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Bioinformatics of Embryonic Exposures: Lipid Metabolism and Gender as Biomedical Variables

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Lipidomics in Health & Disease

Part of the book series: Translational Bioinformatics ((TRBIO,volume 14))

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Abstract

Early pregnancy in the first month is a highly vulnerable window for adverse effects of environmental exposures on the developing embryo. We have demonstrated that three seemingly disparate factors, lithium, homocysteine or alcohol, induce cardiac outflow tract defects, when a single exposure occurs during gastrulation stages. Severity of defects relates to dose, timing of exposure during gastrulation, and gender of the embryo. We sought to define what common process in the developing heart may be altered by maternal lithium and homocysteine exposure and is protected by folic acid dietary supplementation. Using microarray studies and bioinformatics analyses, lipid metabolism was predominantly altered with male embryos displaying greater misexpression of genes than the female. Both placental and cardiac lipid metabolism was altered in a sex-dependent manner.

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References

  • Altmae S, Segura MT, Esteban FJ, Bartel S, Brandi P, Irmler M, Beckers J, Demmelmair H, Lopez-Sabater C, Koletzko B, Krauss-Etschmann S, Campoy C. Maternal pre-pregnancy obesity is associated with altered placental transcriptome. Plos One. 2017;12:e0169223. https://doi.org/10.1371/Journal.Pone.0169223. Ecollection 0162017

    Article  PubMed  PubMed Central  Google Scholar 

  • Andrikopoulos S, Massa CM, Aston-Mourney K, Funkat A, Fam BC, Hull RL, Kahn SE, Proietto J. Differential effect of inbred mouse strain (C57bl/6, Dba/2, 129t2) on insulin secretory function in response to a high fat diet. J Endocrinol. 2005;187:45–53.

    Article  CAS  PubMed  Google Scholar 

  • Aye IL, Lager S, Ramirez VI, Gaccioli F, Dudley DJ, Jansson T, Powell TL. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. Biol Reprod. 2014;90:129. https://doi.org/10.1095/Biolreprod.1113.116186. Epub 112014 Apr 116123

    Article  PubMed  PubMed Central  Google Scholar 

  • Baardman ME, Kerstjens-Frederikse WS, Berger RM, Bakker MK, Hofstra RM, Plosch T. The role of maternal-fetal cholesterol transport in early fetal life: current insights. Biol Reprod. 2013;88:24. https://doi.org/10.1095/Biolreprod.1112.102442. Print 102013 Jan

    Article  PubMed  Google Scholar 

  • Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261:412–7.

    Article  CAS  PubMed  Google Scholar 

  • Barker DJ. Human growth and cardiovascular disease. Nestle Nutr Workshop Ser Pediatr Program. 2008;61:21–38.

    Article  PubMed  Google Scholar 

  • Barker DJ, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006;2:700–7.

    Article  PubMed  Google Scholar 

  • Barnabei MS, Palpant NJ, Metzger JM. Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains. Physiol Genomics. 2010;42a:103–13. https://doi.org/10.1152/Physiolgenomics.00071.02010. Epub 02010 Jul 00013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blüthgen N, Brand K, Cajavec B, Swat M, Herzel H, Beule D. Biological profiling of gene groups utilizing gene ontology. Genome Inform. 2005;16:106–15.

    PubMed  Google Scholar 

  • Boot MJ, Gittenberger-De Groot AC, Van Iperen L, Hierck BP, Poelmann RE. Spatiotemporally separated cardiac neural crest subpopulations that target the outflow tract septum and pharyngeal arch arteries. Anat Rec A Discov Mol Cell Evol Biol. 2003;275:1009–18.

    Article  PubMed  Google Scholar 

  • Bourc’his D, Proudhon C. Sexual dimorphism in parental imprint ontogeny and contribution to embryonic development. Mol Cell Endocrinol. 2008;282:87–94.

    Article  CAS  PubMed  Google Scholar 

  • Calabuig-Navarro V, Haghiac M, Minium J, Glazebrook P, Ranasinghe GC, Hoppel C, Hauguel De-Mouzon S, Catalano P, O'tierney-Ginn P. Effect of maternal obesity on placental lipid metabolism. Endocrinology. 2017;23:2017–00152.

    Google Scholar 

  • Chen J, Han M, Manisastry SM, Trotta P, Serrano MC, Huhta JC, Linask KK. Molecular effects of Lithium exposure during mouse and Chick gastrulation and subsequent valve dysmorphogenesis. Birth Defects Res A Clin Mol Teratol. 2008;82:508–18.

