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neous mutants (at least 13 models, 3 of which have been shown to be due to a specific gene) as well as an increasing list of induced genetic mutants in which the resultant NTD phenotype was often unexpected (Copp and Bernfield, 1994). Most of the models exhibit isolated exencephaly (an anencephaly equivalent in the mouse) and some show solely posterior NTD (Copp and Bernfield, 1994), but most are associated with malformations outside the central nervous system, growth retardation, or both. One model, the curly tail mouse, shows NTD as its sole defect (Gruneberg, 1954). Curly tail mice exhibit both anterior and posterior NTDs, which can closely resemble the common forms of human NTD (Seller and Adinolfi, 1981). As in humans, there is incomplete (60 percent) penetrance, which varies with genetic background. This suggests the presence of modifier genes, one of which has been genetically mapped (Letts et al., 1995).

NUTRITION STUDIES

Several nutritional deprivations can produce NTDs in rodents (Hurley, 1980). For example, zinc deficiency in rats results in 47 percent of offspring with NTDs (Hurley and Shrader, 1972). Severe folate deficiency, induced by dietary depletion together with gut sterilization to reduce microbial sources of folate (Walzern et al., 1983), does not yield NTDs in mice (Heid et al., 1992). However, these studies have not been done in genetic NTD models. One mouse model shows reduced neural abnormalities with huge folic acid supplements (2.5 to 3.0 mg/kg of body weight/day) (Zhao et al., 1996). Despite many other attempts, folate supplementation has not been associated with changes in NTD incidence in rodent models, including the curly tail mouse model (Seller, 1994). Because evidence suggests a genetic basis for erythrocyte folate values in humans (Mitchell et al., 1997), significant interspecies differences are conceivable. Further study is needed to determine whether mice handle folate more efficiently than humans and whether they have a lower threshold for folate sufficiency.

Supplementation with other nutrients can reduce the incidence of NTDs in some rodent models. Methionine supplements reduce the incidence of rat embryo NTD induced by homocysteine in culture (Vanaerts et al., 1994). The axial-defects mouse mutant shows a reduction in posterior NTD penetrance after parenteral methionine in the pregnant dam at the onset of neural tube closure; however, large doses of folic acid and vitamin B12 were without effect (Essien, 1992). Inositol administration can reduce NTD incidence in the



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