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      Hypoxia and Oxidative Stress Are Associated with Reduced Fetal Growth in Twin and Undernourished Sheep Pregnancies

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          Twin gestations in sheep are economically more important than single ones; however, twins are born with lower weight, resulting in higher mortality and lower postnatal growth. Chilean Patagonia is very important for sheep production, but its harsh environment results in low food availability and cold and windy conditions during gestation and lambing periods, with a consequent great mortality of twins (~40%). We postulate that the restriction of fetal growth in twin and undernourished sheep pregnancies is associated with fetal hypoxia and oxidative stress. To prove this, single- and twin-bearing ewes were maintained under Patagonian field conditions and offered only natural pasture (undernourished) or natural pasture plus concentrate supplementation (well nourished). Near term, blood gases and oxidative status were evaluated in cord blood, and fetal biometric traits and placental weight were obtained after cesarean section. Both maternal undernutrition and twinning led to decreased oxygen supply to the fetuses, which was associated with decreased intrauterine growth. Moreover, twinning increased oxidative stress at the feto-placental unit, which might also contribute to the restriction of fetal growth. These results highlight the importance of maternal nutrition, especially for those ewes bearing multiples, and opens new possibilities for nutritional or antioxidant interventions for preventing fetal hypoxia and oxidative stress.

          Abstract

          Low birth weight has profound implications for perinatal mortality and morbidity in lambs, causing higher mortality and lower growth potential. Low birth weight, as a consequence of fetal growth restriction, occurs in undernourished and multiple pregnancies, where hypoxia and oxidative stress could play a critical role. Our aim was to establish the effects of nutritional deprivation and pregnancy rank on fetal growth, oxygenation, and oxidative status in sheep pregnancies under extensive Patagonian conditions. At 30 days after mating, single- and twin-bearing ewes were offered only natural pasture (undernutrition group) or natural pasture plus concentrate supplementation (well-nourished group). At day 140 of gestation, blood gases and redox status were evaluated in venous cord blood, and fetal biometric characteristics were obtained after cesarean section. Both maternal undernutrition and twinning led to decreased oxygen supply to the fetuses ( p = 0.016 and p = 0.050, respectively), which was associated with decreased intrauterine growth (r = 0.446, p < 0.01). Moreover, twinning increased oxidative stress in cord blood ( p < 0.05), which might also contribute to fetal growth restriction. These results reinforce the importance of maternal nutrition, especially for those ewes bearing multiples, and opens new possibilities for nutritional or antioxidant interventions for preventing fetal hypoxia and oxidative stress.

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          Most cited references53

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          Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost?

          The Lancet, 382(9890), 452-477
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            Lipid metabolism during pregnancy and its implications for fetal growth.

            More glucose crosses the placenta than any other substrate, but correlations between its concentration in maternal plasma and fetal growth are not found consistently. The accumulation of maternal fat depots and hyperlipidemia are the two principal changes in lipid metabolism during pregnancy. Although lipids cross the placenta with difficulty, maternal plasma triacylglycerols (TAG) and non-esterified fatty acids (NEFA) correlate with fetal lipids, fetal growth and fat mass under certain conditions. In intrauterine growth restriction, impaired placental transfer of lipophilic compounds (long-chain polyunsaturated fatty acids and lipophilic vitamins) seems to underpin metabolic dysfunction and decreased birth weight. In gestational diabetes mellitus (GDM), maternal TAG and NEFA levels correlate with neonatal anthropometric measures. In GDM, adipocyte fatty acid-binding protein in fetuses correlated with neonatal fat mass; changes in maternal or cord blood leptin, retinol binding protein 4 and adiponectin concentrations have been related to neonatal fat mass or birth weight, although their importance remains to be investigated. The angiopoietin-like protein 4 (ANGPTL-4) is secreted from adipose tissue, liver and placenta, and irreversibly inhibits lipoprotein lipase (LPL) activity. Maternal plasma ANGPTL-4 is decreased in GDM, and it has been proposed to be responsible for an increase in placental LPL activity, which would facilitate a greater fatty acid placental transfer, contributing to the higher fetal fat accumulation. Thus, while evidence suggesting major involvement of maternal lipid metabolism in fetal adiposity and growth exists, the precise mechanisms remain to be elucidated.
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              Role of oxidative stress in intrauterine growth restriction.

