Spezielle Entwicklungsstörungen des Rattenskeletts nach Verabreichung von DL-Serin-(2,3,4-trihydroxybenzyl)-hydrazid

Abstract

Introduction:In humans all epiphyseal growth zones are closed after puberty. In rats some of the epiphyseal cartilage plates remain open for a lifetime. Noxious agents can therefore give rise to alterations in these structures in the rat not only until the end of puberty, but during an entire lifespan. Consequently, it is possible that very severe pathologic changes can develop in this species. Material and methods:Several hundred male and female rats (of the Füllinsdorf Albino or Charles River strain), weighing between 30 and 300 g, were treated with daily oral doses of DL-Serine-(2,3,4,-trihydroxybenzyl)- hydrazide (DL-SH) varying between 25 and 1000 mg/kg. The time of application ranged from 3 days to 18 months. The drug was given by gastric tube or as feed additive. In addition to X-ray and histological investigations, hematological and blood-chemistry studies were carried out, as well as histological evaluations of approximately 30 organs per animal. Results:The principal feature was a derangement in the transformation of chondral into bony tissue in the epiphyseal plate. The cartilaginous tissue loses its columnar arrangement in the hypertrophic zone and takes on a lather-like appearance. The invasion of the cartilage by elements of the bony tissue is impeded by the abundant cartilaginous intercellular substance. Only a few, crippled primary bony trabeculae are formed. The epiphyseal plates have doubled in width after one week of treatment with high dosages and are 7 times broader than normal after four weeks. The demarcation line between chondral and osseous tissue becomes very irregular. In some areas chondral tissue extends deeply into the osseous tissue. Following tensile and compression stress dislocations of the epiphysis occur. In the later course of the experiment the epiphyseal plate becomes narrower following transformation processes (endochondral ossification, proliferation of fibroblasts) which take place in and around the chondral tissue. But the alterations generally are so severe, and the rats are so immobilized, that the general condition cannot be ameliorated. These changes are observed in all of the epiphyseal zones which are not closed before senility. They are especially well-marked in the proximal epiphysis of the tibia, in the head of the humerus, and in the distal epiphyses of radius and ulna. In addition lordosisscoliosis in the spine and marked dislocations of the sternal segments are found. Under a dosage of 100–150 mg/kg/day these findings become markedly apparent even within a few weeks whereas it takes months until they can be detected in animals treated with 25 mg/kg/day. The intensity with which the alterations develop is determined by the intensity of growth. In older animals and in slowly growing young rats (due to a limited feed intake) they appear slowly and are not pronounced. In young and rapidly growing animals rapid and pronounced changes are observed. When very young rats are included in the experiment, irregularities occur also in those epiphyseal growth plates which are closed at puberty (distal tibial epiphysis and metatarsal bones). The described alterations could not be demonstrated in the dog even when 8-week-old puppies were treated with 25 mg/kg/day for more than one year. Discussion:The alterations appearing in the epiphyseal plates of rats after treatment with DL-Serine-(2,3,4-trihydroxybenzyl)-hydrazide cannot be classified precisely as rachitic or osteolathyrogenic changes, although to a certain extent many similarities do exist. These alterations in rats cannot be correlated with lesions in adult humans, since in humans cartilage is not found any more in the epiphyseal plates after puberty.