Animal Models of Epigenetic Inheritance

ABSTRACT

Although genomic DNA is the template of our heredity, it is the coordination and regulation of its expression that results in the wide complexity and diversity seen among organisms. In recent years, an emerging body of evidence has focused on the role of epigenetics as one mechanism by which gene expression can be maintained and modulated throughout the lifetime of an individual. Epigenetics refers to heritable alterations in gene expression that are not mediated by changes in primary DNA sequence and includes mitotic and/or meiotic events. In essence, epigenetic modulation results in functional adaptations of the genomic response to the environment and is believed to play a fundamental role in early developmental plasticity. This article focuses on several animal models that have been developed over the past decade to study epigenetic inheritance, many of which have arisen from the developmental origins of adult health and disease fields.

KEYWORDS

Chromatin - DNA methylation - nutrition - developmental origins of disease - histone modification

REFERENCES

• 1 Estivill X, Armengol L. Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies.  PLoS Genet. 2007;  3(10) 1787-1799
• 2 Eichler E E, Nickerson D A, Altshuler D Human Genome Structural Variation Working Group et al. Completing the map of human genetic variation.  Nature. 2007;  447(7141) 161-165
• 3 Vissers L E, Veltman J A, van Kessel A G, Brunner H G. Identification of disease genes by whole genome CGH arrays.  Hum Mol Genet. 2005;  14 Spec No. 2 R215-223
• 4 Pennisi E. Breakthrough of the year. Human genetic variation.  Science. 2007;  318(5858) 1842-1843
• 5 Rickman L, Fiegler H, Carter N P, Bobrow M. Prenatal diagnosis by array-CGH.  Eur J Med Genet. 2005;  48(3) 232-240
• 6 Sebat J. Major changes in our DNA lead to major changes in our thinking.  Nat Genet. 2007;  39(7, suppl) S3-S5
• 7 Egan C M, Sridhar S, Wigler M, Hall I M. Recurrent DNA copy number variation in the laboratory mouse.  Nat Genet. 2007;  39(11) 1384-1389
• 8 Verschure P J, Visser A E, Rots M G. Step out of the groove: epigenetic gene control systems and engineered transcription factors.  Adv Genet. 2006;  56 163-204
• 9 Jiang Y H, Bressler J, Beaudet A L. Epigenetics and human disease.  Annu Rev Genomics Hum Genet. 2004;  5 479-510
• 10 Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications.  CMAJ. 2006;  174(3) 341-348
• 11 Waddington C H. Towards a theoretical biology.  Nature. 1968;  218(5141) 525-527
• 12 Riggs A, Martienssen R, Russo V. Introduction. In: Epigenetic Mechanisms of Gene Regulation. Plainview, NY; Cold Spring Harbor Laboratory Press 1996: 1-4
• 13 Holliday R. The inheritance of epigenetic defects.  Science. 1987;  238(4824) 163-170
• 14 Morgan H D, Sutherland H G, Martin D I, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse.  Nat Genet. 1999;  23(3) 314-318
• 15 Wolffe A P, Matzke M A. Epigenetics: regulation through repression.  Science. 1999;  286(5439) 481-486
• 16 Egger G, Liang G, Aparicio A, Jones P A. Epigenetics in human disease and prospects for epigenetic therapy.  Nature. 2004;  429(6990) 457-463
• 17 Birney E, Stamatoyannopoulos J A, Dutta A ENCODE Project Consortium et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.  Nature. 2007;  447(7146) 799-816
• 18 Turner B M. Cellular memory and the histone code.  Cell. 2002;  111(3) 285-291
• 19 Nightingale K P, O'Neill L P, Turner B M. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code.  Curr Opin Genet Dev. 2006;  16(2) 125-136
• 20 Turner B M. Histone acetylation and an epigenetic code.  Bioessays. 2000;  22(9) 836-845
• 21 Clayton A L, Hazzalin C A, Mahadevan L C. Enhanced histone acetylation and transcription: a dynamic perspective.  Mol Cell. 2006;  23(3) 289-296
• 22 Mellor J. Dynamic nucleosomes and gene transcription.  Trends Genet. 2006;  22(6) 320-329
