Glucocorticoid Inhibition of RNA Synthesis Responsible for Cleft Palate in Mice: A Model

Abstract

Abstract. A study was undertaken to elucidate the molecular mechanisms by which glucocorticoids induce cleft palate in mice. It was hypothesized that a compound such as triamcinolone acetonide inhibits m-RNA synthesis; that this results later in depressed protein synthesis; and that the latter is ultimately responsible for slowed palate formation and cleft palate. Support for the model derives from the fact that the palatine shelves rise and fuse 3-4 days after the most sensitive time of administration of steroid; RNA synthesis was markedly inhibited 6-24 hr after its administration; and coadministration of cycloheximide partially reversed the tendency toward cleft palate formation.Prenatally administered cortisone produces cleft palate in mice1' 2 and has been reported to inhibit mucopolysaccharide synthesis in the fetal mouse palate.3 4 Larsson3 postulated that the cleft palate was due to the block in the synthesis of mucopolysaccharides (supposedly responsible for the "internal shelf force" that raises the secondary palatine shelf from the horizontal position to the vertical). Alternative explanations are oligohydramnios,5 excessive hydration of palatine tissue,6 and protein catabolism.7To try to clarify the mechanism by which glucocorticoids cause cleft palate in mice, an alternative approach to the problem was taken. The model proposed was predicated on the known inhibition of RNA synthesis by glucocorticoids, responsible for growth suppression in certain target cells in vivo8 and in vitro.9 It was postulated that such an inhibition of mRNA synthesis in the fetal palate would lead to a later inhibition of protein synthesis and hence cleft palate; i.e., protein and RNA synthesis would be out of phase due to the sequential synthesis of mRNA molecules during the 3-4 day period of time that the glucocorticoid was administered and the time that the palatine shelves rise.Experiments were undertaken to test the model with triamcinolone acetonide, 10 since a single dose of extremely small quantities of this glucocorticoid causes cleft palate in mice.11 It was shown that triamcinolone acetonide (hereafter referred to as triamcinolone) inhibits RNA synthesis in mouse embryos within 6 hr of administration, and furthermore that cycloheximide partly prevents induction of the cleft palate.Materials and Methods. The inbred mouse strain C3H/An (Cumberland View Farms, Clinton, Tenn.) was used. Vaginal plugs on the morning following overnight 779

Inhibition of Programmed Cell Death in Mouse Embryonic Palate in Vitro by Cortisol and Phenytoin: Receptor Involvement and Requirement of Protein Synthesis

“…Similarily, cycloheximide also completely prevents the inhibition by cortisol implicating a requirement of protein synthesis for this teratogenic action of cortisol in vitro. Similar conclusions were drawn from the observation that cycloheximide depressed the production of cleft palate by glucocorticoids when administered concurrently in mice in vivo (28).…”

Diphenylhydantoin: An Alternative Ligand of a Glucocorticoid Receptor Affecting Prostaglandin Generation in A/J Mice

“…Both drugs reduce fetal movements during palatal differentiation, and delay shelf elevation from a vertical to horizontal position (6). Both cortisone (7) and DPH (8) cause an inhibition of RNA and protein synthesis in mouse fetal palates, and susceptibility to DPH-induced clefting correlates with the inhibition (8). Since glucocorticoids probably produce cleft palate by a glucocorticoid-receptor mechanism (9, 10), we have hypothesized that DPH and glucocorticoids may bind to a common receptor (11).…”

“…We now report the use of cloned prolactin DNA The cultured clonal cell line (GH) provided a system in which to study the transcriptional regulation of the prolactin and growth hormone genes by both polypeptide and steroid hormones (7,8). Because many of these hormones are thought to act via second messengers, prolactin gene expression was investigated to evaluate potential regulatory effects produced by elevation of intracellular cyclic AMP.…”

Vitamin B12 Counteracts Dexamethasone-Induced Proliferation and Apoptosis During Key Periods of Palatogenesis in Mice

“…30 -35 Previous studies showed that DEX inhibited synthesis of protein, DNA and RNA. 36,37 Vitamin B 12 counteracts DEX-induced cleft palate by improving MEPM cell proliferation, which is associated with rescuing synthesis of DNA. Previous experiments have also demonstrated that Vitamin B 12 could improve mouse embryonic growth parameters, which were inhibited by ethanol in vitro.…”