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Nutritional Stress and Fetal Epigenetics in the Brain

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Handbook of Nutrition, Diet, and Epigenetics

Abstract

The developing brain is vulnerable to various adverse environmental conditions during early pregnancy. Maternal nutrition is considered as one of the most influential environmental factors during fetal brain development. The imbalance of maternal diet affects trajectories of neurologic process development and disrupts the architecture of fetal brain, thus leading to increased susceptibility of brain to neurological disorders later in life. Epigenetic mechanisms are essential for the developing brain reprograming and have been determined to underpin the environmental stress-induced fetal origins of adult diseases. Overwhelming evidence obtained from epidemiological studies in humans and experimental studies in maternal nutrition-restriction animal models has indicated that the effects of maternal nutrition on the epigenome and phenotype alternations in offspring are mediated by epigenetic mechanisms. Current studies focusing on immature brain development also showed that maternal malnutrition, such as over-/undernutrition and specific component deficiency, affects fetal brain development via deregulation of epigenetic mechanisms. Thus, the better understanding to the mechanisms of maternal nutrition stress in fetal brain development will potentially lead to early diagnosis and effective treatment for neurological diseases later in life.

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Abbreviations

5caC:

5-Carboxylcytosine

5mC:

5-Methylcytosine

ACE-1:

Angiotensin-converting enzyme-1

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

ANGPT2:

Angiopoietin 2

Avy:

Viable yellow agouti

BDNF:

Brain-derived neurotrophic factor

CDKN3:

Cyclin-dependent kinases 3

DAT:

Dopamine reuptake transporter

DNMTs:

DNA methyltransferases

GR:

Glucocorticoid receptor

HDACs:

Histone deacetylases

ICR:

Imprinting control region

IGF2:

Insulin-like growth factor 2

IGF2-DMR:

IGF2 differentially methylated region

Kap:

Kinase-associated phosphatase

MBD:

Methyl-CpG-binding proteins

MOR:

μ-Opioid receptor

NPCs:

Neural progenitor cells

PENK:

Preproenkephalin

PGCs:

Primordial germ cells

PPAR:

Peroxisome proliferator-activated receptor

RTT:

Rett syndrome

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

SHH:

Sonic hedgehog

SVZ:

Subventricular zone

TET1:

Ten-eleven translocation methylcytosine dioxygenase 1

VEGFC:

Vascular endothelial growth factor-C

References

  • Akhtar A, Gasser SM (2007) The nuclear envelope and transcriptional control. Nat Rev Genet 8:507–517

    Article  CAS  PubMed  Google Scholar 

  • Albright CD, Friedrich CB, Brown EC et al (1999) Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum. Brain Res Dev Brain Res 115:123–129

    Article  CAS  PubMed  Google Scholar 

  • Andersen SL (2003) Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27:3–18

    Article  PubMed  Google Scholar 

  • Antonow-Schlorke I, Schwab M, Cox LA et al (2011) Vulnerability of the fetal primate brain to moderate reduction in maternal global nutrient availability. Proc Natl Acad Sci U S A 108:3011–3016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barker DJ, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1:1077–1081

    Article  CAS  PubMed  Google Scholar 

  • Bennis-Taleb N, Remacle C, Hoet JJ et al (1999) A low-protein isocaloric diet during gestation affects brain development and alters permanently cerebral cortex blood vessels in rat offspring. J Nutr 129:1613–1619

    Article  CAS  PubMed  Google Scholar 

  • Borengasser SJ, Kang P, Faske J et al (2014) High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS One 9:e84209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bystron I, Blakemore C, Rakic P (2008) Development of the human cerebral cortex: boulder committee revisited. Nat Rev Neurosci 9:110–122

    Article  CAS  PubMed  Google Scholar 

  • Chahrour M, Jung SY, Shaw C et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang GQ, Gaysinskaya V, Karatayev O et al (2008) Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity. J Neurosci 28:12107–12119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chango A, Pogribny IP (2015) Considering maternal dietary modulators for epigenetic regulation and programming of the fetal epigenome. Forum Nutr 7:2748–2770

