Metabolomic analysis reveals differences in umbilical vein plasma metabolites between normal and growth-restricted fetal pigs during late gestation.
ABSTRACT Intrauterine growth restriction (IUGR) remains a major problem for both human health and animal production due to its association with high rates of neonatal morbidity and mortality, low efficiency of food utilization, permanent adverse effects on postnatal growth and development, and long-term health and productivity of the offspring. However, the underlying mechanisms for IUGR are largely unknown. In this study, one IUGR fetus and one normal body weight (NBW) fetus were obtained from each of 9 gilts at each of 2 gestational ages (d 90 and 110). Metabolomes of umbilical vein plasma in IUGR and NBW fetuses were determined by MS, while hormones, amino acids, and related metabolites in maternal and fetal plasma were measured using assay kits and chromatographic methods. Metabolites (including glucose, urea, ammonia, amino acids, and lipids) in umbilical vein plasma exhibited a cluster of differences between IUGR and NBW fetuses on d 90 and 110 of gestation. These changes in the IUGR group are associated with disorders of nutrient and energy metabolism as well as endocrine imbalances, which may contribute to the retardation of fetal growth and development. The findings help provide information regarding potential mechanisms responsible for IUGR in swine and also have important implications for the design of effective strategies to prevent, diagnose, and treat IUGR in other mammalian species, including humans.
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ABSTRACT: Intrauterine Growth Restriction (IUGR) due to placental insufficiency occurs in 5-10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development. METHODOLOGYPRINCIPAL FINDINGS: At gestation day 25, IUGR was induced in two New Zealand rabbits by 40-50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR. IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty acid profiles and oxidative stress mechanisms. Overall findings identified aspargine, ornithine, N-acetylaspartylglutamic acid, N-acetylaspartate and palmitoleic acid as potential metabolite candidates to develop clinical biomarkers for the perinatal diagnosis of IUGR related abnormal neurodevelopment.PLoS ONE 01/2013; 8(5):e64545. · 3.73 Impact Factor
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ABSTRACT: A thrifty energy metabolism has been suggested in intrauterine growth restricted (IUGR) offspring. We characterized energy metabolism and substrate oxidation patterns in IUGR pigs in response to food restriction (FR) and refeeding (RFD). Female pigs with low (L; 1.1 kg; n = 20) or normal birth weight (N; 1.5 kg; n = 24) were fed ad libitum after weaning. Half of L and N pigs were food restricted (R; LR, NR) from days 80 to 100 (57 % of ad libitum) and refeed from days 101 to 131, while the remaining pigs were fed ad libitum (control, C). Using indirect calorimetry, carbohydrate and fat oxidation (COX, FOX), energy expenditure (EE) and balance (EB), resting metabolic rate (RMR) [all related to kg body weight(0.62) (BW)] and RQ were determined at 4 days before (day 76) and after (day 83) beginning of FR, 4 days before (day 97) and after (day 104) end of FR and 25 days after beginning of RFD (day 125). Body fat and muscle weights were determined at day 131. In spite of higher relative food intake (FI), BW was lower in L pigs. In L pigs, physical activity was lower at age 76 and 83 days compared to N pigs. IUGR did not affect EE or RMR, but resulted in higher COX and lower FOX, causing greater and earlier onset of fat deposition. During FR, EE and RMR of R pigs dropped below that of C pigs, and BW gain was delayed by 30 % irrespective of birth weight. In response to FR, COX decreased and FOX increased. During FR, in LR pigs FOX was ~50 % of that in NR pigs. After 4 days, but not 25 days of RFD, EB and fat synthesis were higher in pigs previously subjected to FR, indicating early catch-up fat. In R pigs, BW and the abdominal fat proportion were lower at 131 days. Differences in food intake and substrate oxidation pattern, but not in EE and RMR, between L and N pigs were reflected in higher body fat proportions but lower body and muscle weights in L pigs. Refeeding following FR was initially associated with increased FI, a more positive EB and a more intense stimulation of fat synthesis which did not persist after 25 days of refeeding.European Journal of Nutrition 08/2013; · 3.13 Impact Factor
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ABSTRACT: Epidemiological and experimental data indicate that caloric restriction in early postnatal life may improve liver lipid metabolism in low birth weight individuals. The present study investigated transcriptional and metabolic responses to low (U) and normal (N) birth weight (d 75, T1) and postnatal feed restriction (R, 60% of controls, d 98, T2) followed by subsequent refeeding until d 131 of age (T3). Liver tissue studies were performed with a total of 42 female pigs which were born by multiparous German landrace sows. Overall, 194 genes were differentially expressed in the liver of U vs. N (T1) animals with roles in lipid metabolism. The total mean area and number of lipid droplets (LD) was about 4.6- and 3.7 times higher in U compared to N. In U, the mean LD size (µm(2)) was 24.9% higher. 3-week feed restriction reduced total mean area of LDs by 58.3 and 72.7% in U and N, respectively. A functional role of the affected genes in amino acid metabolism was additionally indicated. This was reflected by a 17.0% higher arginine concentration in the liver of UR animals (vs. NR). To evaluate persistency of effects, analyses were also done after refeeding period at T3. Overall, 4 and 22 genes show persistent regulation in U and N animals after 5 weeks of refeeding, respectively. These genes are involved in e.g. processes of lipid and protein metabolism and glucose homeostasis. Moreover, the recovery of total mean LD area in U and N animals back to the previous T1 level was observed. However, when compared to controls, the mean LD size was still reduced by 23.3% in UR, whereas it was increased in NR (+24.7%). The present results suggest that short-term postnatal feed restriction period programmed juvenile U animals for an increased rate of hepatic lipolysis in later life.PLoS ONE 01/2013; 8(11):e76705. · 3.73 Impact Factor