We are proposing that supplemental choline, administered during critical periods of development, permanently alters brains function. In order to understand the effect 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 adult; 3) Milk is a rich source for choline concentration is 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. 6) The rate of de novo biosynthesis of choline within brain is rapid due to a novel form of the methyltransferase which is present which is only present during the first 5 days of life. During our initial period of funding we have found that: 1) choline, administered to the rat dam during days E12-17, is metabolized to betaine and phosphatidylcholine (Ptd(Cho); and these are delivered to the placenta and may be the vectors for transport of choline or methyl-groups to the fetus; and 2) radiolabel from the supplemental choline dose to the dam is delivered to fetal tissue including brain, but only the mass of brain phosphocholine is increased after treatment. We propose to continue our experiments t o determine the pharmacokinetics of supplemental choline in the rat during the perinatal period. In addition, we propose to study the effects of choline deficiency and betaine supplementation during various periods during perinatal development. Finally, we propose experiments which will determine the physiologic changes in choline metabolism that occur throughout pregnancy, gestation and early development of the rat.
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