Many forms of intrauterine growth retardation (IUGR) may represent the end result of fetal metabolic adaptation to an imbalance between supply and demand of metabolic substrates. Using heat stress beginning early in gestation, we have developed a model for exploring fetal metabolic adaptation to a broad spectrum shortage of metabolic substrates. In this model, fetal weight is 53%, placental weight is 42% and brain/liver weight ratio is 212% of control. We have demonstrated placental insufficiency in this model of severe fetal growth retardation (PI-IUGR model) with respect to the rate of glucose transport from placenta to fetus at standardized values of maternal and fetal plasma glucose concentrations. It is our hypothesis that the placental insufficiency extends to amino acid transport, thus inducing in the fetus a type of metabolic adaptation which is different from that observed in other forms of fetal growth retardation. Specifically, we will test the hypothesis that fetal glucose production is not increased in the PI-IUGR model, in sharp contrast with the hypoglycemia/hypoinsulinemic IUGR models of Project I. The hypothesis that placental insufficiency extends to amino acids will be tested by measuring umbilical amino acid uptake by detailed tracer analysis of feto-placental leucine uptake and metabolism. We will perform studies of placental transfer and fetal uptake of oxygen and glucose in the PI-IUGR model at mid-gestation before a change in somatic growth would be expected and test the reversibility of such placental insufficiency with a return to normal environmental conditions. Specific in vitro studies will address cellular and molecular responses to the unique fetal metabolic milieu in these fetuses; these important mechanistic studies also can be compared with the same studies performed on tissues from the hypoglycemic/hypoinsulinemic animals in Project I, thereby increasing the power of determining the importance and specificity of each mechanism for mediating the systemic changes in fetal metabolic substrate supply that result in each of our unique forms of IUGR. Such studies will provide an understanding of the various adaptative metabolic strategies which allow for survival of the IUGR fetus.
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