Most cases of cleft lip, one of the five most common human malformations, are considered to have multifactorial etiology. One of the factors appears to be anticonvulsant drugs, including phenytoin (Dilantin Registered Trademark), with cleft lip affecting about 10 percent of the abnormal children born to the approximately 0.5-1.0 percent of mothers on this therapy. We have found that phenytoin doses which give blood levels comparable to those used therapeutically in man increases the cleft lip incidence 5-10 times in genetically predisposed A/J (A) mice and that the developmental alterations are similar to those found in CL/Fr mice which have a very high incidence of spontaneous cleft lip. Also we have found that a simple environment alteration (maternal hyperoxia) dramatically reduces the cleft lip incidence in both animal models. The proposed studies are designed to increase our understanding of the developmental alterations and to focus on other methods for reducing the malformation incidence in both animal models. In studies described in this proposal, the distribution and biotransformation of phenytoin in A mice will be continued. Biochemical and autoradiographic procedures will be emphasized to further evaluate already determined growth alterations. The mechanism of action appears to be largely maternal. Modification of methods recently developed by Chatot and colleagues will be utilized. Embryonic sera obtained from Macaca fascicularis at six hours following phenytoin administration will be examined for phenytoin metabolites, elevated cortisol, depressed folate, etc. Significant alterations can be tested in whole embryo culture. Possible preventive measures will also be tested (e.g. by folate administration). Patterned after recently successful procedures (primarily dietary supplementation) for reducing recurrence rates of neural tube defects and a similar suggestive studies for cleft lip, the CL/Fr strain will be used to test vitamin and other """"""""dietary"""""""" supplements, particularly folic acid. In this, as well as the above study, developmental alterations will be compared to those resulting from maternal hyperoxia.
| Bronsky, P T; Johnston, M C; Sulik, K K (1986) Morphogenesis of hypoxia-induced cleft lip in CL/Fr mice. J Craniofac Genet Dev Biol Suppl 2:113-28 |
| Hicks, H E; Banes, A J (1985) The in vivo biosynthesis of embryonic proteins after maternal administration of phenytoin in the mouse. Proc Soc Exp Biol Med 180:483-7 |
| Hicks, H E; Spalding, P M; Banes, A J (1985) The water, DNA, collagen and noncollagen protein contents in embryos after maternal administration of a teratogenic dose of phenytoin. Toxicol Lett 25:41-6 |
