Intrauterine Growth Retardation: Altered Hepatic Energy and Redox States in the Fetal Rat

Abstract

ABSTRACT. We determined the extent to which ligating both maternal uterine arteries affects fetal hepatic energy and redox states in the fetal rat. Bilateral maternal uterine artery ligation on d 18 of the rat's 21.5-d gestation significantly inhibits fetal growth; sham surgery limits growth to a lesser extent. Within 12 h of surgery and persisting to d 19, small-for-gestational age (SGA) fetuses had significantly diminished ATPIADP and adenylate charge ratios, whereas sham fetuses had values intermediate between SGA and normal. Hepatic mitochondrial redox state demonstrated similar changes. Cytosolic redox state in SGA fetuses at 12 and 24 h after surgery was significantly elevated. SGA fetuses had significantly diminished plasma insulin and elevated glucagon concentrations. On d 19 and 20, hepatic ATPIADP and cytosolic NAD+/NADH correlated directly for sham and normal but not SGA fetuses. Alterations in glucose, insulin, and glucagon availability and hypoxia were responsible for the changes in energy and redox states. They may also have disassociated hepatic cytosolic from mitochondrial redox states and altered the equilibrium between adenine and nicotinamide nucleotides. These altered cellular functions retarded fetal growth. Newborn SGA, sham, and normal rat pups had similar hepatic ATPIADP, cytosolic, and mitochondrial redox states at 10 and 240 min after delivery suggesting that the hypoglycemia which developed in SGA pups was not attributable to alterations in these variables. (Pediatr Res 27: 56-63,1990) Abbreviations AC, acetoacetate SGA, small-for-gestational age Intrauterine growth retardation is often ascribed to "uteroplacental insufficiency," a poorly defined clinical term suggesting compromised maternal-fetal relations (1). To determine the factors responsible for intrauterine growth retardation, we performed bilateral uterine artery ligation in the maternal rat. This technique, which can be considered an extreme example of "uteroplacental insufficiency," alters a number of physiologic variables including gaseous exchange and metabolic fuel availability. Alterations in these variables are known to affect fetal growth; however, the mechanisms by which this occurs are not completely understood. Particularly unclear is the impact of these alterations on cellular metabolic processes. For these reasons we Our data indicate that bilateral maternal uterine artery ligation in the rat acutely decreases fetal hepatic ATP/ADP and mitochondrial NAD+/NADH relations but increases cytosolic NAD+/NADH. These changes and alterations in other physiologic variables contributed to development of fetal growth retardation. During the neonatal period, ATP/ADP, adenylate charge ratio, and redox states increase appropriately in SGA newborn rat pups. Alterations in these variables are not directly responsible for the hypoglycemia that develops in the SGA newborn rat. MATERIALS AND METHODSSurgery. We have reported the details of our surgical techniques (2). In brief, on d 18 of their 2 1.5-d gestation, we assigned timed...

Carbohydrate and Energy Metabolism in the Brain of Rats With Thromboxane A2-Induced Fetal Growth Restriction

“…As glycogen storage in fetal brains is minimal (27), the supply of free glucose via glycogenolysis from glycogen storage tissues such as the liver and kidney plays an important role in the survival of the fetus during times of stress. It has been demonstrated that accumulation of fetal hepatic glycogen is decreased in animal models of FGR (25), and in our study we also observed that FGR brains had lower glycogen content. Taken together, these experimental data suggest that FGR brains may have a low tolerance to the effects of undernutrition and adaptive glycogenolysis.…”

“…In general, glucose transportation across the placenta and the blood-brain-barrier is facilitated by carrier-mediated diffusion that is dependent on the concentration gradient. Ogata et al (25) showed that growth-retarded fetuses had significantly diminished plasma glucose concentrations 10 and 240 min after uterine artery ligation, which recovered to normal ranges by the 21st gestational day. Our results support the hypothesis that fetal glycogen degradation with resultant hyperglycemia ensures an adequate supply of substrates to vital tissues such as the brain, and provides, at least, some measure of fetal tolerance to interruptions in placental oxygen transport (26).…”

“…We did not evaluate glycogen storage in the liver or plasma insulin levels in this study. However, Ogata et al (25) measured serum glucose and insulin levels and glycogen content in FGR rats and showed that insulin levels were low, despite glucose levels and glycogen storage both being decreased. Therefore, we speculate that the cause of hypoglycemia in FGR rats may be due to reduced storage of glycogen.…”

Effect of intrauterine growth retardation on liver and long-term metabolic risk

“…There is abundant evidence that liver is a target for programming. The exposure to uteroplacental insufficiency alters the expression of genes encoding enzymes involved with hepatic energy production, 51 decreasing hepatic oxidative phosphorylation 52 and affecting liver glucose transport. 53 The impaired suppression of endogenous hepatic glucose production is an important component of the peripheral insulin resistance associated with type 2 diabetes.…”

Uteroplacental Insufficiency Alters Liver and Skeletal Muscle Branched-Chain Amino Acid Metabolism in Intrauterine Growth-Restricted Fetal Rats

“…To test our hypothesis, we performed bilateral uterine artery ligation on pregnant Sprague-Dawley rats to induce uteroplacental insufficiency and subsequent growth restriction. Fetal rats in this well-characterized model are significantly lighter than controls that undergo identical anesthesia and sham surgery, and litter size does not differ between control and IUGR groups (4,(15)(16)(17)(18)(19)(20)(21). BCKAD activity was subsequently measured in fetal liver with a radiochemical assay.…”