Morphological and autoradiographic studies of cleft palate induced in rat embryos by maternal hypervitaminosis A.

IN the laboratory many teratogenic procedures have been found to produce cleft palate in conjunction with other congenital malformations (Kalter & Warkany, 1959), but only in embryos of cortisone treated mice has this malformation been reported to occur singly (Baxter & Fraser, 1950). However, a carefully controlled treatment with hypervitaminosis A can produce a high incidence of cleft palate which is only rarely accompanied by other malformations (Giroud & Martinet, 1956). These two teratogenic treatments have other similarities in that both similarly affect the ultimate chemical composition of tissues. That is, both in vivo and in vitro, cortisone depresses the ability of tissues to synthesize chondroitin sulfate (Layton, 1951a, 19516; Schiller & Dorfman, 1957) and, in animals receiving excessive doses of vitamin A, chondroitin sulfate was removed from the matrix of epiphyseal and articular cartilages (Thomas et ah, 1960). In addition, incorporation of S-labelled inorganic sulfate into embryonic limbs cultivated in vitro was inhibited by the presence of vitamin A in the culture medium (Fell, Mellanby &Pelc, 1956). It was suggested by Larsson (1960) that the occurrence of cleft palate in response to cortisone treatment might be due to interference in the synthesis of chondroitin sulfuric acid. It was demonstrated later by this author (Larsson, 1962) that in mouse embryos from cortisone treated mothers there was a reduced S-incorporation (presumably into sulfated-mucopolysaccharides) in the palatine shelves as well as in other regions of the embryo. Since the morphological sequence of cortisone induced cleft palate had been described previously (Walker & Fraser, 1957), the present experiment endeavored (1) to compare this sequence with early