    Article  CAS  PubMed  Google Scholar 

  • Czeizel AE, Dudas I, Vereczkey A, Banhidy F. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Nutrients. 2013;5:4760–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan Y, Sun F, Que S, Li Y, Yang S, Liu G. Prepregnancy maternal diabetes combined with obesity impairs placental mitochondrial function involving Nrf2/are pathway and detrimentally alters metabolism of offspring. Obes Res Clin Pract. 2017;19:30002–9.

    Google Scholar 

  • Ferencz C. A case-control study of cardiovascular malformations in Liveborn infants: the morphogenetic relevance of epidemiologic findings. In: Clark EB, Takao A, editors. Developmental cardiology: morphogenesis and function. Mount Kisco: Futura Publishing Co., Inc.; 1990. p. 523–39.

    Google Scholar 

  • Fielding CJ, Fielding PE. Membrane cholesterol and the regulation of signal transduction. Biochem Soc Trans. 2004;32:65–9.

    Article  CAS  PubMed  Google Scholar 

  • Funkat A, Massa CM, Jovanovska V, Proietto J, Andrikopoulos S. Metabolic adaptations of three inbred strains of mice (C57bl/6, Dba/2, and 129t2) in response to a high-fat diet. J Nutr. 2004;134:3264–9.

    Article  CAS  PubMed  Google Scholar 

  • Gabory A, Attig L, Junien C. Sexual dimorphism in environmental epigenetic programming. Mol Cell Endocrinol. 2009;304:8–18.

    Article  CAS  PubMed  Google Scholar 

  • Grewal J, Carmichael SL, Ma C, Lammer EJ, Shaw GM. Maternal Periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res A Clin Mol Teratol. 2008;82:519–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gui YH, Linask KK, Khowsathit P, Huhta JC. Doppler echocardiography of normal and abnormal embryonic mouse heart. Ped Res. 1996;40:633–42.

    Article  CAS  Google Scholar 

  • Gurvitz M, Stout K. Ebstein’s anomaly of the tricuspid valve. Curr Cardiol Rep. 2007;9:336–42.

    Article  PubMed  Google Scholar 

  • Han M, Trotta P, Coleman C, Linask KK. Mct-4, A511/Basigin and Ef5 expression patterns during early chick cardiomyogenesis indicate cardiac cell differentiation occurs in a hypoxic environment. Dev Dyn. 2006;235:124–31.

    Article  CAS  PubMed  Google Scholar 

  • Han M, Serrano MC, Lastra-Vicente R, Brinez P, Acharya G, Huhta JC, Chen R, Linask KK. Folate rescues Lithium-, homocysteine- and Wnt3a-induced vertebrate cardiac anomalies. Dis Model Mech. 2009;2:467–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han M, Neves AL, Serrano M, Brinez P, Huhta JC, Acharya G, Linask KK. Effects of alcohol, Lithium, and homocysteine on nonmuscle myosin-ii in the mouse placenta and human trophoblasts. Am J Obstet Gynecol. 2012;207(140):E147–19.

    Google Scholar 

  • Han M, Evsikov AV, Zhang L, Lastra-Vicente R, Linask KK. Embryonic exposures of lithium and homocysteine and folate protection affect lipid metabolism during mouse cardiogenesis and placentation. Reprod Toxicol. 2016;61:82–96. https://doi.org/10.1016/J.Reprotox.2016.1003.1039. Epub 2016 Mar 1015

    Article  PubMed  CAS  Google Scholar 

  • Herrera E, Amusquivar E, Lopez-Soldado I, Ortega H. Maternal lipid metabolism and placental lipid transfer. Horm Res. 2006a;65:59–64. Epub 2006 Apr 2010

    PubMed  CAS  Google Scholar 

  • Herrera E, Lopez-Soldado I, Limones M, Amusquivar E, Ramos MP. Lipid metabolism during the perinatal phase, and its implications on postnatal development. Int J Vitam Nutr Res. 2006b;76:216–24.

