Placental Development and Nutritional Environment

  • Kosuke TaniguchiEmail author
  • Tomoko Kawai
  • Kenichiro Hata
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1012)


The placenta is considered to have developed recently in mammalian evolution. While the fundamental function of the placenta, i.e., providing nutrients and oxygen to the fetus and receiving waste products, is the same in all mammals, the morphology of the placenta varies substantially in a species-dependent manner. Therefore, considerable interest exists in understanding placental development and function in mammals from a molecular biological viewpoint. Numerous recent studies have shown that various environmental factors before and during pregnancy, including nutrition, affect placental formation and function and that alterations in placental formation and function can influence the developing fetus and the offspring after birth. To date, the relationship between nutrition and the placenta has been investigated in several species, various model organisms, and humans. In this chapter, we discuss the current knowledge of the placenta and the epigenome and then highlight the effects of nutrition during pregnancy on the placenta and the fetus and on the offspring after birth.


Epigenome Placenta DNA methylation Genomic imprinting Retrotransposons 


  1. 1.
    Benirschke K, Burton GJ, Baergen RN. Pathology of the human placenta. 6th ed. Berlin/Heidelberg: Springer; 2012.CrossRefGoogle Scholar
  2. 2.
    David AL, Jauniaux E. Ultrasound and endocrinological markers of first trimester placentation and subsequent fetal size. Placenta. 2016;40:29–33.CrossRefPubMedGoogle Scholar
  3. 3.
    Heinonen S, Taipale P, Saarikoski S. Weights of placentae from small-for-gestational age infants revisited. Placenta. 2001;22:399–404.CrossRefPubMedGoogle Scholar
  4. 4.
    Enders AC, Carter AM. What can comparative studies of placental structure tell us? A review. Placenta. 2004;25(Suppl A):S3–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Tarrade A, Panchenko P, Junien C, Gabory A. Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism. J Exp Biol. 2015;218:50–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Thornburg KL, O’Tierney PF, Louey S. Review: the placenta is a programming agent for cardiovascular disease. Placenta. 2010;31(Suppl):S54–9.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Monk D. Genomic imprinting in the human placenta. Am J Obstet Gynecol. 2015;213:S152–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Hanna CW, McFadden DE, Robinson WP. DNA methylation profiling of placental villi from karyotypically normal miscarriage and recurrent miscarriage. Am J Pathol. 2013;182:2276–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Ono R, Nakamura K, Inoue K, Naruse M, Usami T, Wakisaka-Saito N, et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat Genet. 2006;38:101–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Sekita Y, Wagatsuma H, Nakamura K, Ono R, Kagami M, Wakisaka N, et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat Genet. 2008;40:243–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim J, Frey WD, He H, Kim H, Ekram MB, Bakshi A, et al. Peg3 mutational effects on reproduction and placenta-specific gene families. PLoS One. 2013;8:e83359.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Moore GE, Ishida M, Demetriou C, Al-Olabi L, Leon LJ, Thomas AC, et al. The role and interaction of imprinted genes in human fetal growth. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370:20140074.CrossRefGoogle Scholar
  13. 13.
    Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, et al. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Res. 2014;24:554–69.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sanchez-Delgado M, Court F, Vidal E, Medrano J, Monteagudo-Sanchez A, Martin-Trujillo A, et al. Human oocyte-derived methylation differences persist in the placenta revealing widespread transient imprinting. PLoS Genet. 2016;12:e1006427.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gu Y, Sun J, Groome LJ, Wang Y. Differential miRNA expression profiles between the first and third trimester human placentas. Am J Physiol Endocrinol Metab. 2013;304:E836–43.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Higashijima A, Miura K, Mishima H, Kinoshita A, Jo O, Abe S, et al. Characterization of placenta-specific microRNAs in fetal growth restriction pregnancy. Prenat Diagn. 2013;33:214–22.CrossRefPubMedGoogle Scholar
  17. 17.
