Skip to main content
SpringerLink
Log in

Fetal Origins of Obesity and Diabetes

  • Chapter
  • First Online:
Management of Pediatric Obesity and Diabetes

Part of the book series: Nutrition and Health ((NH))

Key Points

The intrauterine environment creates epigenetic marks, which can increase the lifelong risks of developing obesity or T2DM. Maternal obesity during pregnancy can increase the lifelong risks of developing obesity or T2DM. Although it remains unknown whether alteration of the intrauterine environment can reduce the lifelong risks of developing obesity and/or T2DM, maternal health during gestation impacts the lifelong health of the offspring.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Thompson D, Wolf AM (2001) The medical-care cost burden of obesity. Obes Rev 2:189–197

    PubMed  CAS  Google Scholar 

  2. O’Rahilly S, Farooqi IS (2008) Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions. Diabetes 57:2905–2910

    PubMed  Google Scholar 

  3. Comuzzie AG, Williams JT, Martin LJ, Blangero J (2001) Searching for genes underlying normal variation in human adiposity. J Mol Med 79:57–70

    PubMed  CAS  Google Scholar 

  4. Jonsson A, Franks PW, Palmer CNA, Cecil J, Hetherington M (2009) Obesity, FTO gene variant, and energy intake in children. N Engl J Med 360:1571–1572

    PubMed  CAS  Google Scholar 

  5. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894

    PubMed  CAS  Google Scholar 

  6. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI; Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM; KORA, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O’Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L; Nurses’ Health Study, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK; Diabetes Genetics Initiative, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M; SardiNIA Study, Vogel CI, Wallace C, Waterworth DM, Weedon MN; Wellcome Trust Case Control Consortium, Willer CJ; FUSION, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775

    Google Scholar 

  7. Hardy R, Wills A, Wong A, Elks CE, Wareham NJ, Loos RJF, Kuh D, Ong KK (2010) Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 19:545–552

    PubMed  CAS  Google Scholar 

  8. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908

    PubMed  CAS  Google Scholar 

  9. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401

    PubMed  CAS  Google Scholar 

  10. Carmelli D, Cardon LR, Fabsitz R (1994) Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments? Am J Hum Genet 55:566–573

    PubMed  CAS  Google Scholar 

  11. Mitchell BD, Kammerer CM, Mahaney MC, Blangero J, Comuzzie AG, Atwood LD, Haffner SM, Stern MP, MacCluer JW (1996) Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. Arterioscler Thromb Vasc Biol 16:281–288

    PubMed  CAS  Google Scholar 

  12. Hong Y, Pedersen NL, Brismar K, de Faire U (1997) Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet 60:143–152

    PubMed  CAS  Google Scholar 

  13. Arya R, Blangero J, Williams K, Almasy L, Dyer TD, Leach RJ, O’Connell P, Stern MP, Duggirala R (2002) Factors of insulin resistance syndrome-related phenotypes are linked to genetic locations on chromosomes 6 and 7 in non-diabetic Mexican-Americans. Diabetes 51:841–847

    PubMed  CAS  Google Scholar 

  14. de Andrade M, Olswold C, Kardia SL, Boerwinkle E, Turner ST (2002) Multivariate linkage analysis using phenotypes related to the insulin resistance-metabolic disorder. 11th Annual Meeting of the International Genetic Epidemiology Society. Genet Epidemiol 23:275

    Google Scholar 

  15. Loos RJ, Katzmarzyk PT, Rao DC, Rice T, Leon AS, Skinner JS, Wilmore JH, Rankinen T, Bouchard C (2003) Genome-wide linkage scan for the metabolic syndrome in the HERITAGE Family Study. J Clin Endocrinol Metab 88:5935–5943

    PubMed  CAS  Google Scholar 

  16. Butte NF, Comuzzie AG, Cole SA, Mehta NR, Cai G, Tejero M, Bastarrachea R, Smith EO (2005) Quantitative genetic analysis of the metabolic syndrome in Hispanic children. Pediatr Res 58:1243–1248

