Folate Deficiency Alone Does Not Produce Neural Tube Defects in Mice

Abstract

The incidence of neural tube defects was studied in mouse embryos from dams fed an amino acid-based diet containing 45, 91, 136, 181, 227 or 453 nmol folic acid/kg diet (Experiment 1) or 227, 453, 566, 680, 906, 1132, 1698 or 2266 nmol folic acid/kg diet (Experiment 2). Reproductive tracts were examined 12 d postcoitum and gross and microscopic examination of all embryos was performed. A single implantation was found at levels less than or equal to 181 nmol folic acid/kg diet. With one exception, bred mice fed 227 or 453 nmol folic acid/kg diet in Experiment 1 had 100% resorptions. In Experiment 2, 100% of implantations in mice fed 227 nmol folic acid/kg diet and approximately 75% of implantations in mice fed 453 or 566 nmol folic acid/kg diet resorbed. The 906 nmol folic acid/kg diet was sufficient for successful pregnancy. Mice fed 227 nmol folic acid/kg diet in Experiment 2 weighed approximately 80% of mice fed higher levels of folic acid. Inadequate dietary folic acid resulted in fewer and smaller embryos (which developed normally). These results suggest that folate deficiency alone is insufficient to produce neural tube defects in Swiss-Webster mice. Because individual micronutrients (e.g., folate) can be omitted from the amino acid-based diet, the specific role of folic acid in neurulation can now be studied systematically.

The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

“…That said, spontaneous neural tube defects in the mouse, as in humans, are rarely encountered. The incidence in wild-type mice is estimated to be 0.3-4.2 per 1000 pups (22,62). Furthermore, severe dietary folate deficiency in mice results in failure to implant, or in embryonic resorption, rather than in viable embryos with neural tube defects (22,62), similar to the phenotype seen when folate transport is defective due to the absence of Folbp1.…”

“…The incidence in wild-type mice is estimated to be 0.3-4.2 per 1000 pups (22,62). Furthermore, severe dietary folate deficiency in mice results in failure to implant, or in embryonic resorption, rather than in viable embryos with neural tube defects (22,62), similar to the phenotype seen when folate transport is defective due to the absence of Folbp1. Even assuming that an enzyme deficiency were associated with a 10-fold increase in the incidence of neural tube defects, few studies of sufficient statistical power have been conducted to allow detection of such an increase.…”

Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid

“…However, it was essential to learn the dynamics of L-Hcys passage into the serum and to compare these results with other experimental and epidemiologic results, to determine actual serum levels of L-Hcys. Therefore, 5 mol of L-Hcys as L-Hcys thiolactone or 14) and evaluated for the occurrence of grossly or histologically visible defects in neural tube closure. D,L-Hcys (10 mol) gave the best rate of (survival) ϫ (% defects).…”

“…However, the highly specific and predictable nature of the congenital defects caused by folate deficiency argues against a generalized lesion: although derivatives of the neural ectoderm are effected more than other tissues by folate deficiency, all of the embryonic tissues are dividing rapidly during the susceptible developmental period (6,7). Furthermore, it appears that the degree and duration of folate deficiency necessary to inhibit DNA synthesis may be greater than the conditions that are necessary to produce congenitally disordered organ sytems (6), and folate deficiency is not by itself sufficient to produce neural tube defects in mice (14). These data argue that folate deficiency does not induce congenital neural tube and heart defects by generally limiting the availability of nucleic acids but by producing some more specific effect upon a narrow region of the neural ectoderm.…”

Acetylation of p-aminobenzoylglutamate, a folic acid catabolite, by recombinant human arylamine N-acetyltransferase and U937 cells

“…Folic acid is an essential vitamin in humans and may be important in the prevention of neural tube defects as well as a variety of other malformations in developing embryos [9]. During the second and third trimester of pregnancy, folic acid requirement increases significantly due to a higher rate of folate turnover [10].…”