Inactivation of folate binding protein-1 (Folbp1) adversely impacts murine embryonic development, as nullizygous embryos (Folbp1 -/-) die in utero. Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects. We examined whether maternal supplementation with L-N5-methyl-tetrahydrofolate (L-5M-THF) has superior protective effects on embryonic development of Folbp1 -/-fetuses compared with L-N5-formyl-tetrahydrofolate (L-5F-THF). We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1 -/-embryos. Folbp1 -/-pups presented with a range of malformations involving the neural tube, craniofacies, eyes, and abdominal wall. The frequencies of these malformations decreased with increasing folate dose, regardless of the form used. There was no additional benefit provided by L-5M-THF compared with L-5F-THF. Despite rescuing the phenotype in Folbp1 -/-embryos, no significant elevation of Folbp1 -/-maternal folate levels was observed with supplementation.

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Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.

Unlike our previous findings with arsenate, enhanced susceptibility of Folbp2(-/-) mice to in utero VPA exposure was demonstrated in some dietary folate regimens. Thus, our data indicate a relatively frail relationship between Folbp2 and VPA-induced NTDs.