    PubMed  CAS  Google Scholar 

  17. Grattan DR (2008) Programming from maternal obesity: eating too much for two? Endocrinology 149:5345–5347

    PubMed  CAS  Google Scholar 

  18. Armitage JA, Taylor PD, Poston L (2005) Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol 565:3–8

    PubMed  CAS  Google Scholar 

  19. Ravelli G, Stein Z, Susser M (1976) Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 7:349–354

    Google Scholar 

  20. Ravelli A, van Der Meulen J, Osmond C, Barker D, Bleker O (1999) Obesity at the age of 50 years in men and women exposed to famine prenatally. Am J Clin Nutr 70:811–816

    PubMed  CAS  Google Scholar 

  21. Fernandez-Twinn DS, Ozanne SE (2006) Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav 88:234–243

    PubMed  CAS  Google Scholar 

  22. Ward MA, Neville TL, Reed JJ, Taylor JB, Hallford DM, Soto-Navarro SA, Vonnahme KA, Redmer DA, Reynolds LP, Caton JS (2008) Effects of selenium supply and dietary restriction on maternal and fetal metabolic hormones in pregnant ewe lambs online. J Anim Sci 86:1254–1262

    PubMed  CAS  Google Scholar 

  23. Mathews F, Yudkin P, Neil A (1999) Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. Br Med J 319:339–343

    CAS  Google Scholar 

  24. von Kries R, Toschke A, Koletzko B, Slikker W (2002) Maternal smoking during pregnancy and childhood obesity. Am J Epidemiol 156:954–996

    Google Scholar 

  25. Reece EA (2010) The fetal and maternal consequences of gestational diabetes mellitus. J Matern Fetal Neonatal Med 23:199–203

    PubMed  Google Scholar 

  26. Vohr BR, Boney CM (2008) Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 21:149–157

    PubMed  CAS  Google Scholar 

  27. Ogland B, Vatten LJ, Romundstad PR, Nilsen ST, Forman MR (2009) Pubertal anthropometry in sons and daughters of women with preeclamptic or normotensive pregnancies. Arch Dis Child 94:855–859

    PubMed  CAS  Google Scholar 

  28. Jones AP, Simson EL, Friedman MI (1984) Gestational undernutrition and the development of obesity in rats. J Nutr 114:1484–1492

    PubMed  CAS  Google Scholar 

  29. Jones AP, Olster DH, States B (1996) Maternal insulin manipulations in rats organize body weight and noradrenergic innervation of the hypothalamus in gonadally intact male offspring. Brain Res Dev Brain Res 97:16–21

    PubMed  CAS  Google Scholar 

  30. Levin BE (2006) Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis. Philos Trans R Soc Lond B Biol Sci 361:1107–1121

    PubMed  CAS  Google Scholar 

  31. Levin BE (2009) Synergy of nature and nurture in the development of childhood ­obesity. Int J Obes (Lond) 33:S53–S56

    Google Scholar 

  32. Levin BE (2010) Interaction of perinatal and pre-pubertal factors with genetic predisposition in the development of neural pathways involved in the regulation of energy homeostasis. Brain Res 1350:10–17

    PubMed  CAS  Google Scholar 

  33. Newbold RR, Padilla-Banks E, Snyder RJ, Phillips TM, Jefferson WN (2007) Developmental exposure to endocrine disruptors and the obesity epidemic. Reprod Toxicol 23:290–296

    PubMed  CAS  Google Scholar 

  34. Callaway LK, Prins JB, Chang AM, McIntyre HD (2006) The prevalence and impact of overweight and obesity in an Australian obstetric population. Med J Aust 184:56–59

    PubMed  Google Scholar 

  35. Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE (1995) Body weight and mortality among women. N Engl J Med 333:677–685

    PubMed  CAS  Google Scholar 

  36. Knight B, Shields BM, Hill A, Powell RJ, Wright D, Hattersley AT (2007) The impact of maternal glycemia and obesity on early postnatal growth in a nondiabetic Caucasian population. Diab Care 30:777–783

    Google Scholar 

  37. Shankar K, Harrell A, Liu X, Gilchrist JM, Ronis MJJ, Badger TM (2008) Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol 294:R528–R538

