acid (FA), methionine (ME) or a combination of 
      both. METHODS: Four groups of time-pregnant Swiss Webster mice were injected 
      intraperitoneally with 50 mg/kg RA on gestational day (GD) 10. Likewise, 4.0 
      mg/kg FA and 187 mg/kg ME were administered on GD 8-11. The experiment included a 
      control group (RA plus H2O) and three experimental groups, (RA plus therapeutic 
      doses of FA, ME, or FA + ME). Necropsies were carried out on GD 18 and pups were 
      analyzed for teratogenic effects. RESULTS: Litters that received no therapy 
      exhibited 100% CP with individual pups showing 76% susceptibility. Each therapy 
      administered separately reduced the frequency of CP to approximately 6%, and the 
      combination of FA and ME completely prevented the occurrence of RA-induced cleft 
      palate (0%). A second experiment was conducted in which therapy levels were 
      decreased by 25%. Litters that did not receive therapy experienced 100% clefting 
      and individual pups exhibited CP at 86%. These therapies administered separately 
      did not alter significantly the frequency of cleft palate. The combined doses of 
      FA and ME, however, lowered significantly the frequency of cleft palate to 46%. 
      Decreases in limb and tail defects with FA + ME therapy were also observed in 
      both experiments. CONCLUSIONS: Although FA and ME, at appropriate levels, can 
      reduce individually the frequency of RA-induced cleft palate and other defects in 
      mice, the results from the present study suggest that there is an additive 
      interaction between the two therapeutic agents that can reduce further the 
      teratogenic impact of RA. Further studies are needed to assess the mechanism of 
      action of concomitant doses of FA and ME in the reduction of drug-induced birth 
      defects.
FAU - Reynolds, Paul R
AU  - Reynolds PR
AD  - Department of Physiology and Developmental Biology, Brigham Young University, 
      Provo, Utah, USA. paul.reynolds@CHMCC.org
FAU - Schaalje, G Bruce
AU  - Schaalje GB
FAU - Seegmiller, Robert E
AU  - Seegmiller RE
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Birth Defects Res A Clin Mol Teratol
JT  - Birth defects research. Part A, Clinical and molecular teratology
JID - 101155107
RN  - 0 (Teratogens)
RN  - 5688UTC01R (Tretinoin)
RN  - 935E97BOY8 (Folic Acid)
RN  - AE28F7PNPL (Methionine)
SB  - IM
MH  - Abnormalities, Drug-Induced/*prevention & control
MH  - Animals
MH  - Bone and Bones/abnormalities/drug effects
MH  - Cleft Palate/chemically induced/*prevention & control
MH  - Disease Models, Animal
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Female
MH  - Folic Acid/administration & dosage/*therapeutic use
MH  - Injections, Intraperitoneal
MH  - Methionine/administration & dosage/*therapeutic use
MH  - Mice
MH  - Pregnancy
MH  - Teratogens/toxicity
MH  - Tretinoin/administration & dosage/toxicity
EDAT- 2003/06/12 05:00
MHDA- 2003/10/28 05:00
CRDT- 2003/06/12 05:00
PHST- 2003/06/12 05:00 [pubmed]
PHST- 2003/10/28 05:00 [medline]
PHST- 2003/06/12 05:00 [entrez]
AID - 10.1002/bdra.10036 [doi]
PST - ppublish
SO  - Birth Defects Res A Clin Mol Teratol. 2003 Mar;67(3):168-73. doi: 
      10.1002/bdra.10036.