• 23 Shi Y. Histone lysine demethylases: emerging roles in development, physiology and disease.  Nat Rev Genet. 2007;  8(11) 829-833
• 24 Shi Y, Whetstine J R. Dynamic regulation of histone lysine methylation by demethylases.  Mol Cell. 2007;  25(1) 1-14
• 25 Barski A, Cuddapah S, Cui K et al.. High-resolution profiling of histone methylations in the human genome.  Cell. 2007;  129(4) 823-837
• 26 Guenther M G, Levine S S, Boyer L A, Jaenisch R, Young R A. A chromatin landmark and transcription initiation at most promoters in human cells.  Cell. 2007;  130(1) 77-88
• 27 Shi Y, Lan F, Matson C et al.. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.  Cell. 2004;  119(7) 941-953
• 28 Tsankova N, Renthal W, Kumar A, Nestler E J. Epigenetic regulation in psychiatric disorders.  Nat Rev Neurosci. 2007;  8(5) 355-367
• 29 Karagiannis T C, El-Osta A. Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?.  Leukemia. 2007;  21(1) 61-65
• 30 Minucci S, Pelicci P G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.  Nat Rev Cancer. 2006;  6(1) 38-51
• 31 Mann B S, Johnson J R, Cohen M H, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.  Oncologist. 2007;  12(10) 1247-1252
• 32 Ferrante R J, Kubilus J K, Lee J et al.. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.  J Neurosci. 2003;  23(28) 9418-9427
• 33 Avila A M, Burnett B G, Taye A A et al.. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy.  J Clin Invest. 2007;  117(3) 659-671
• 34 Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai L H. Recovery of learning and memory is associated with chromatin remodelling.  Nature. 2007;  447(7141) 178-182
• 35 Kim T H, Abdullaev Z K, Smith A D et al.. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome.  Cell. 2007;  128(6) 1231-1245
• 36 Ruthenburg A J, Li H, Patel D J, Allis C D. Multivalent engagement of chromatin modifications by linked binding modules.  Nat Rev Mol Cell Biol. 2007;  8(12) 983-994
• 37 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome.  Nature. 2000;  403(6769) 501-502
• 38 Oswald J, Engemann S, Lane N et al.. Active demethylation of the paternal genome in the mouse zygote.  Curr Biol. 2000;  10(8) 475-478
• 39 Ehrlich M, Gama-Sosa M A, Huang L H et al.. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells.  Nucleic Acids Res. 1982;  10(8) 2709-2721
• 40 Bestor T H. Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain.  EMBO J. 1992;  11(7) 2611-2617
• 41 Li E, Bestor T H, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.  Cell. 1992;  69(6) 915-926
• 42 Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.  Cell. 1999;  99(3) 247-257
• 43 Lyko F, Ramsahoye B H, Kashevsky H et al.. Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila.  Nat Genet. 1999;  23(3) 363-366
• 44 Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases.  J Mol Biol. 1988;  203(4) 971-983
• 45 Chen T, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b.  Mol Cell Biol. 2003;  23(16) 5594-5605
• 46 Rhee I, Bachman K E, Park B H et al.. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.  Nature. 2002;  416(6880) 552-556
• 47 Takai D, Jones P A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22.  Proc Natl Acad Sci U S A. 2002;  99(6) 3740-3745
• 48 Jones P A. The DNA methylation paradox.  Trends Genet. 1999;  15(1) 34-37
• 49 Holliday R, Pugh J E. DNA modification mechanisms and gene activity during development.  Science. 1975;  187(4173) 226-232
• 50 Riggs A D. X inactivation, differentiation, and DNA methylation.  Cytogenet Cell Genet. 1975;  14(1) 9-25
• 51 McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes.  Cell. 1984;  37(1) 179-183
• 52 Surani M A, Barton S C, Norris M L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.  Nature. 1984;  308(5959) 548-550
• 53 Gluckman P D, Hanson M A. The developmental origins of the metabolic syndrome.  Trends Endocrinol Metab. 2004;  15(4) 183-187