    PubMed  CAS  Google Scholar 

  38. Samuelsson A-M, Matthews PA, Argenton M, Christie MA, McConnell JM, Jansen EHJM, Piersma AH, Ozanne SE, Fernandez-Twinn D, Remacle C, Rowlerson A, Poston L, Taylor PD (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51:383–392

    PubMed  CAS  Google Scholar 

  39. Samuelsson A-M, Morris A, Igosheva N, Kirk SL, Pombo JMC, Coen CW, Poston L, Taylor PD (2010) Evidence for sympathetic origins of hypertension in juvenile offspring of obese rats. Hypertension 55:76–82

    PubMed  CAS  Google Scholar 

  40. Mamun AA, O’Callaghan M, Callaway L, Williams G, Najman J, Lawlor DA (2009) Associations of gestational weight gain with offspring body mass index and blood pressure at 21 years of age. Evidence from a birth cohort study. Circulation 119:1720–1727

    PubMed  Google Scholar 

  41. Salsberry PJ, Reagan PB (2005) Dynamics of early childhood overweight. Pediatrics 116:1329–1338

    PubMed  Google Scholar 

  42. Rosenberg TJ, Garbers S, Lipkind H, Chiasson MA (2005) Maternal obesity and diabetes as risk factors for adverse pregnancy outcomes: differences among 4 racial/ethnic groups. Am J Public Health 95:1544–1551

    Google Scholar 

  43. Cagnacci A, Renzi A, Arangino S, Alessandrini C, Volpe A (2004) Influences of maternal weight on the secondary sex ratio of human offspring. Hum Reprod 19:442–444

    PubMed  CAS  Google Scholar 

  44. Wrotniak BH, Shults J, Butts S, Stettler N (2008) Gestational weight gain and risk of overweight in the offspring at age 7 years in a multicenter, multiethnic cohort study. Am J Clin Nutr 87:1818–1824

    PubMed  CAS  Google Scholar 

  45. Gillman MW (2008) The first months of life: a critical period for development of obesity. Am J Clin Nutr 87:1587–1589

    PubMed  CAS  Google Scholar 

  46. Harder T, Roepke K, Diller N, Stechling Y, Dudenhausen JW, Plagemann A (2009) Birth weight, early weight gain, and subsequent risk of type 1 diabetes: systematic review and meta-analysis. Am J Epidemiol 169:1428–1436

    PubMed  Google Scholar 

  47. Botton J, Heude B, Maccario J, Ducimetière P, Charles M-A (2008) Postnatal weight and height growth velocities at different ages between birth and 5 y and body composition in adolescent boys and girls. Am J Clin Nutr 87:1760–1768

    PubMed  CAS  Google Scholar 

  48. Nelson SM, Matthews P, Poston L (2010) Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod Update 16:255–275

    PubMed  Google Scholar 

  49. Surkan PJ, Hsieh CC, Johansson ALV, Dickman PW, Cnattingius S (2004) Reasons for increasing trends in large for gestational age births. Obstet Gynecol 104:720–726

    PubMed  Google Scholar 

  50. Sewell MF, Huston-Presley L, Super DM, Catalano P (2006) Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol 195:1100–1103

    PubMed  Google Scholar 

  51. Durnwald C, Huston-Presley L, Amini S, Catalano P (2004) Evaluation of body composition of large-for-gestational-age infants of women with gestational diabetes mellitus compared with women with normal glucose tolerance levels. Am J Obstet Gynecol 191:804–808

    PubMed  CAS  Google Scholar 

  52. Ahlsson FSE, Diderholm B, Ewald U, Gustafsson J (2007) Lipolysis and insulin sensitivity at birth in infants who are large for gestational age. Pediatrics 120:958–965

    PubMed  Google Scholar 

  53. Dyer JS, Rosenfeld CR, Rice J, Rice M, Hardin DS (2007) Insulin resistance in Hispanic large-for gestational-age neonates at birth. J Clin Endocrinol Metab 92:3836–3843

    PubMed  CAS  Google Scholar 

  54. Catalano PM, Presley L, Minium J, Hauguel-de Mouzon S (2009) Fetuses of obese mothers develop insulin resistance in utero. Diab Care 32:1076–1080

