Apparent lability of neural tube closure in laboratory animals and humans

Neural tube defects (NTDs), a set of structural abnormalities affecting the brain, spinal cord, and the skeletal and connective tissues that protect t hem, are common malformations among humans and laboratory animals. The embr yogenesis of the neural tube is presented to convey the complexity of the p henomenon, the multiplicity of requisite cellular and subcellular processes , and the precise timing of events that must occur for successful neural tu be development. Interruption, even transitory, of any of these intricate pr ocesses or disruption of an embryo's developmental schedule can lead to an NTD. The population distribution of human NTDs demonstrates that genetic pr edisposition functions in susceptibility to NTDs. Data from animal studies support these concepts. NTDs are common outcomes in developmental toxicity safety assessments, occurring among control and treated groups. Numerous ag ents have caused increased levels of NTDs in laboratory animals, and specie s with shorter gestational periods appear more prone to toxicant-induced NT Ds than those with longer gestations. Data from post-implantation whole emb ryo culture, although not predictive of human risk, are useful in studying neurulation mechanisms and in demonstrating the importance of maintaining e mbryonic schedules of development. We conclude that the concept that NTDs a re produced by only a few toxicants that selectively target the developing nervous system is untenable. Rather, the combination of the time in gestati on that an agent is applied, its dose, and its ability to disrupt critical processes in neurulation leads to NTDs, We further conclude that, because o f both the relatively high prevalence and the multifactorial nature of NTDs , the mere occurrence of an NTD is insufficient for inferring that the defe ct was caused by an exogenous agent. (C) 1999 Wiley-Liss, Inc.