Combination therapy with folic acid and methionine in the prevention of retinoic acid‐induced cleft palate in mice

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Abstract
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 left 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. Birth Defects Research (Part A) 67168–173, 2003.