The Fetal Cleft Palate: I. Characterization of a Congenital Model

Abstract

Any animal model of a human congenital anomaly established by iatrogenic methods involving intrauterine fetal manipulation has limited clinical applicability. A congenital model that more closely simulates the etiopathogenesis of a human anomaly may provide data that can more readily be extrapolated to that anomaly and, therefore, be used in diagnostic and management strategies. The present work provides a description and characterization of a congenital model of cleft palate in the goat. Palatal shelf closure normally occurs at approximately day 38 of gestation in the caprine species. Sixteen pregnant goats were gavaged twice daily during gestational days 32 through 41 [term, 145 days] with a plant slurry of Nicotiana glauca containing the piperidine alkaloid teratogen anabasine. Gross analysis and measurement of fetal clefts were performed at 60, 70, and 85 days gestation (four fetuses were studied at each time point). Seventeen clefted kids were sacrificed at specific intervals after birth (2 weeks, and 1, 3, and 6 months); after skull debridement and preparation, they were compared with 12 unclefted control kids. Complete clefting of the secondary palate occurred in 97 percent of the fetuses. In all cases, the cleft extended from the posterior aspect of the alveolar ridge to the uvula; the majority of these clefts were bilateral, with complete detachment of the vomer. Morphologically, these clefts were similar to human clefts. Eighteen percent of clefted newborn kids demonstrated gross maxillary hypoplasia and midfacial retrusion at birth with a relative Class III malocclusion. Direct measurement of the congenital caprine skulls confirmed these findings. The incidence of midfacial growth abnormalities in these clefted animals raises questions regarding the etiopathogenesis of facial dysmorphology that is unrelated to scarring of the maxilla. This congenital cleft palate model is currently being used to explore these questions and others related to craniofacial growth and palatal function after in utero repair.

Contraction-Induced Injury to Single Permeabilized Muscle Fibers from Normal and Congenitally-Clefted Goat Palates

“…Under these circumstances, the fibers of the cleft palate might not have been exposed to the appropriate environmental cues to convert to or to maintain mature slow type 1 fibers. Loading abnormalities were possible during the induction of the cleft palate when the fetal neck was hyper-flexed and the tongue was wedged between the palatal shelves (Weinzweig et al, 1999). Following the induction of the cleft, atypical loading persisted in that the LVP muscle fibers were abnormally attached to the posterior edge of the palatal bone and, consequently, were exposed to forces along the posterior-anterior direction rather than the medial-lateral orientation of normal palatal LVP fibers (Weinzweig et al, 2002).…”

“…The cleft palate was induced by gavaging pregnant goats with an extract of Nicotiana glauca plant slurry twice daily from day 32 to 41 of gestation, the critical developmental period when palatal shelf closure occurs (Weinzweig et al, 1999). As a consequence, the neck of the fetal goat remained hyperflexed and caused the tongue to obstruct the closure of the palatal shelves resulting in complete clefts of the secondary palates (Weinzweig et al, 1999). Each goat was sacrificed using an overdose of Beuthanasia (Schering-Plough Animal Health Corp., Kenilworth, NJ).…”

Human relevance framework evaluation of a novel rat developmental toxicity mode of action induced by sulfoxaflor

“…There are two important fi ndings that distinguish these agents from that of sulfoxafl or. Ultrasound studies using a goat model demonstrate decreased or eliminated fetal activity when the mother goat is fed anabasine (Weinzweig et al 1999) that was associated with the observed muscle contractures, as well as cleft palate presumably resulting from inactive glossal muscle during palate closure. While the MoA of the plant alkaloids on the fetus is not known, it could be speculated that the previously noted sedation or biphasic stimulation-depression seen in adults may be operant in the fetus and responsible for the inhibition of fetal movement.…”

Effect of Cleft Palate Repair on the Susceptibility to Contraction-Induced Injury of Single Permeabilized Muscle Fibers from Congenitally-Clefted Goat Palates

“…During gestational days 32 to 41 (palatal fusion occurs at gestational day 38), cleft palates were induced by gavaging pregnant goats with an extract of Nicotiana glauca plant slurry twice daily (Panter and Keeler, 1992;Weinzweig et al, 1999). The extract causes the neck of the fetal goat to remain hyperflexed, thereby causing the tongue to elevate and obstruct the migration of the palatal shelves to the midline.…”

“…The extract causes the neck of the fetal goat to remain hyperflexed, thereby causing the tongue to elevate and obstruct the migration of the palatal shelves to the midline. Thus, palatal fusion is physically inhibited in 97% of cases, with complete clefting of the secondary palate in all cases (Weinzweig et al, 1999). …”