    CAS  Google Scholar 

  55. Ford SP, Zhang L, Zhu M, Miller MM, Smith DT, Hess BW, Moss GE, Nathanielsz PW, Nijland MJ (2009) Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. Am J Physiol Regul Integr Comp Physiol 297:R835–R843

    PubMed  CAS  Google Scholar 

  56. Fontana L, Eagon JC, Colonna M, Klein S (2007) Impaired mononuclear cell immune function in extreme obesity is corrected by weight loss. Rejuvenation Res 10:41–46

    PubMed  Google Scholar 

  57. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P (2004) Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110:1564–1571

    PubMed  CAS  Google Scholar 

  58. Challier JC, Basu S, Bintein T, Minium J, Hotmire K, Catalano PM, Hauguel-de Mouzon S (2008) Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 29:274–281

    PubMed  CAS  Google Scholar 

  59. Romero R, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, Berry SM (1998) A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 179:186–193

    PubMed  CAS  Google Scholar 

  60. Romero R, Maymon E, Pacora P, Gomez R, Mazor M, Yoon BH, Berry SM (2000) Further observations on the fetal inflammatory response syndrome: A potential homeostatic role for the soluble receptors of tumor necrosis factor [alpha]. Am J Obstet Gynecol 183:1070–1077

    PubMed  CAS  Google Scholar 

  61. Napoli C, D’Armiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G, Palinski W (1997) Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 100:2680–2690

    PubMed  CAS  Google Scholar 

  62. Urashima M, Sakuma M, Teramoto S, Fuyama Y, Eto Y, Kondo K, Tanaka T (2005) Gene expression profiles of peripheral and cord blood mononuclear cells altered by thymic stromal lymphopoietin. Pediatr Res 57:563–569

    PubMed  CAS  Google Scholar 

  63. de Ferranti S, Mozaffarian D (2008) The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 54:945–955

    PubMed  Google Scholar 

  64. Hotamisligil GS (2008) Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond) 32:S52–S54

    CAS  Google Scholar 

  65. Wooding P, Burton G (eds) (2008) Comparative placentation: structures, functions and evolution. Springer, Berlin, p 302

    Google Scholar 

  66. Kim KH, Park MK, Peeters CC, Poolman JT, Shearer MH, Kennedy RC, Nahm MH (1994) Comparison of non-human primate antibodies against Haemophilus influenza type b polysaccharide with human antibodies in oligoclonality and in vivo protective potency. Infect Immun 62:2426–2431

    PubMed  CAS  Google Scholar 

  67. Altmann J, Schoeller D, Altmann SA, Muruthi P, Sapolsky RM (1993) Body size and fatness of free-living baboons reflect food availability and activity levels. Am J Primatol 30:149–161

    Google Scholar 

  68. Comuzzie AG, Cole SA, Martin L, Carey KD, Mahaney MC, Blangero J (2003) The baboon as a nonhuman primate model for the study of the genetics of obesity. Obes Res 11:75–80

    PubMed  Google Scholar 

  69. Chavez AO, Lopez-Alvarenga JC, Tejero ME, Triplitt C, Bastarrachea RA, Sriwijitkamol A, Tantiwong P, Voruganti VS, Musi N, Comuzzie AG, DeFronzo RA, Folli F (2008) Physiological and molecular determinants of insulin action in the baboon. Diabetes 57:899–908

    PubMed  CAS  Google Scholar 

  70. Schlabritz-Loutsevitch NE, Moore CM, Lopez-Alvarenga JC, Dunn BG, Dudley D, Hubbard GB (2008) The baboon model (Papio hamadryas) of fetal loss: maternal weight, age, reproductive history and pregnancy outcome. J Med Primatol 37:337–345

    PubMed  Google Scholar 

  71. Enders AC, Lantz KC, Peterson PE, Hendrickx AG (1997) From blastocyst to placenta: the morphology of implantation in the baboon. Hum Reprod Update 3:561