    CAS  Google Scholar 

  • Chen PY, Ganguly A, Rubbi L et al (2013) Intrauterine calorie restriction affects placental DNA methylation and gene expression. Physiol Genomics 45:565–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Craciunescu CN, Albright CD, Mar MH et al (2003) Choline availability during embryonic development alters progenitor cell mitosis in developing mouse hippocampus. J Nutr 133:3614–3618

    Article  CAS  PubMed  Google Scholar 

  • Dauncey MJ (2014) Nutrition, the brain and cognitive decline: insights from epigenetics. Eur J Clin Nutr 68:1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Davis EP, Sandman CA, Buss C et al (2013) Fetal glucocorticoid exposure is associated with preadolescent brain development. Biol Psychiatry 74:647–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davison JM, Mellott TJ, Kovacheva VP et al (2009) Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 284:1982–1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dean W, Santos F, Stojkovic M et al (2001) Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc Natl Acad Sci U S A 98:13734–13738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan G, Beard C, Chen RZ et al (2001) DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 21:788–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan G, Martinowich K, Chin MH et al (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132:3345–3356

    Article  CAS  PubMed  Google Scholar 

  • Fenelon K, Xu B, Lai CS et al (2013) The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J Neurosci 33:14825–14839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Florian ML, Nunes ML (2010) Effects of intra-uterine and early extra-uterine malnutrition on seizure threshold and hippocampal morphometry of pup rats. Nutr Neurosci 13:265–273

    PubMed  Google Scholar 

  • Gallagher EA, Newman JP, Green LR et al (2005) The effect of low protein diet in pregnancy on the development of brain metabolism in rat offspring. J Physiol 568:553–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao J, Wang WY, Mao YW et al (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466:1105–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Georgieff MK (2007) Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 85:614S–620S

    CAS  PubMed  Google Scholar 

  • Gluckman PD, Hanson MA (2004) Living with the past: evolution, development, and patterns of disease. Science 305:1733–1736

    Article  CAS  PubMed  Google Scholar 

  • Goffin D, Allen M, Zhang L et al (2012) Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci 15:274–283

    Article  CAS  Google Scholar 

  • Gong L, Pan YX, Chen H (2010) Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 5:619–626

    Article  CAS  PubMed  Google Scholar 

  • Goyal R, Goyal D, Leitzke A et al (2010) Brain renin-angiotensin system: fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod Sci 17:227–238

    Article  CAS  PubMed  Google Scholar 

  • Guy J, Gan J, Selfridge J et al (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147

    Article  PubMed  PubMed Central  Google Scholar 

  • Han K, Gennarino VA, Lee Y et al (2013) Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev 27:485–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heijmans BT, Tobi EW, Stein AD et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049

    Article  PubMed  PubMed Central  Google Scholar 

  • Hemberger M, Redies C, Krause R et al (1998) H19 and Igf2 are expressed and differentially imprinted in neuroectoderm-derived cells in the mouse brain. Dev Genes Evol 208:393–402

    Article  CAS  PubMed  Google Scholar 

  • Hisahara S, Chiba S, Matsumoto H et al (2008) Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci U S A 105:15599–15604

    Article  PubMed  PubMed Central  Google Scholar 

  • Hsieh J, Nakashima K, Kuwabara T et al (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 101:16659–16664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huffman K (2012) The developing, aging neocortex: how genetics and epigenetics influence early developmental patterning and age-related change. Front Genet 3:212

    Article  PubMed  PubMed Central  Google Scholar 

  • Jepsen K, Solum D, Zhou T et al (2007) SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450:415–419

    Article  CAS  PubMed  Google Scholar 

  • Keverne EB, Pfaff DW, Tabansky I (2015) Epigenetic changes in the developing brain: effects on behavior. Proc Natl Acad Sci U S A 112:6789–6795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim H, Jang WY, Kang MC et al (2016) TET1 contributes to neurogenesis onset time during fetal brain development in mice. Biochem Biophys Res Commun 471:437–443

