TERATOGENIC MECHANISM OF DRUG-INDUCED ANOMALIES OF EXTREMITIES IN RATS
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In order to clarify the teratogenic mechanism of oligodactyly, we have carried out some experimental studies in rats. In this paper we report the results and discuss the teratogenic mechanism of the anomalies of the extremities. 1. Ulnar ray deficiency, cleft hand, central ray polydactyly, and central ray syndactyly were induced in W: Gun rats, and radial ray deficiency was induced only in W KAH/H km rats. The features of these anomalies in rats were the same as in humans. The critical periods of ulnar ray deficiency and radial ray deficiency seemed to be earlier than those of central polydactyly, syndactyly, and cleft hand. The critical period of cleft hand was identical to those of central polydactyly and central syndactyly, and advanced cases of central polydactyly or syndactyly in which the fusion area extended as far as the proximal phalanx and metacarpus, became identical to the cleft hand. These findings suggest that radial and ulnar ray deficiencies belong to longitudinal ray deficiency, and the central polydactyly, syndactyly, and cleft hand might be formed by the same teratogenic mechanism, that is, failure of separation of finger ray. 2. DNA synthesis and cell condensation in the developing hand plate of normal and preaxial oligodactylic rats treated with myleran on the day of 12.0th gestation were examined using a BrdU/anti-BrdU immunohistochemical study. DAN-synthesizing cells were distributed uniformly in the mesenchyme of the hand on day 12.0 in normal rat embryos. From day 13.0. these cells were distributed in the interdigital mesenchymal areas, leaving rare labeled cells in the sites of cell condensation. When the labeled mesenchymal cells were followed from day 12.0 until day 14.0, they were found to be concentrated in the digital rays. We concluded that cell migration rather than cell proliferation in the digital-ray area could be an initial step in digital-ray formation. In the oligodactylic hand plate, mesenchymal cell condensation was delayed and preaxial digital rays were not formed. On day 13.0 the number of DNA-synthesizing cells was much less than normal in all areas of the hand plate, and cell necrosis of the epidermis and mesenchyme near the epidermis was prominent. On day 14.0, DNA-synthesizing cells decreased in the epidermis rather than in the mesenchyme. From these results, we conclude that the mechanism of this oligodactyly could involve a mesenchymal cell deficit and restriction of migration.
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