We are proposing that supplemental choline, administered during critical periods of development, permanently alters brain function. In order to understand the effects of supplemental choline, we need to elucidate the factors which contribute to normal choline metabolism during the perinatal period. We have made the following observations about choline availability during the perinatal period: 1) Plasma or serum choline concentrations are 6-7 fold higher in the fetus and neonate than they are in the adult. There is a progressive decline in blood choline concentration that begins in utero; 2) Brain choline concentration is more than 2-fold higher in the neonate than in the adult; 3) Administration of choline to mother results in increased plasma choline concentration in the fetus. The fetus has much higher plasma choline concentration than does the mother (4-8 fold higher); 4) Milk is a rich source for choline, concentrations being highest just after parturition; 5) The oxidation of choline is extremely slow in the neonate, and activity turns on between 10-40 days postnatal. This results in a prolonged half-life for choline in the neonate; 6) The rate of de novo biosynthesis of choline within liver is also relatively slow in the neonate, and turns on during the first week of life. In brain, however, a novel form of the enzyme is present which is only present during the first 5 days of life, and results in enhanced de novo biosynthesis of choline during this period. We propose to determine the pharmacokinetics of supplemental choline in the rat during the perinatal period. In the rat fetus (male and female) we will determine how much of a choline dose administered to mother reaches the fetus? In fetuses and pups we will determine which organs in the pup accumulate the administered choline, and within organs what choline metabolites are formed and at what rates. We also propose to determine the extent to which physiologic changes occur in the availability of choline to perinatal brain. We will study the changes in [choline] (and choline metabolites) in maternal blood and in fetal blood during gestation, as well as the changes in fetal brain [choline] and [acetylcholine] during gestation. We will measure liver, kidney and carcass choline (and choline metabolites) contents during development, and determine when during gestation bulk of choline is accumulated. We also will characterize phosphatidylethanolamine-N-methyltransferase, choline dehydrogenase and betaine aldehyde dehydrogenase activities in rat liver and brain during development. Because milk is an important source of choline for the neonate, we will determine whether rat milk choline concentration changes during development (as we have described for human milk).
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