Metabolomic Analysis Reveals Differences in Umbilical Vein Plasma Metabolites between Normal and Growth-Restricted Fetal Pigs during Late Gestation

China AgriculturalUniversity, Beijing, China.
Journal of Nutrition (Impact Factor: 3.88). 04/2012; 142(6):990-8. DOI: 10.3945/jn.111.153411
Source: PubMed


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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    • "When labelled phenylalanine and leucine boluses are injected intravenously in mothers undergoing C-section, the fetal/maternal (F/M) ratio of tracer enrichment is lower in IUGR than in control pregnancies (Paolini et al. 2001). Little is known about the maternal–fetal transfer of l-tryptophan (l-Trp); although l-Trp transport in placental plasma membrane by system L transporters is lower with IUGR (Lager and Powell 2012) and IUGR fetuses have lower Trp concentrations (−24 %) (Lin et al. 2012), the maternal and fetal metabolism of tryptophan has not, to our knowledge , been assessed using in vivo tracer kinetics. l-Trp is an essential amino acid for protein synthesis, and a precursor of physiologically important compounds, such as 5-HT and niacin (vitamin B 3 ), the former being a key neuromediator and the latter being a precursor to NAD. "
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    ABSTRACT: L-Tryptophan (L-Trp) is a precursor for serotonin (5-HT) and nicotinamide adenine dinucleotide (NAD) synthesis. Both 5-HT and NAD may impact energy metabolism during gestation given that recent studies have demonstrated that increased 5-HT production is crucial for increasing maternal insulin secretion, and that sirtuin, an NAD(+)-dependent protein deacetylase, regulates endocrine signaling. Infants born with intrauterine growth restriction (IUGR) are at a higher risk of metabolic disease once they reach adulthood. IUGR is associated with altered maternal-fetal amino acid transfer. Whether IUGR affects L-Trp metabolism in mother and fetus has not been fully elucidated. Recently, we developed an analytical method using stable isotope-labeled L-Trp to explore the metabolism of L-Trp and its main metabolites, L-kynurenine (L-Kyn), 5-HT and quinolinic acid (QA). In this study, dams submitted to dietary protein restriction throughout gestation received intravenous infusions of stable isotope-labeled (15)N2-L-Trp to determine whether L-Trp metabolism is affected by IUGR. Samples were obtained from maternal, fetal and umbilical vein plasma, as well as the amniotic fluid (AF), placenta and liver of the mother and the fetus after isotope infusion. We observed evidence for active L-Trp transfer from mother to fetus, as well as de novo synthesis of 5-HT in the fetus. Plasma 5-HT was decreased in undernourished mothers. In IUGR fetuses, maternal-fetal L-Trp transfer remained unaffected, but conversion to QA was impaired, implying that NAD production also decreased. Whether such alterations in tryptophan metabolism during gestation have adverse consequences and contribute to the increased risk of metabolic disease in IUGR remains to be explored.
    Amino Acids 09/2015; DOI:10.1007/s00726-015-2072-4 · 3.29 Impact Factor
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    • "On the basis of utilization of amino acids for protein synthesis, the maternal supply of amino acids differs both quantitatively and qualitatively with advancing gestation. Arginine, containing four nitrogen atoms per molecule, is the most abundant nitrogen carrier in fetus, while glutamine is the most abundant nitrogen supplier in porcine umbilical vein during late gestation (Table 1) (Lin et al. 2012). Thus, the rate of fetal glutamine accretion is the greatest throughout the gestation in pigs (Wu et al. 1999). "
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    ABSTRACT: Intrauterine growth restriction (IUGR) is one of the most common concerns in human obstetrics and domestic animal production. It is usually caused by placental insufficiency, which decreases fetal uptake of nutrients (especially amino acids) from the placenta. Amino acids are not only building blocks for protein but also key regulators of metabolic pathways in fetoplacental development. The enhanced demands of amino acids by the developing conceptus must be met via active transport systems across the placenta as normal pregnancy advances. Growing evidence indicates that IUGR is associated with a reduction in placental amino acid transport capacity and metabolic pathways within the embryonic/fetal development. The positive relationships between amino acid concentrations in circulating maternal blood and placental amino acid transport into fetus encourage designing new therapies to prevent or treat IUGR by enhancing amino acid availability in maternal diets or maternal circulation. Despite the positive effects of available dietary interventions, nutritional therapy for IUGR is still in its infancy. Based on understanding of the underlying mechanisms whereby amino acids promote fetal growth and of their dietary requirements by IUGR, supplementation with functional amino acids (e.g., arginine and glutamine) hold great promise for preventing fetal growth restriction and improving health and growth of IUGR offspring.
    Amino Acids 03/2014; 46(7). DOI:10.1007/s00726-014-1725-z · 3.29 Impact Factor
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    • "The extracted compound list for each file was exported as Compound Exchange Format (. cef) file for further Mass Profiler Professional (version B.2.00, Agilent) statistical analysis. The resulting feature files for each sample were processed by ANOVA and PCA analysis utilizing the MPP software, which aligned, normalized, visualized and filtered the molecular features (MFs), for further processing [18], [19], [20], [21]. Subsequently, hierarchical clustering (condition tree) was applied to the data files. "
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    ABSTRACT: Metabolomics, the systematic analysis of potential metabolites in a biological specimen, has been increasingly applied to discovering biomarkers, identifying perturbed pathways, measuring therapeutic targets, and discovering new drugs. By analyzing and verifying the significant difference in metabolic profiles and changes of metabolite biomarkers, metabolomics enables us to better understand substance metabolic pathways which can clarify the mechanism of Traditional Chinese Medicines (TCM). Corydalis yanhusuo alkaloid (CA) is a major component of Qizhiweitong (QZWT) prescription which has been used for treating gastric ulcer for centuries and its mechanism remains unclear completely. Metabolite profiling was performed by high-performance liquid chromatography combined with time-of-flight mass spectrometry (HPLC/ESI-TOF-MS) and in conjunction with multivariate data analysis and pathway analysis. The statistic software Mass Profiller Prossional (MPP) and statistic method including ANOVA and principal component analysis (PCA) were used for discovering novel potential biomarkers to clarify mechanism of CA in treating acid injected rats with gastric ulcer. The changes in metabolic profiling were restored to their base-line values after CA treatment according to the PCA score plots. Ten different potential biomarkers and seven key metabolic pathways contributing to the treatment of gastric ulcer were discovered and identified. Among the pathways, sphingophospholipid metabolism and fatty acid metabolism related network were acutely perturbed. Quantitative real time polymerase chain reaction (RT-PCR) analysis were performed to evaluate the expression of genes related to the two pathways for verifying the above results. The results show that changed biomarkers and pathways may provide evidence to insight into drug action mechanisms and enable us to increase research productivity toward metabolomics drug discovery.
    PLoS ONE 01/2014; 9(1):e82499. DOI:10.1371/journal.pone.0082499 · 3.23 Impact Factor
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