Background Intrauterine growth restricted (IUGR) infants are at increased risk for neurodevelopmental deficits that suggest the hippocampus and cerebral cortex may be particularly vulnerable. Objective Evaluate regional neurochemical profiles in IUGR and normally grown (NG) 7-day old rat pups using in vivo 1H magnetic resonance (MR) spectroscopy at 9.4T. Methods IUGR was induced via bilateral uterine artery ligation at gestational day 19 in pregnant Sprague Dawley dams. MR spectra were obtained from the cerebral cortex, hippocampus and striatum at P7 in IUGR (N=12) and NG (N=13) rats. Results In the cortex, IUGR resulted in lower concentrations of phosphocreatine, glutathione, taurine, total choline, total creatine (P<0.01) and [glutamate]/[glutamine] ratio (P <0.05). Lower taurine concentrations were observed in the hippocampus (P<0.01) and striatum (P <0.05). Conclusion IUGR differentially affects the neurochemical profile of the P7 rat brain regions. Persistent neurochemical changes may lead to cortex-based long-term neurodevelopmental deficits in human IUGR infants.

Background Hypoglycemia (HG) is common in IUGR neonates. In normally grown (NG) neonatal rats, acute HG causes neuronal injury in the brain, cerebral cortex more vulnerable than the hippocampus (HPC). We hypothesized that the IUGR brain is less vulnerable to hypoglycemia-induced injury while preserving the regional variation in vulnerability. Methods We induced IUGR via bilateral uterine artery ligation on gestational day 19 (term 22d) rats. On postnatal day 14, insulin-induced HG of equivalent severity and duration (blood glucose <40mg/dl for 240 min) was produced in IUGR and NG (IUGR/HG and NG/HG) groups. Neuronal injury in the cortex and HPC was quantified 6-72 hr later using Fluoro-Jade B (FJB) histochemistry. The mRNA expression of monocarboxylate transporters, MCT1 and MCT2, and glucose transporters, GLUT1, and GLUT3 was determined using qPCR. Results There were fewer FJB+ cells in the cortex of IUGR/HG; no difference was observed in FJB+ cells in HPC. Core body temperature was lower in IUGR/HG compared with NG/HG. MCT2 expression was increased in the IUGR cortex. Conclusion Hypoglycemia-induced neuronal injury is decreased in the cortex of the developing IUGR brain. Adaptations including systemic hypothermia and enhanced delivery of alternative substrates via MCT2 might protect against hypoglycemia-induced neuronal injury in IUGR.

Accumulating evidence suggests that the early-life environment has lasting effects on health and disease into adulthood. The current concept of developmental origins of adulthood disease has expanded beyond the original observation by Barker and colleagues correlating low birth weight with adulthood cardiovascular and metabolic disorders. Notably, the fetal-neonatal nutritional environment has a significant role in influencing an individual’s wellness in adulthood. During critical periods of fetal and neonatal development, tissues and organ systems are most vulnerable to nutrient deficiencies. Through fetal programming mechanisms such as epigenetic modification, a biochemical process that regulates gene expression without altering the genetic code, developing tissues adapt to nutrient-poor environments to preserve normal development of critical organ systems, including the brain. However, these programmed adaptations can have negative long-term health consequences if the postnatal environment does not match the fetal-neonatal environment in which the programming occurred. These long-term adverse health outcomes constitute the true cost to society, in both increased medical costs and the indirect cost of lost productivity. Here we review the effects of nutrient deficiencies on fetal programming and subsequent health outcomes, as well as the potential mechanisms that underlie fetal programming. This review contains 3 Figures, 2 Tables and 115 references Key words: critical period, epigenetics, fetal programming, iron, long-chain polyunsaturated fatty acids, neurodevelopment, nutrient deficiency, protein-energy, vitamins, zinc