The nutritional status of the mother is a key factor for the development and growth of the fetus. Vitamin A is an essential nutrient for the developing embryo, which depends on maternal circulating vitamin A (or retinoids) to fulfill its needs. Indeed, embryonic vitamin A-deficiency as well as -excess result in fetal malformations, representing a serious problem in both the developing world and the industrialized countries. Humans rely mainly on provitamin A carotenoids as a source of vitamin A. ?-carotene is the best-characterized vitamin A precursor and the most abundant supply of this nutrient in the human diet. Two enzymes, ?-carotene-15, 15'-oxygenase (CMO I) and ?-carotene-9, 10'-oxygenase (CMO II), have been identified as catalysts for the cleavage of specific double bonds of ?-carotene, resulting in the formation of vitamin A. At present, the role of ?-carotene in maternal-fetal nutrition is not well understood. Evidences from the literature suggest that this carotenoid may be an important, localized source of vitamin A for the developing tissues. We plan to address this crucial biological question by using mice lacking both CMO I and retinol-binding protein (RBP), the sole specific carrier for retinol in the circulation. We will also use mice lacking low density lipoprotein receptor (LDLr) or class B scavenger receptor (SR-BI) or lipoprotein lipase (LPL) to investigate the role of these key players of the lipid metabolism in facilitating the maternal-fetal transfer of ?-carotene.
Three specific aims are proposed: (1) To identify factors that modulate the expression of CMO I and CMO II during mouse development. (2) To determine whether ?-carotene is an alternative source of vitamin A for embryonic synthesis of retinoids. (3) To investigate the mechanisms of uptake and processing of ?-carotene by the maternal-fetal barrier (i.e., placenta and yolk sac). These studies will ultimately expand our knowledge of maternal-fetal nutrition and dietary contribution to embryonic development, thus providing new insight into appropriate dietary practices during pregnancy. These studies have a significant impact on human health, since they aim at reducing the incidence of fetal malformations associated with an abnormal maternal intake of micronutrients, such as vitamins.
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