Diurnal variation of folate concentrations in mouse embryo and plasma: the protective effect of folinic acid on valproic-acid-induced teratogenicity is time dependent.
The diurnal variation of folate concentrations in mouse plasma and embryo between day 8.5 and day 9.5 of gestation (light cycle = 0900-2100) were determined by high-performance liquid chromatography. Folate concentrations in the embryo were high during the evening hours, decreased during the night, reached their lowest levels at 0500, and then increased again during the day. High levels of folates may be related to increased food intake by the pregnant mice. Small changes of the two major maternal plasma folate metabolites were observed. The relative amount of each folate metabolite in the embryo, as compared to the total folate concentration, remained in a narrow range. The main metabolites were tetrahydrofolic acid (THF) (32.4% +/- 2.1% of total folates), 5-CHO-THF (24.2% +/- 2.3%), and 10-CHO-THF (17.0% +/- 1.9%). A dramatic alteration of these ratios occurred only between 1100 and 1400. The relative content of THF increased (52.7% +/- 2.5%), whereas the relative concentration of 5-CHO-THF in the embryo decreased (6.5% +/- 1.9%). Before 1000 when the ratios of folate metabolites were stable, the rate of valproic acid-induced neural tube defects was reduced from 49% of living fetuses to 12% by coapplication of folinic acid via subcutaneously implanted minipumps. During the period in which dramatic changes in ratios between the folate metabolites in the embryo occurred, no protective effect of folinic acid on valproic acid-induced exencephaly could be observed. Our results indicate that the diurnal variation of folate metabolism in the embryo is important in regard to valproic acid teratogenesis and its protection by folate supplementation.
Wegner
C
C
Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm / Q000502:physiology*; D003656:Decidua / Q000502:physiology; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D002955:Leucovorin / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D011247:Pregnancy; D014635:Valproic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity
D014635:Valproic Acid; D005492:Folic Acid; D002955:Leucovorin