Vitamin A (retinol) supplied by the mother to her fetus is essential for normal embryogenesis, fetal development, and neonatal survival. The major source of vitamin A in mammals is oxidative cleavage of the principal dietary provitamin A carotenoid, beta-carotene (betaC). Epidemiologic and animal investigations indicate betaC and other carotenoids have pregnancy-promoting actions. An intriguing finding is that several of these properties apparently are independent of provitamin A activity. In Preliminary Studies, we have shown that placental trophoblast metabolizes betaC to retinol via the principal betaC cleavage enzyme, betaC-15,15'-dioxygenase (betaCDO). In addition, we have shown specific provitamin A and non-pro vitamin A carotenoids modulate placental growth and differentiation by actions on trophoblast gene expression. These observations have prompted the following experimental questions: (a) Does placental regulation of BetaC to retinoid metabolism serve a physiologic role akin to the placental enzymatic barrier functions which maintain intrauterine glucocorticoid and vitamin D homeostasis?; and (b) Do specific dietary carotenoids promote normal pregnancy by a combination of genomic and nongenomic events in uteroplacental target cells? This proposal addresses deficiencies of current understanding about nutritional regulation of intrauterine physiology. In order to characterize the cellular changes induced by carotenoids and to determine relevant molecular mechanisms, we will combine: well-characterized trophoblast cell culture models, systems for uniform delivery of bioavailable carotenoids over a wide concentration range, and biochemical and molecular biological analysis of carotenoid metabolism in intact cells and placental tissue. We will test the hypotheses: (a) Placental betaC-1 5,1 5'-dioxygenase (betaCDO) activity is the major (or sole) enzymatic route for fetal biotransformation to retinal, the precursor of retinoic acids. (b) Nutrient and hormonal regulation of placental betaCDO gene expression and enzyme activity modulate fetal exposure to potentially deleterious fluctuations of maternal vitamin A. We also will determine which specific carotenoids are important gestational age-dependent regulators of placental gene expression and trophoblast proliferation, migration/invasiveness and survival. Finally, we will establish whether these biological activities require carotenoid conversion to retinoids or carotenoid antioxidant activities. These studies will provide new information about potentially critical aspects of intrauterine homeostasis. Consequently, this research will increase understanding and suggest interventional strategies for vitamin A deficiency in pregnancy, a major global public health problem.
