ALTERED HEPATIC GENE-EXPRESSION OF ENZYMES INVOLVED IN ENERGY-METABOLISM IN THE GROWTH-RETARDED FETAL-RAT

Intrauterine growth retardation (IUGR) resulting from placental insuff iciency is a common complication of pregnancy. Bilateral uterine arter y ligation of the pregnant rat is a model which mimics intrauterine gr owth retardation in the human. IUGR rat fetuses have altered hepatic e nergy and redox states, with reduced fetal hepatic ATP/ADP ratio, incr eased cytosolic NAD(+)/NADH ratio, and decreased mitochondrial NAD(+)/ NADH ratio. These critical changes in energy metabolism contribute to IUGR. The effects of these changes at the molecular level are largely unknown. To address these effects we compared hepatic mRNA populations of IUGR and normal fetuses and neonates using mRNA differential displ ay, a polymerase chain reaction-based method for assaying transcriptio nal differences under various conditions. We isolated and sequenced 18 cDNA products whose mRNA levels were elevated in IUGR compared with n ormal fetal and neonatal liver. These analyses demonstrated that NADH- ubiquinone oxireductase subunit 4L mRNA (ND-4L) was significantly incr eased in liver of IUGR fetuses and neonates. This suggested that IUGR may be associated with altered expression of genes involved in the gen eration of ATP and NADH. Therefore, we measured mRNA levels of adenine -nucleotide translocator-2 (ANT-2), glucose-6-phosphate dehydrogenase (G6PD), mitochondrial malate dehydrogenase (MMD), ornithine transcarba mylase (OTC), and phosphofructokinase-2 (PFK-2) using a semiquantitati ve reverse transcriptase-polymerase chain reaction-based technique. In the IUGR fetus, ND-4L, ANT-2, G6PD, and MMD mRNA levels were signific antly elevated; PFK-2 mRNA levels were unchanged, and OTC levels were decreased. In the IUGR newborn rat, mRNA levels of all 6 enzymes were increased suggesting that the metabolic state of the growth retarded n ewborn remains abnormal after birth. Uteroplacental insufficiency affe cts the immediate and long-term metabolic milieu of the growth retarde d animal, and forces specific adjustments, including the expression of mRNA encoding enzymes involved with hepatic energy production.