    Article  CAS  PubMed  Google Scholar 

  • Knuesel I, Chicha L, Britschgi M et al (2014) Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 10:643–660

    Article  CAS  PubMed  Google Scholar 

  • Kovacheva VP, Mellott TJ, Davison JM et al (2007) Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 282:31777–31788

    Article  CAS  PubMed  Google Scholar 

  • Lee HS (2015) Impact of maternal diet on the epigenome during in utero life and the developmental programming of diseases in childhood and adulthood. Forum Nutr 7:9492–9507

    CAS  Google Scholar 

  • Levenson JM, Roth TL, Lubin FD et al (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281:15763–15773

    Article  CAS  PubMed  Google Scholar 

  • Levitt P (2003) Structural and functional maturation of the developing primate brain. J Pediatr 143:S35–S45

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Gonzalez P, Zhang L (2012) Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions. Prog Neurobiol 98:145–165

    Article  PubMed  PubMed Central  Google Scholar 

  • Li G, Zhang W, Baker MS et al (2014) Major epigenetic development distinguishing neuronal and non-neuronal cells occurs postnatally in the murine hypothalamus. Hum Mol Genet 23:1579–1590

    Article  CAS  PubMed  Google Scholar 

  • Lillycrop KA, Slater-Jefferies JL, Hanson MA et al (2007) Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97:1064–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marti E, Bovolenta P (2002) Sonic hedgehog in CNS development: one signal, multiple outputs. Trends Neurosci 25:89–96

    Article  CAS  PubMed  Google Scholar 

  • Ma Q, Zhang L (2015) Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia. Progress in neurobiology 124:28–48

    Google Scholar 

  • McMillen IC, Robinson JS (2005) Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85:571–633

    Article  CAS  PubMed  Google Scholar 

  • Mehedint MG, Craciunescu CN, Zeisel SH (2010) Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc Natl Acad Sci U S A 107:12834–12839

    Article  PubMed  PubMed Central  Google Scholar 

  • Mehler MF (2008) Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 86:305–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michalik L, Desvergne B, Dreyer C et al (2002) PPAR expression and function during vertebrate development. Int J Dev Biol 46:105–114

    CAS  PubMed  Google Scholar 

  • Nabel CS, Kohli RM (2011) Molecular biology. Demystifying DNA demethylation. Science 333:1229–1230

    Article  CAS  PubMed  Google Scholar 

  • Niculescu MD, Lupu DS (2009) High fat diet-induced maternal obesity alters fetal hippocampal development. Int J Dev Neurosci 27:627–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niculescu MD, Craciunescu CN, Zeisel SH (2006) Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 20:43–49

    Article  CAS  PubMed  Google Scholar 

  • Nijland MJ, Mitsuya K, Li C et al (2010) Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability. J Physiol 588:1349–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nogueiras R, Habegger KM, Chaudhary N et al (2012) Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 92:1479–1514

    Article  CAS  PubMed  Google Scholar 

  • Qureshi IA, Mehler MF (2013) Understanding neurological disease mechanisms in the era of epigenetics. JAMA Neurol 70:703–710

    Article  PubMed  PubMed Central  Google Scholar 

  • Qureshi R, Sacan AA (2013) Novel method for the normalization of microRNA RT-PCR data. BMC Med Genet 6(Suppl 1):S14

    Google Scholar 

  • Ranade SC, Sarfaraz Nawaz M, Kumar Rambtla P et al (2012) Early protein malnutrition disrupts cerebellar development and impairs motor coordination. Br J Nutr 107:1167–1175

    Article  CAS  PubMed  Google Scholar 

  • Rudenko A, Dawlaty MM, Seo J et al (2013) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79:1109–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanches EF, Arteni NS, Spindler C et al (2012) Effects of pre- and postnatal protein malnutrition in hypoxic-ischemic rats. Brain Res 1438:85–92