    Tang Q, Wu W, Xu X, Huang L, Gao Q, Chen H, et al. miR-141 contributes to fetal growth restriction by regulating PLAG1 expression. PLoS One. 2013;8:e58737.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Li J, Song L, Zhou L, Wu J, Sheng C, Chen H, et al. A MicroRNA signature in gestational diabetes mellitus associated with risk of Macrosomia. Cell Physiol Biochem. 2015;37:243–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Li J, Chen L, Tang Q, Wu W, Gu H, Liu L, et al. The role, mechanism and potentially novel biomarker of microRNA-17-92 cluster in macrosomia. Sci Rep. 2015;5:17212.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Whitehead CL, McNamara H, Walker SP, Alexiadis M, Fuller PJ, Vickers DK, et al. Identifying late-onset fetal growth restriction by measuring circulating placental RNA in the maternal blood at 28 weeks’ gestation. Am J Obstet Gynecol. 2016;214:521 e1-8.Google Scholar
  21. 21.
    Suzuki S, Ono R, Narita T, Pask AJ, Shaw G, Wang C, et al. Retrotransposon silencing by DNA methylation can drive mammalian genomic imprinting. PLoS Genet. 2007;3:e55.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Naruse M, Ono R, Irie M, Nakamura K, Furuse T, Hino T, et al. Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition. Development. 2014;141:4763–71.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, Catzeflis F, et al. Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials. Proc Natl Acad Sci U S A. 2015;112:E487–96.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bjerregaard B, Lemmen JG, Petersen MR, Ostrup E, Iversen LH, Almstrup K, et al. Syncytin-1 and its receptor is present in human gametes. J Assist Reprod Genet. 2014;31:533–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update. 2011;17:397–417.CrossRefPubMedGoogle Scholar
  26. 26.
    Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–300.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cropley JE, Suter CM, Beckman KB, Martin DI. Germ-line epigenetic modification of the murine a vy allele by nutritional supplementation. Proc Natl Acad Sci U S A. 2006;103:17308–12.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. 2014;1255903:345.Google Scholar
  29. 29.
    Coan PM, Vaughan OR, Sekita Y, Finn SL, Burton GJ, Constancia M, et al. Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice. J Physiol. 2010;588:527–38.CrossRefPubMedGoogle Scholar
  30. 30.
    Gallo P, Cioffi L, Limauro R, Farris E, Bianco V, Sassi R, et al. SGA children in pediatric primary care: what is the best choice, large or small? A 10-year prospective longitudinal study. Glob Pediatr Health. 2016;3:2333794X16659993.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Chiavaroli V, Giannini C, D’Adamo E, de Giorgis T, Chiarelli F, Mohn A. Insulin resistance and oxidative stress in children born small and large for gestational age. Pediatrics. 2009;124:695–702.CrossRefPubMedGoogle Scholar
  32. 32.
    Matta J, Carette C, Levy Marchal C, Bertrand J, Petera M, Zins M, et al. Weight for gestational age and metabolically healthy obesity in adults from the Haguenau cohort. BMJ Open. 2016;6:e011367.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mericq V, Martinez-Aguayo A, Uauy R, Iniguez G, Van der Steen M, Hokken-Koelega A. Long-term metabolic risk among children born premature or small for gestational age. Nat Rev Endocrinol. 2017;13:50–62.CrossRefPubMedGoogle Scholar
  34. 34.
    Han DY, Murphy R, Morgan AR, Lam WJ, Thompson JM, Wall CR, et al. Reduced genetic influence on childhood obesity in small for gestational age children. BMC Med Genet. 2013;14:10.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnell D, Golder S, et al. Hyperglycaemia and risk of adverse perinatal outcomes: systematic review and meta-analysis. BMJ. 2016;354:i4694.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lin XH, Wu DD, Gao L, Zhang JY, Pan HT, Wang H, et al. Altered DNA methylation in neonates born large-for-gestational-age is associated with cardiometabolic risk in children. Oncotarget. 2016;7:86511.PubMedPubMedCentralGoogle Scholar
  37. 37.
    El Hajj N, Pliushch G, Schneider E, Dittrich M, Muller T, Korenkov M, et al. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes. 2013;62:1320–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cote S, Gagne-Ouellet V, Guay SP, Allard C, Houde AA, Perron P, et al. PPARGC1alpha gene DNA methylation variations in human placenta mediate the link between maternal hyperglycemia and leptin levels in newborns. Clin Epigenetics. 2016;8:72.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Reichetzeder C, Dwi Putra SE, Pfab T, Slowinski T, Neuber C, Kleuser B, et al. Increased global placental DNA methylation levels are associated with gestational diabetes. Clin Epigenetics. 2016;8:82.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chen PY, Ganguly A, Rubbi L, Orozco LD, Morselli M, Ashraf D, et al. Intrauterine calorie restriction affects placental DNA methylation and gene expression. Physiol Genomics. 2013;45:565–76.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yura S, Itoh H, Sagawa N, Yamamoto H, Masuzaki H, Nakao K, et al. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab. 2005;1:371–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Diaz M, Garcia C, Sebastiani G, de Zegher F, Lopez-Bermejo A, Ibanez L. Placental and cord blood methylation of genes involved in energy homeostasis: association with fetal growth and neonatal body composition. Diabetes. 2017;66:779–84.CrossRefPubMedGoogle Scholar