    Article  CAS  PubMed  Google Scholar 

  • Hirschmugl B, Desoye G, Catalano P, Klymiuk I, Scharnagl H, Payr S, Kitzinger E, Schliefsteiner C, Lang U, Wadsack C, Hauguel-De Mouzon S. Maternal obesity modulates intracellular lipid turnover in the human term placenta. Int J Obes (Lond). 2017;41:317–23. https://doi.org/10.1038/Ijo.2016.1188. Epub 2016 Oct 1026

    Article  CAS  Google Scholar 

  • Hogers B, Deruiter M, Baasten A, Gittenberger-De Groot A, Poelmann R. Intracardiac blood flow patterns related to the yolk sac circulation of the Chick embryo. Circ Res. 1995;76:871–7.

    Article  CAS  PubMed  Google Scholar 

  • Hogers B, Deruiter MC, Gittenberger-De Groot AC, Poelmann RE. Extraembryonic venous obstructions lead to cardiovascular malformations and can be Embryolethal. Cardiovasc Res. 1999;41:87–99.

    Article  CAS  PubMed  Google Scholar 

  • Hom J, Quintanilla R, Hoffman D, De Mesy Bentley K, Molkentin JD, Shey-Shing S, Porter GA. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell. 2011;21:469–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hubbell E, Liu W, Mei R. Robust estimators for expression analysis. Bioinformatics. 2002;18:1585–92.

    Article  CAS  PubMed  Google Scholar 

  • Huhta JC, Linask K. When should we prescribe high-dose folic acid to prevent congenital heart defects? Curr Opin Cardiol. 2015;30:125–31.

    Article  PubMed  Google Scholar 

  • Huhta JC, Linask K, Bailey L. Recent advances in the prevention of congenital heart disease. Curr Opin Pediatr. 2006;18:484–9.

    Article  PubMed  Google Scholar 

  • Klein PS, Melton DA. A molecular mechanism for the effect of Lithium on development. Proc Natl Acad Sci U S A. 1996;93:8455–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linask KK. The heart-placenta Axis in the first month of pregnancy: induction and prevention of cardiovascular birth defects. J Pregnancy. 2013;2013:320413.

    Article  PubMed  PubMed Central  Google Scholar 

  • Linask KK, Han M. Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: folate prevention. Birth Defects Res A Clin Mol Teratol. 2016;106:749–60. https://doi.org/10.1002/Bdra.23526. Epub 22016 Jun 23514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Linask KK, Han M, Bravo-Valenzuela NJ. Changes in vitelline and utero-placental hemodynamics: implications for cardiovascular development. Front Physiol. 2014;5:390. Ecollection 2014

    Article  PubMed  PubMed Central  Google Scholar 

  • Lindinger A, Schwedler G, Hense HW. Prevalence of congenital heart defects in newborns in Germany: results of the first registration year of the Pan study (July 2006 to June 2007). Klinische Padiatrie. 2010;222:321–6.

    Article  CAS  PubMed  Google Scholar 

  • Liu WM, Mei R, Di X, Ryder TB, Hubbell E, Dee S, Webster TA, Harrington CA, Ho MH, Baid J, Smeekens SP. Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics. 2002;18:1593–9.

    Article  CAS  Google Scholar 

  • Loffredo CA. Epidemiology of cardiovascular malformations: prevalence and risk factors. Am J Med Genet. 2000;97:319–25.

    Article  CAS  PubMed  Google Scholar 

  • Manisastry SM, Han M, Linask KK. Early temporal-specific responses and differential sensitivity to Lithium and Wnt-3a exposure during heart development. Dev Dyn. 2006;235:2160–74.

    Article  CAS  PubMed  Google Scholar 

  • Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, Mussatto KA, Uzark K, Goldberg CS, Johnson WH Jr, Li J, Smith SE, Bellinger DC, Mahle WT. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation. 2012;126:1143–72.

    Article  PubMed  Google Scholar 

  • Mcgrath KE, Koniski AD, Malik J, Palis J. Circulation is established in a stepwise pattern in the mammalian embryo. Blood. 2003;101:1669–75.

    Article  CAS  PubMed  Google Scholar 

  • Myatt L, Maloyan A. Obesity and placental function. Semin Reprod Med. 2016;34:42–9.

    Article  CAS  PubMed  Google Scholar 

  • Osol G, Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda). 2009;24:58–71.

