Induktion von Mißbildungen durch N-Methyl-N-nitrosoharnstoff (MNH)

Abstract After observing multiple malformations in a stillborn infant whose mother was in contact with MNU during pregnancy, the inhalation of evaporated MNU solution or diazomethane was regarded as a possible cause. An attempt was made to reproduce the same conditions in experiments with rats. Material and methods: The experiments were carried out with 46 pregnant rats yielding 370 fetuses. With the aid of an atomizer a solution of 50 mg MNU was atomized in a container of 12 liters. In each test up to 3 rats were exposed for 30 min (group Al). In other groups (B1–3) rats placed into the same container breathed diazomethane which was produced by dropping NaOH on MNU. During this experiment, rats were apathetic and their respiration was accelerated. In group C1–9, MNU was injected intraveneously or intraperitoneally. Animals which had no contact neither with complete MNU nor with its decomposition products served as control (group D1). Rats were killed at the 21st day of pregnancy. After laparotomy, fetuses were weighed and fixed in Bouin's solution or in ethanol. Fetuses were examined macroscopically. Afterwards the head and the trunk were dissected. In a number of cases the skeleton was stained with alizarin red S. Results: Malformations that affected the skeleton and the central nervous system could be found only in those experiments in which rats were exposed to the complete teratogenic agent. By means of external inspection microcephalia, micrognathia, cleft palate, micromelia, syn- and polydactylia, lordosis and skoliosis of the spinal column as well as deviations of the extremities were observed. Above this, by bone preparation by alizarin red S malformations of the skull (micrognathia, aplasia of the zygomatic bone) hypoplasia and deformations of the clavicula, scapula, ribs as well as of bones of the extremities were found. MNU led to complex malformations in the central nervous system comprising microencephalia, hydrocephalus as well as defects of the septum pellucidum and the corpus callosum. Frequency and spectrum of malformations depended on the dosage and the age of pregnancy. As the embryotoxic activity was relatively low at day 13 and as malformations were observed in all cases, this day proved to be the most effective one. In contrast to the application of MNU, after inhalation of diazomethane malformations did not occur. However, as a toxic effect a significant increase in dead fetuses and a reduction of the body weight was registered. After inhalation of atomized MNU solution, neither malformations nor toxic injuries could be observed. The experiments do not support the hypothesis, that anomalies found in the stillborn infant are caused by mother's contact with MNU. As demonstrated, in most cases it is very difficult to prove any interrelationship between a chemical agent and the occurrence of malformations in man. Therefore, similar observations should be published even if the connection cannot be ascertained exactly, for only by an accumulation of related cases a positive correlation can be verified.