A morphological, electron microscopic, and biochemical study was undertaken to analyze the genesis of
hadacidin-induced
cleft palate in hamster fetuses. Gross and light microscopic observations indicated that
hadacidin affected the growth of vertical palatal shelves to induce
cleft palate. Electron microscopic observations showed that initial
hadacidin-induced changes were seen in the mesenchymal cells. Within 12 hr of
drug administration, the perinuclear space was swollen and a lysosomal response injury was evident in the mesenchymal cells. Subsequently, 24 hr after
hadacidin treatment, lysosomes appeared in the epithelial cells; changes were also seen in the basal lamina which included separation of the lamina densa from the basal cells, duplication of lamina densa, and complete loss of basal lamina. Between 36 and 42 hr post-treatment, the cellular and basal lamina changes subsided, and the epithelium of vertical shelves underwent stratification. Biochemical determination of
enzyme acid phosphatase indicated that the levels of
enzyme activity in both the control and treated palatal tissues corresponded to the appearance of lysosomes. Measurement of cAMP levels suggested that the peak activity of cAMP corresponded to that of
enzyme acid phosphatase and cell injury. The cAMP activity in
hadacidin-injured cells, however, was significantly lower in comparison to that of the dying cells of control palates.
Hadacidin treatment also affected
DNA synthesis in the developing primordia of the palate. It was suggested that
hadacidin injures the precursor cells of the palate prior to the appearance of the primordia, and subsequently affects their proliferative behavior,
stunting the vertical growth of the palatal shelves and inducing a
cleft palate.