    Google Scholar 

  • Pecks U, Rath W, Maass N, Berger B, Lueg I, Farrokh A, Farrokh S, Eckmann-Scholz C. Fetal gender and gestational age differentially affect Pcsk9 levels in intrauterine growth restriction. Lipids Health Dis. 2016;15:193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ptitsyn A. Computational analysis of gene expression space associated with metastatic cancer. Bmc Bioinformatics. 2009;10:S6. https://doi.org/10.1186/1471-2105-1110-S1111-S1186.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rai A, Cross JC. Development of the hemochorial maternal vascular spaces in the placenta through endothelial and Vasculogenic mimicry. Dev Biol. 2014;387:131–41. https://doi.org/10.1016/J.Ydbio.2014.1001.1015. Epub 2014 Jan 1028

    Article  PubMed  CAS  Google Scholar 

  • Richardson JE, Bult CJ. Visual annotation display (Vlad): a tool for finding functional themes in lists of genes. Mamm Genome. 2015;26:567–73. https://doi.org/10.1007/S00335-00015-09570-00332. Epub 02015 Jun 00336

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosenquist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci U S A. 1996;93:15227–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruiz-Palacios M, Prieto-Sanchez MT, Ruiz-Alcaraz AJ, Blanco-Carnero JE, Sanchez-Campillo M, Parrilla JJ, Larque E. Insulin treatment may alter fatty acid carriers in placentas from gestational diabetes subjects. Int J Mol Sci. 2017;18(6):E1203. https://doi.org/10.3390/Ijms18061203.

    Article  PubMed  Google Scholar 

  • Serrano M, Han M, Brinez P, Linask KK. Fetal alcohol syndrome: cardiac birth defects in mice and prevention with folate. Am J Obstet Gynecol. 2010;203:75 E77–15.

    Article  CAS  Google Scholar 

  • Smedts HP, Rakhshandehroo M, Verkleij-Hagoort AC, De Vries JH, Ottenkamp J, Steegers EA, Steegers-Theunissen RP. Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects. Eur J Nutr. 2008;47:357–65.

    Article  CAS  PubMed  Google Scholar 

  • Smedts HP, Van Uitert EM, Valkenburg O, Laven JS, Eijkemans MJ, Lindemans J, Steegers EA, Steegers-Theunissen RP. A derangement of the maternal lipid profile is associated with an elevated risk of congenital heart disease in the offspring. Nutr Metab Cardiovasc Dis. 2012;22:477–85.

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Wood PA. Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models. J Inherit Metab Dis. 2010;33:539–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang LS, Wlodarczyk BJ, Santillano DR, Miranda RC, Finnell RH. Developmental consequences of abnormal folate transport during murine heart morphogenesis. Birth Defects Res A Clin Mol Teratol. 2004;70:449–58.

    Article  CAS  PubMed  Google Scholar 

  • Thiam A, Farese RJ, Walther T. The biophysics and cell biology of lipid droplets. Nat Rev. 2013;14:775–86.

    Article  CAS  Google Scholar 

  • Walker D, Fisher C, Sherman A, Wybrecht B, Kyndely K. Fetal alcohol Spectrum disorders prevention: an exploratory study of Women's use of, attitudes toward, and knowledge about alcohol. J Am Acad Nurse Pract. 2005;17:187–93.

    Article  PubMed  Google Scholar 

  • Zhang F, Phiel C, Spece L, Gurvich N, Klein P. Inhibitory phosphorylation of glycogen synthase kinase-3 (Gsk-3) in response to Lithium. J Biol Chem. 2003;278:33067–77.

    Article  CAS  PubMed  Google Scholar 

  • Zhao QM, Ma XJ, Jia B, Huang GY. Prevalence of congenital heart disease at live birth: an accurate assessment by echocardiographic screening. Acta Paediatrica (Oslo, Norway: 1992). 2013;102:397–402.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, USF Morsani College of Medicine, Tampa and St. Petersburg, FL, USA

    K. K. Linask

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  1. K. K. Linask
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Correspondence to K. K. Linask .

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Editors and Affiliations

  1. Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai, China

    Xiangdong Wang

  2. Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical School, Shanghai, China

    Duojiao Wu

  3. Institutes of Biomedicine, Fudan University, Shanghai, China

    Huali Shen

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Linask, K.K. (2018). Bioinformatics of Embryonic Exposures: Lipid Metabolism and Gender as Biomedical Variables. In: Wang, X., Wu, D., Shen, H. (eds) Lipidomics in Health & Disease. Translational Bioinformatics, vol 14. Springer, Singapore. https://doi.org/10.1007/978-981-13-0620-4_3

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