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Ishihara K, Kato R (2000) Mechanisms of Igf2/H19 imprinting: DNA methylation, chromatin and long-distance gene regulation. J Biochem 127:711–715

    Article  CAS  PubMed  Google Scholar 

  • Sauvageot CM, Stiles CD (2002) Molecular mechanisms controlling cortical gliogenesis. Curr Opin Neurobiol 12:244–249

    Article  CAS  PubMed  Google Scholar 

  • Seckl JR, Meaney MJ (2004) Glucocorticoid programming. Ann N Y Acad Sci 1032:63–84

    Article  CAS  PubMed  Google Scholar 

  • Seisenberger S, Andrews S, Krueger F et al (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata M, Nakao H, Kiyonari H et al (2011) MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors. J Neurosci 31:3407–3422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stachowiak EK, Oommen S, Vasu VT et al (2013) Maternal obesity affects gene expression and cellular development in fetal brains. Nutr Neurosci 16:96–103

    Article  CAS  PubMed  Google Scholar 

  • Stead JD, Neal C, Meng F et al (2006) Transcriptional profiling of the developing rat brain reveals that the most dramatic regional differentiation in gene expression occurs postpartum. J Neurosci 26:345–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stiles J, Jernigan TL (2010) The basics of brain development. Neuropsychol Rev 20:327–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Torres N, Bautista CJ, Tovar AR et al (2010) Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipid composition in the rat. Am J Physiol Endocrinol Metab 298:E270–E277

    Article  CAS  PubMed  Google Scholar 

  • Tozuka Y, Wada E, Wada K (2009) Diet-induced obesity in female mice leads to peroxidized lipid accumulations and impairment of hippocampal neurogenesis during the early life of their offspring. FASEB J 23:1920–1934

    Article  CAS  PubMed  Google Scholar 

  • Trujillo I, Surzenko N, Wang Y et al (2016) DNA methylation and microRNA expression are altered by choline deficiency during mouse brain development. FASEB J 30(Suppl 1):912.7

    Google Scholar 

  • Tuesta LM, Zhang Y (2014) Mechanisms of epigenetic memory and addiction. EMBO J 33:1091–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vangeison G, Rempe DA (2009) The Janus-faced effects of hypoxia on astrocyte function. Neuroscientist 15:579–588

    Article  PubMed  PubMed Central  Google Scholar 

  • Vucetic Z, Kimmel J, Totoki K et al (2010) Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 151:4756–4764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker SP, Wachs TD, Gardner JM et al (2007) Child development: risk factors for adverse outcomes in developing countries. Lancet 369:145–157

    Article  PubMed  Google Scholar 

  • Wang Y, Surzenko N, Friday WB et al (2016) Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring. FASEB J 30:1566–1578

    Article  CAS  PubMed  Google Scholar 

  • Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waterland RA, Dolinoy DC, Lin JR et al (2006) Maternal methyl supplements increase offspring DNA methylation at Axin fused. Genesis 44:401–406

    Article  CAS  PubMed  Google Scholar 

  • Wheldon LM, Abakir A, Ferjentsik Z et al (2014) Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells. Cell Rep 7:1353–1361

    Article  CAS  PubMed  Google Scholar 

  • Williams-Wyss O, Zhang S, MacLaughlin SM et al (2014) Embryo number and periconceptional undernutrition in the sheep have differential effects on adrenal epigenotype, growth, and development. Am J Physiol Endocrinol Metab 307:E141–E150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang RR, Cui QY, Murai K et al (2013) Tet1 regulates adult hippocampal neurogenesis and cognition. Cell Stem Cell 13:237–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA, USA

    Qingyi Ma & Lubo Zhang

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  1. Qingyi Ma
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  2. Lubo Zhang
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Correspondence to Qingyi Ma .

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Editors and Affiliations

  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Ma, Q., Zhang, L. (2019). Nutritional Stress and Fetal Epigenetics in the Brain. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_9

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_9

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