Developmental analysis of cephalic axial dysraphic disorders in arsenic-treated hamster embryos

Parenteral injection of pregnant golden hamsters with inorganic arsenic salts early in gestation results, by term, in markedly elevated embryonic-fetal mortality (approximately equal to 50%) and, in surviving fetuses, a high (approximately equal to 90%) incidence of cephalic axial dysraphic disorders ("neural tube defects"), particularly exencephaly/anencephaly and encephaloceles. The present investigation traces the day by day development of these embryopathic effects of arsenic in the hamster with an emphasis on the pathogenesis of cephalic axial dysraphic disorders. Pregnant golden hamsters were given an intraperitoneal injection of sodium arsenate (20 mg/kg) on the 8th day (08.00) of their 16 day gestation period. Matched control dams were injected with an equivalent volume of distilled water by the same route and at the same stage of gestation. Experimental and control dams were sacrificed beginning 24 h after treatment and at regular daily intervals thereafter until term. Embryos and fetuses delivered from sacrificed dams were examined for abnormalities both grossly and histologically. In embryos delivered earliest after treatment (24-48 h) the principal deleterious effect of arsenic observed was retarded growth (elevation, approximation, and fusion) of the cephalic neural folds. This growth retardation ranged in severity among embryos. In the most severely afflicted there was a site wherein the opposing cephalic neural folds had completely failed to appose and fuse ("closure"). This failure of closure of all four tissue components of the neural folds (surface ectoderm, paraxial mesoderm, neural crest cells, neuroectoderm) resulted in a persistent dorsal opening in the head, i.e., cranioschisis aperta. The extent and appearance of this opening varied from a small, ovoid aperture in the dorsal midbrain (mesencephalic) region of the head to a widely open cleft involving the fore and hindbrain regions as well as the midbrain region. In less severely afflicted early embryos, the cephalic neural folds had elevated and met in the dorsal midline but had only incompletely fused, i.e., cranioschisis occulta. Microscopic study of these latter embryos revealed that in the affected region(s), complete closure of the surface ectoderm component of the neural folds had taken place, but only partial closure of the mesoderm, neural crest and neuroectoderm components. The different types of cephalic axial dysraphic disorders presenting in arsenic-treated fetuses delivered at later gestational stages (predominantly exencephaly and encephaloceles) could all be traced back and related to one or the other of these early forms of disturbed neurulation.