              The objectives of this study were to determine the role of oxidative stress in intrauterine growth restriction (IUGR) and to investigate the possible molecular mechanism(s) leading to oxidant stress in IUGR. Parameters of the oxidative and antioxidant system were evaluated in maternal plasma, umbilical cord blood, and placental tissue of pregnant women with IUGR fetuses. The same samples were obtained from women with normal pregnancies and were evaluated. The results of this study indicate that while the levels of malondialdehyde (MDA) and xanthine oxidase (XO) were higher in maternal plasma, umbilical cord plasma, and placental tissues of the patients with IUGR when compared to the control group [MDA: 142.8 +/- 18.0 vs. 86.4 +/- 22.5 nmol/ml, 151.6 +/- 25.8 vs. 93.3 +/- 7.4 nmol/ml, and 0.72 +/- 0.19 vs. 0.42 +/- 0.09 nmol/mg protein, respectively (for all p < 0.0005); XO: 1.251 +/- 0.674 vs. 0.20 +/- 0.019 mIU/ml (p < 0.0005), 1.97 +/- 0.73 vs. 0.237 +/- 0.143 mIU/ml (p < 0.0005), and 0.023 +/- 0.0012 vs. 0.012 +/- 0.004 mIU/ml (p < 0.025), respectively], the levels of antioxidant potential were identified to be lower in maternal plasma, umbilical cord plasma, and placental tissues of the patients with IUGR: 63.3 +/- 11.9 vs. 198.0 +/- 31.9 U/ml (p < 0.0005), 32.6 +/- 3.7 vs. 206.5 +/- 27.1 U/ml (p < 0.0005), and 0.56 +/- 0.23 vs. 1.16 +/- 0.29 U/ml (p < 0.0005), respectively. On the other hand, the activities of adenosine deaminase of the IUGR patients were higher than those of the control group in maternal plasma (204.8 +/- 103.5 vs. 115.6 +/- 31.8 U/l, p < 0.01) and umbilical cord blood samples (584.2 +/- 285.2 vs. 147.9 +/- 44.8 U/l, p < 0.0005) which may suggest that oxidative stress has a role in IUGR. Moreover, an increased superoxide dismutase activity in maternal plasma (128.2 +/- 37.4 vs. 88.8 +/- 16.6 U/ml, p < 0.005) and cord blood (162.1 +/- 37.0 vs. 116.6 +/- 20.7 U/ml, p < 0.005) and an increased glutathione peroxidase activity in maternal plasma (1.83 +/- 0.26 vs. 1.47 +/- 0.31 IU/ml, p < 0.01) and placental tissue (0.007 +/- 0.0015 vs. 0.003 +/- 0.0012 IU/ml, p < 0.0005) were detected, while decreased catalase activities in cord blood (23,717 +/- 3,538 vs. 16,397 +/- 2,771 IU/ml, p < 0.0005) and placental tissue (47.2 +/- 17.2 vs. 70.7 +/- 11.3 IU/ml, p < 0.005) were identified in IUGR groups. In the light of the results of this study, it can be stated that the oxidative stress increases in patients with IUGR. Providing high-risk patients with an antioxidant may be useful in the prevention or treatment of IUGR, although it is a condition with no certain treatment outcome. 2007 S. Karger AG, Basel
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                Author and article information

                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                19 November 2018
                November 2018
                : 8
                : 11
                : 217
                Affiliations
                [1 ]INIA-Kampenaike, Punta Arenas 6212707, Chile; fsales@ 123456inia.cl
                [2 ]Faculty of Veterinary Sciences, University of Chile, Santiago 8820808, Chile; operalta@ 123456uchile.cl (O.A.P.); eileen.narbona@ 123456gmail.com (E.N.); mdlreyes@ 123456uchile.cl (M.D.l.R.)
                [3 ]AgResearch Grasslands, Palmerston North 4442, New Zealand; Sue.McCoard@ 123456agresearch.co.nz
                [4 ]INIA-Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain; agbulnes@ 123456gmail.com
                [5 ]Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
                [6 ]Faculty of Agricultural Sciences, University of Chile, Santiago 8820808, Chile
                Author notes
                [* ]Correspondence: vparragu@ 123456uchile.cl ; Tel.: +56-2-2978-5548
                Author information
                https://orcid.org/0000-0002-0917-4475
                Article
                animals-08-00217
                10.3390/ani8110217
                6262616
                30463237
                9f399104-4905-440b-ba84-0eca1005051c
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 October 2018
                : 14 November 2018
                Categories
                Article

                ovine gestation,fetal growth,nutrition,oxygen supply,placental–fetal redox

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