• 54 Dolinoy D C, Weidman J R, Jirtle R L. Epigenetic gene regulation: linking early developmental environment to adult disease.  Reprod Toxicol. 2007;  23(3) 297-307
• 55 Santos F, Dean W. Epigenetic reprogramming during early development in mammals.  Reproduction. 2004;  127(6) 643-651
• 56 Weidman J R, Maloney K A, Jirtle R L. Comparative phylogenetic analysis reveals multiple non-imprinted isoforms of opossum Dlk1.  Mamm Genome. 2006;  17(2) 157-167
• 57 Anway M D, Cupp A S, Uzumcu M, Skinner M K. Epigenetic transgenerational actions of endocrine disruptors and male fertility.  Science. 2005;  308(5727) 1466-1469
• 58 Ho S M, Tang W Y, Belmonte de Frausto J, Prins G S. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4.  Cancer Res. 2006;  66(11) 5624-5632
• 59 Dolinoy D C, Weidman J R, Waterland R A, Jirtle R L. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome.  Environ Health Perspect. 2006;  114(4) 567-572
• 60 Fernandez-Twinn D S, Ozanne S E. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome.  Physiol Behav. 2006;  88(3) 234-243
• 61 Gluckman P D, Hanson M A. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective.  Pediatr Res. 2004;  56(3) 311-317
• 62 Lucas A. Programming by early nutrition in man.  Ciba Found Symp. 1991;  156 38-50 discussion 50-35
• 63 McMillen I C, Robinson J S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.  Physiol Rev. 2005;  85(2) 571-633
• 64 Waterland R A, Garza C. Early postnatal nutrition determines adult pancreatic glucose-responsive insulin secretion and islet gene expression in rats.  J Nutr. 2002;  132(3) 357-364
• 65 Cheung P, Allis C D, Sassone-Corsi P. Signaling to chromatin through histone modifications.  Cell. 2000;  103(2) 263-271
• 66 Pham T D, MacLennan N K, Chiu C T, Laksana G S, Hsu J L, Lane R H. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney.  Am J Physiol Regul Integr Comp Physiol. 2003;  285(5) R962-R970
• 67 Ke X, Lei Q, James S J et al.. Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR rats.  Physiol Genomics. 2006;  25(1) 16-28
• 68 Rakyan V K, Chong S, Champ M E et al.. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission.  Proc Natl Acad Sci U S A. 2003;  100(5) 2538-2543
• 69 Waterland R A, Jirtle R L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation.  Mol Cell Biol. 2003;  23(15) 5293-5300
• 70 Wolff G L, Kodell R L, Moore S R, Cooney C A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice.  FASEB J. 1998;  12(11) 949-957
• 71 Waterland R A, Dolinoy D C, Lin J R, Smith C A, Shi X, Tahiliani K G. Maternal methyl supplements increase offspring DNA methylation at Axin Fused.  Genesis. 2006;  44(9) 401-406
• 72 Fernandez-Twinn D S, Ozanne S E, Ekizoglou S et al.. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction.  Br J Nutr. 2003;  90(4) 815-822
• 73 Krechowec S O, Vickers M, Gertler A, Breier B H. Prenatal influences on leptin sensitivity and susceptibility to diet-induced obesity.  J Endocrinol. 2006;  189(2) 355-363
• 74 Lillycrop K A, Phillips E S, Jackson A A, Hanson M A, Burdge G C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.  J Nutr. 2005;  135(6) 1382-1386
• 75 Ogata E S, Bussey M E, Finley S. Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat.  Metabolism. 1986;  35(10) 970-977
• 76 Ogata E S, Bussey M E, LaBarbera A, Finley S. Altered growth, hypoglycemia, hypoalaninemia, and ketonemia in the young rat: postnatal consequences of intrauterine growth retardation.  Pediatr Res. 1985;  19(1) 32-37
• 77 Economides D L, Nicolaides K H, Campbell S. Metabolic and endocrine findings in appropriate and small for gestational age fetuses.  J Perinat Med. 1991;  19(1–2) 97-105
• 78 Economides D L, Nicolaides K H, Gahl W A, Bernardini I, Evans M I. Plasma amino acids in appropriate- and small-for-gestational-age fetuses.  Am J Obstet Gynecol. 1989;  161(5) 1219-1227
