Beitrag zur teratogenen wirkung von N-methyl-N-nitroso-harnstoff auf embryonale gehirnanlagen der ratte nach autoradiographischen untersuchungen

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Introduction: The influence of a carcinogenic and teratogenic substance, MNU, on the number of DNA-synthesizing cells and on the mitotic rate in embryonal brain-anlagen of the rat is investigated; relations to necrobiotic events and to the development of malformations are shown. Material and methods: 30 female Wistar rats were given 45 mg/kg body weight MNU via gastric tube between the 13th and 14th day of pregnancy. Each animal was given 3H Thymidine (2 μCi/g body weight) i.p. one hour before sacrifice. Autoradiographic studies of the embryos were done 3, 5, 8, 15 and 24 hours after the application of MNU, thereafter in daily intervals. Labeling indices ( 3H-index), mitotic indices and the number of pyknoses as well as alterations in brain-histomorphology were studied in telencephalic, diencephalic and mesencephalic anlagen. Results: Within the first 8 hours after application of MNU, no decrease in the number of DNA-synthesizing cells in the region of the embryonal brain-matrix could be found, whereas necrobiotic events with pyknosis were already detectable at 5 hours. 5 hours after MNU treatment, the labeling index surpassed that of untreated controls for a brief period; this relative increase is considered to be due to the appearance of non-evaluable pyknoses. As the rate of pyknoses increases, the fraction of DNA-synthesizing cells ( 3H-index) decreases sharply 15 hours after MNU. At 24 hours, neighter DNA synthesis nor mitoses are measurable since an evaluable brain-matrix can no longer be detected. Merely minimal regenerates are found. The necrotic brain matrix is replaced by loose embryonal mesenchyme with glia-like components. Embryos at term will not survive and have grave malformations of their facial and skull regions and are anencephalic due to loss brain-substance. Discussion: The dosedependent increased severity of malformations observed in the present findings is discussed and compared with results published by others. The autoradiographic studies demonstrate that the alterations seen within the first 8 hours after MNU treatment — when no decrease in the number of DNA synthesizing cells could be detected — differ from those seen after other teratogens (e.g., X-rays) which cause an earlier decrease of the labeling-index. A delaying effect of the placenta is possible.