Abstract
Lipid metabolism and the actions of valproic acid, a human teratogen, have been studied in the organogenesis-stage rat conceptus, using whole embryo culture techniques. All major lipid classes, particularly phospholipids, cholesterol and triacylglycerols, were synthesized de novo from acetate by the conceptus. Oleic acid and glucose were also incorporated into complex lipids. The pattern of lipid biosynthesis was dependent on the developmental stage of the conceptus. Despite this lipid biosynthetic activity, cholesterol uptake experiments suggested that the rat conceptus derives most of its required lipid from exogenous sources. Valproic acid stimulated de novo synthesis of cholesterol, and concomitantly reduced cholesterol esterification, in the yolk sac during an eight hour exposure. These effects were also induced by butyric acid, which produces valproic acid-like dysmorphologies in vitro, but not by the non-teratogen valpromide. Some observations suggested that the initial action was inhibition of cholesterol uptake at the yolk sac. Subsequent studies disproved this hypothesis and also suggested that the increased levels of newly synthesized cholesterol were not responsible, per se, for the valproic acid teratogenicity. The specific actions of valproic acid on yolk sac cholesterol synthesis and esterification were, nevertheless, dose-dependent in culture, and were also induced in conceptuses exposed to valproic acid in utero. This contrasts with several other major biochemical pathways, previously studied in the conceptus, which are not affected by valproic acid. It is likely, therefore, that these changes in lipid metabolism are related to the initial teratogenic insult of valproic acid.