Experimental study of the central nervous system malformations. Mechanism of the neural tube malformations induced by ethylnitrosourea administration at the stage of embryogenesis (author's transl)

Abstract

The purpose of this paper is to study the mechanism and pathogenesis of neural tube malformations on the basis of experimental investigations by ethylnitrosourea (ENU) administration at various stages of embryogenesis. The method used here consisted of intraperitoneal injection of a single dose of ENU into a number of pregnant SD-JCL rats at various stages of the embryogenesis. Various doses of ENU were used. The dead and resorbed conceptuses were counted and all living features were examined by gross observation and by light and scanning electron microscopic study. The following results and conclusions were obtained. Various types of neural tube malformations could be induced by administration of a given dosage of ENU on the 9.5 days of gestation; anencephaly, exencephaly, encephalomeningocele, cranial meningocele, hydrocephalus, aplasia cutis congenita and Chiari malformation. These neural tube malformations were selectively produced when ENU was injected at specific stages of the embryogenesis. There was a stage specific susceptibility in producing neural tube malformations. The stage, when the exposure of ENU permitted selective production of neural tube malformations, was followed by a stage, when embryonal mortality was the highest. As for the matter of dosage of ENU given, smaller dosages permitted normal development, and larger dosages had embryotoxic effects. There was a teratogenic zone of dosage, a specific dosage for producing neural tube malformations. Neural tube malformations were induced when ENU was treated at the very early developmental stage of neural tube formation, namely at the embryonic stage of initial appearance and early development of the neural plate and groove. Light and scanning electron microscopic study suggested that the neural tube malformations may result from abnormal process of the matrix layer cells in early neural plate, which will lead to the disturbance of proliferation, migration and differentiation of the matrix layer cells.