  43. 43.
    Caviedes L, Iniguez G, Hidalgo P, Castro JJ, Castano E, Llanos M, et al. Relationship between folate transporters expression in human placentas at term and birth weights. Placenta. 2016;38:24–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Geng Y, Gao R, Chen X, Liu X, Liao X, Li Y, et al. Folate deficiency impairs decidualization and alters methylation patterns of the genome in mice. Mol Hum Reprod. 2015;21:844–56.CrossRefPubMedGoogle Scholar
  45. 45.
    Ahmed T, Fellus I, Gaudet J, MacFarlane AJ, Fontaine-Bisson B, Bainbridge SA. Effect of folic acid on human trophoblast health and function in vitro. Placenta. 2016;37:7–15.CrossRefPubMedGoogle Scholar
  46. 46.
    Li Y, Gao R, Liu X, Chen X, Liao X, Geng Y, et al. Folate deficiency could restrain decidual angiogenesis in pregnant mice. Forum Nutr. 2015;7:6425–45.Google Scholar
  47. 47.
    Ge J, Wang J, Zhang F, Diao B, Song ZF, Shan LL, et al. Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance. Genet Mol Res. 2015;14:8021–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Kawai T, Yamada T, Abe K, Okamura K, Kamura H, Akaishi R, et al. Increased epigenetic alterations at the promoters of transcriptional regulators following inadequate maternal gestational weight gain. Sci Rep. 2015;5:14224.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1:1077–81.CrossRefPubMedGoogle Scholar
  50. 50.
    Painter RC, de Rooij SR, Bossuyt PM, Simmers TA, Osmond C, Barker DJ, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2006;84:322–7. quiz 466-7PubMedCrossRefGoogle Scholar
  51. 51.
    Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr. 1999;70:811–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Syddall HE, Sayer AA, Simmonds SJ, Osmond C, Cox V, Dennison EM, et al. Birth weight, infant weight gain, and cause-specific mortality: the Hertfordshire Cohort Study. Am J Epidemiol. 2005;161:1074–80.CrossRefPubMedGoogle Scholar
  53. 53.
    Roseboom TJ, Painter RC, de Rooij SR, van Abeelen AF, Veenendaal MV, Osmond C, et al. Effects of famine on placental size and efficiency. Placenta. 2011;32:395–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Barker DJ, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol. 2010;54:525–30.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    van Abeelen AF, de Rooij SR, Osmond C, Painter RC, Veenendaal MV, Bossuyt PM, et al. The sex-specific effects of famine on the association between placental size and later hypertension. Placenta. 2011;32:694–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Reynolds RM, Godfrey KM, Barker M, Osmond C, Phillips DI. Stress responsiveness in adult life: influence of mother’s diet in late pregnancy. J Clin Endocrinol Metab. 2007;92:2208–10.CrossRefPubMedGoogle Scholar
  57. 57.
    Herrick K, Phillips DI, Haselden S, Shiell AW, Campbell-Brown M, Godfrey KM. Maternal consumption of a high-meat, low-carbohydrate diet in late pregnancy: relation to adult cortisol concentrations in the offspring. J Clin Endocrinol Metab. 2003;88:3554–60.CrossRefPubMedGoogle Scholar
  58. 58.
    Kanitz E, Otten W, Tuchscherer M, Grabner M, Brussow KP, Rehfeldt C, et al. High and low protein ratio carbohydrate dietary ratios during gestation alter maternal-fetal cortisol regulation in pigs. PLoS One. 2012;7:e52748.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Metges CC, Gors S, Lang IS, Hammon HM, Brussow KP, Weitzel JM, et al. Low and high dietary protein:carbohydrate ratios during pregnancy affect materno-fetal glucose metabolism in pigs. J Nutr. 2014;144:155–63.CrossRefPubMedGoogle Scholar
  60. 60.
    Paquette AG, Houseman EA, Green BB, Lesseur C, Armstrong DA, Lester B, et al. Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics. 2016;11:603–13.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Kosuke Taniguchi
    • 1
    Email author
  • Tomoko Kawai
    • 1
  • Kenichiro Hata
    • 1
  1. 1.Department of Maternal-Fetal BiologyNational Research Institute for Child Health and DevelopmentTokyoJapan

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