Sterol Metabolism During Pregnancy and Development

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Birth defects are the leading cause of infant death within the first year of life. In the United States, one out of every 33 babies is born with birth defects, including those that affect body chemistry (i.e. metabolic defects). Particularly disfiguring defects can occur when cholesterol biosynthesis is disturbed. This pathway produces a key structural component of plasma membranes, precursors for steroid hormones, and activates sonic hedgehog, a protein key for neuronal patterning. Children affected with Smith-Lemli-Opitz Syndrome (SLOS) have a defect in the enzyme 3-hydroxysteroid 7-reductase (DHCR7), which converts 7-dehydrocholesterol to cholesterol. Affected children have low plasma cholesterol concen-trations, congenital birth defects, mental retardation, and failure to thrive. Based on the carrier frequency of the gene, SLOS is one of the most common congenital defects. The severity of this defect underscores the importance of cholesterol availability in fetal development. Recent data in humans have also suggested that maternal plasma cholesterol may be involved in the regulation of fetal growth. This is important for public health since large-for-gestationally aged infants have an increased risk to develop a number of diseases in adulthood, including obesity and diabetes. Our overall hypothesis is that the transport of cholesterol from the maternal to fetal circulation is regulated by sterol balance and source of maternal sterol in cells which separate the two circulations: trophoblasts (placental cells) and endodermal cells (yolk sac cells). We will test our hypothesis with 3 aims. 1) Determine the importance of maternal HDL vs LDL in delivery of cholesterol to the fetus. Based on preliminary studies, we hypothesize that maternal HDL-CH is preferentially delivered to the fetal circulation while LDL-CH preferentially remains within placental and yolk sac cells for basic cellular maintenance during a negative sterol balance. Once basic sterol needs are met, maternal LDL- as well as HDL-CH can be transported to the fetus. A trophoblast cell line, perfused human placentas, and rodent yolk sacs will be used in this aim. 2) Determine the role of apoE-containing lipoproteins in delivery of cholesterol to the fetus. The placenta has a high content of apoE receptors and can take up apoE-containing lipoproteins at significant rates. We hypothesize that apoE-containing lipoproteins are a substantial source of sterol for the placenta and the fetus once basic sterol needs of trophoblasts are met. We will test our hypothesis in apoE+/+, apoE-/-, and apoE+/- mice. 3) Delineate factors that regulate the transfer of maternal cholesterol to the fetus. We hypothesize that the route of export from the placenta (efflux/secretion) will be affected by sterol balance, source of cholesterol (LDL/HDL), and acceptors in the fetal plasma. We will test this hypothesis in a trophoblast cell line with various acceptors (fetal SLOS HDL) and human placentas. Data gleaned from these studies will help form a basis for new nutritional and perhaps pharmaceutical strategies to enhance fetal development under various conditions.