• 79 Nicolaides K H, Economides D L, Soothill P W. Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses.  Am J Obstet Gynecol. 1989;  161(4) 996-1001
• 80 Economides D L, Nicolaides K H, Gahl W A, Bernardini I, Bottoms S, Evans M. Cordocentesis in the diagnosis of intrauterine starvation.  Am J Obstet Gynecol. 1989;  161(4) 1004-1008
• 81 Economides D L, Nicolaides K H. Blood glucose and oxygen tension levels in small-for-gestational-age fetuses.  Am J Obstet Gynecol. 1989;  160(2) 385-389
• 82 Simmons R A, Templeton L J, Gertz S J. Intrauterine growth retardation leads to the development of type 2 diabetes in the rat.  Diabetes. 2001;  50(10) 2279-2286
• 83 Tsirka A E, Gruetzmacher E M, Kelley D E, Ritov V H, Devaskar S U, Lane R H. Myocardial gene expression of glucose transporter 1 and glucose transporter 4 in response to uteroplacental insufficiency in the rat.  J Endocrinol. 2001;  169(2) 373-380
• 84 Vileisis R A, D'Ercole A J. Tissue and serum concentrations of somatomedin-C/insulin-like growth factor I in fetal rats made growth retarded by uterine artery ligation.  Pediatr Res. 1986;  20(2) 126-130
• 85 Fu Q, McKnight R A, Yu X, Wang L, Callaway C W, Lane R H. Uteroplacental insufficiency induces site-specific changes in histone H3 covalent modifications and affects DNA-histone H3 positioning in day 0 IUGR rat liver.  Physiol Genomics. 2004;  20(1) 108-116
• 86 Fu Q, McKnight R A, Yu X, Callaway C W, Lane R H. Growth retardation alters the epigenetic characteristics of hepatic dual specificity phosphatase 5.  FASEB J. 2006;  20(12) 2127-2129
• 87 Strauss R S, Pollack H A. Epidemic increase in childhood overweight, 1986–1998.  JAMA. 2001;  286(22) 2845-2848
• 88 Slyper A H. The pediatric obesity epidemic: causes and controversies.  J Clin Endocrinol Metab. 2004;  89(6) 2540-2547
• 89 Speiser P W, Rudolf M C, Anhalt H Obesity Consensus Working Group et al. Childhood obesity.  J Clin Endocrinol Metab. 2005;  90(3) 1871-1887
• 90 Newman III W P, Freedman D S, Voors A W et al.. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study.  N Engl J Med. 1986;  314(3) 138-144
• 91 Brown S A, Rogers L K, Dunn J K, Gotto Jr A M, Patsch W. Development of cholesterol homeostatic memory in the rat is influenced by maternal diets.  Metabolism. 1990;  39(5) 468-473
• 92 Guo F, Jen K L. High-fat feeding during pregnancy and lactation affects offspring metabolism in rats.  Physiol Behav. 1995;  57(4) 681-686
• 93 Khan I Y, Taylor P D, Dekou V et al.. Gender-linked hypertension in offspring of lard-fed pregnant rats.  Hypertension. 2003;  41(1) 168-175
• 94 Khan I Y, Dekou V, Douglas G et al.. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.  Am J Physiol Regul Integr Comp Physiol. 2005;  288(1) R127-R133
• 95 Buckley A J, Keserü B, Briody J, Thompson M, Ozanne S E, Thompson C H. Altered body composition and metabolism in the male offspring of high fat-fed rats.  Metabolism. 2005;  54(4) 500-507
• 96 Khan I, Dekou V, Hanson M, Poston L, Taylor P. Predictive adaptive responses to maternal high-fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring.  Circulation. 2004;  110(9) 1097-1102
• 97 Aagaard-Tillery K M, Grove K, Bishop J et al.. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome.  J Mol Endocrinol. 2008;  41(2) 91-102
• 98 Nijland M J, Ford S P, Nathanielsz P W. Prenatal origins of adult disease.  Curr Opin Obstet Gynecol. 2008;  20(2) 132-138
• 99 Jacobs R, Owens J A, Falconer J, Webster M E, Robinson J S. Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia.  J Dev Physiol. 1988;  10(2) 113-121
• 100 Fletcher A J, Goodfellow M R, Forhead A J et al.. Low doses of dexamethasone suppress pituitary-adrenal function but augment the glycemic response to acute hypoxemia in fetal sheep during late gestation.  Pediatr Res. 2000;  47(5) 684-691
• 101 Fletchert A J, Edwards C M, Gardner D S, Fowden A L, Giussani D A. Neuropeptide Y in the sheep fetus: effects of acute hypoxemia and dexamethasone during late gestation.  Endocrinology. 2000;  141(11) 3976-3982
• 102 Gardner D S, Fletcher A J, Fowden A L, Giussani D A. Plasma adrenocorticotropin and cortisol concentrations during acute hypoxemia after a reversible period of adverse intrauterine conditions in the ovine fetus during late gestation.  Endocrinology. 2001;  142(2) 589-598
• 103 Gardner D S, Fletcher A J, Bloomfield M R, Fowden A L, Giussani D A. Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus.  J Physiol. 2002;  540(Pt 1) 351-366
• 104 Gardner D S, Giussani D A, Fowden A L. Hindlimb glucose and lactate metabolism during umbilical cord compression and acute hypoxemia in the late-gestation ovine fetus.  Am J Physiol Regul Integr Comp Physiol. 2003;  284(4) R954-R964
• 105 Giussani D A, Phillips P S, Anstee S, Barker D J. Effects of altitude versus economic status on birth weight and body shape at birth.  Pediatr Res. 2001;  49(4) 490-494
• 106 Llanos A J, Riquelme R A, Sanhueza E M et al.. Regional brain blood flow and cerebral hemispheric oxygen consumption during acute hypoxaemia in the llama fetus.  J Physiol. 2002;  538(Pt 3) 975-983
• 107 Min S W, Ko H, Kim C S. Power spectral analysis of heart rate variability during acute hypoxia in fetal lambs.  Acta Obstet Gynecol Scand. 2002;  81(11) 1001-1005
• 108 Barbera A, Giraud G D, Reller M D, Maylie J, Morton M J, Thornburg K L. Right ventricular systolic pressure load alters myocyte maturation in fetal sheep.  Am J Physiol Regul Integr Comp Physiol. 2000;  279(4) R1157-R1164
• 109 Cleal J K, Poore K R, Boullin J P et al.. Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood.  Proc Natl Acad Sci U S A. 2007;  104(22) 9529-9533
• 110 Davis L, Thornburg K L, Giraud G D. The effects of anaemia as a programming agent in the fetal heart.  J Physiol. 2005;  565(Pt 1) 35-41
• 111 Houdijk E C, Engelbregt M J, Popp-Snijders C, Delemarre-Vd Waal H A. Endocrine regulation and extended follow-up of longitudinal growth in intrauterine growth-retarded rats.  J Endocrinol. 2000;  166(3) 599-608
• 112 Sanders M, Fazzi G, Janssen G, Blanco C, De Mey J. Prenatal stress changes rat arterial adrenergic reactivity in a regionally selective manner.  Eur J Pharmacol. 2004;  488(1-3) 147-155
• 113 Sanders M W, Fazzi G E, Janssen G M, de Leeuw P W, Blanco C E, De Mey J G. Reduced uteroplacental blood flow alters renal arterial reactivity and glomerular properties in the rat offspring.  Hypertension. 2004;  43(6) 1283-1289
• 114 Vickers M H, Ikenasio B A, Breier B H. IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming.  Endocrinology. 2001;  142(9) 3964-3973
• 115 Vickers M H, Reddy S, Ikenasio B A, Breier B H. Dysregulation of the adipoinsular axis—a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming.  J Endocrinol. 2001;  170(2) 323-332
• 116 Siebel A L, Mibus A, De Blasio M J et al.. Improved lactational nutrition and postnatal growth ameliorates impairment of glucose tolerance by uteroplacental insufficiency in male rat offspring.  Endocrinology. 2008;  149(6) 3067-3076
• 117 Louey S, Jonker S S, Giraud G D, Thornburg K L. Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes.  J Physiol. 2007;  580(Pt. 2) 639-648
• 118 Broberg C S, Giraud G D, Schultz J M, Thornburg K L, Hohimer A R, Davis L E. Fetal anemia leads to augmented contractile response to hypoxic stress in adulthood.  Am J Physiol Regul Integr Comp Physiol. 2003;  285(3) R649-R655
• 119 Woods L L, Ingelfinger J R, Nyengaard J R, Rasch R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats.  Pediatr Res. 2001;  49(4) 460-467
• 120 White M M, Zhang L. Effects of chronic hypoxia on maternal vasodilation and vascular reactivity in guinea pig and ovine pregnancy.  High Alt Med Biol. 2003;  4(2) 157-169