    PubMed  CAS  Google Scholar 

  72. Kriewaldt FN, Hendrickx AG (1968) Reproductive parameters in the baboon. Lab Anim Care 18:361–370

    PubMed  CAS  Google Scholar 

  73. Beehner JC, Nguyen N, Wango EO, Alberts SC, Altmann J (2006) The endocrinology of pregnancy and fetal loss in wild baboons. Horm Behav 49:688–699

    PubMed  CAS  Google Scholar 

  74. Jen KL, Hansen BC, Metzger BL (1985) Adiposity, anthropometric measures, and plasma insulin levels of rhesus monkeys. Int J Obes 9:213–224

    PubMed  CAS  Google Scholar 

  75. Ferrara N, Smith DT (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    PubMed  CAS  Google Scholar 

  76. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567

    PubMed  CAS  Google Scholar 

  77. MacDorman MF, Atkinson JO (1999) Infant mortality statistics from the 1997 period linked birth/infant death data set. Natl Vital Stat Rep 47:1–23

    PubMed  CAS  Google Scholar 

  78. McIntire DD, Bloom SL, Casey BM, Leveno KJ (1999) Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 340:1234–1238

    PubMed  CAS  Google Scholar 

  79. Hay WW Jr, Catz CS, Grave GD, Yaffe SJ (1997) Workshop summary: fetal growth: its regulation and disorders. Pediatrics 99:585–591

    PubMed  Google Scholar 

  80. O’Keeffe MJ, O’Callaghan M, Williams GM, Najman JM, Bor W (2003) Learning, cognitive, and attentional problems in adolescents born small for gestational age. Pediatrics 112:301–307

    PubMed  Google Scholar 

  81. Jelliffe-Pawlowski LL, Hansen RL (2004) Neurodevelopmental outcome at 8 months and 4 years among infants born full-term small-for-gestational-age. J Perinatol 24:505–514

    PubMed  Google Scholar 

  82. Lundgren M, Cnattingius S, Jonsson B, Tuvemo T (2004) Intellectual performance in young adult males born small for gestational age. Growth Horm IGF Res 14(Suppl A):7–8

    Google Scholar 

  83. Bernstein I, Gabbe SG (1989) Intrauterine growth retardation. In: Gabbe SG, Niebyl JR, Simpson JL, Annas GJ (eds) Obstetrics: normal and problem pregnancies, 3rd edn. Churchill Livingstone, New York, pp 863–886

    Google Scholar 

  84. Meas T, Deghmoun S, Armoogum P, Alberti C, Levy-Marchal C (2008) Consequences of being born small for gestational age on body composition: an 8-year follow-up study. J Clin Endocrinol Metab 93:3804–3809

    PubMed  CAS  Google Scholar 

  85. Innes KE, Byers TE, Marshall JA, Baron A, Orleans M, Hamman RF (2003) Association of a woman’s own birth weight with her subsequent risk for pregnancy-induced hypertension. Am J Epidemiol 158:861–870

    PubMed  Google Scholar 

  86. Innes KE, Byers TE, Marshall JA, Baron A, Orleans M, Hamman RF (2002) Association of a woman’s own birth weight with subsequent risk for gestational diabetes. JAMA 287:2534–2541

    PubMed  Google Scholar 

  87. Frontini MG, Srinivasan SR, Xu J, Berenson GS (2004) Low birth weight and longitudinal trends of cardiovascular risk factor variables from childhood to adolescence: the Bogalusa heart study. BMC Pediatr 4:22

    PubMed  Google Scholar 

  88. Rich-Edwards JW, Colditz GA, Stampfer MJ et al. (1999) Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 130:278–284

    PubMed  CAS  Google Scholar 

  89. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA (1996) Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. BMJ 312:406–410

    PubMed  CAS  Google Scholar 

  90. Lawlor DA, Ronalds G, Clark H, Smith GD, Leon DA (2005) Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen children of the 1950s prospective cohort study. Circulation 112:1414–1418

    PubMed  Google Scholar 

  91. Huxley R, Neil A, Collins R (2002) Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet 360:659–665

    PubMed  Google Scholar 

  92. Huxley R, Owen CG, Whincup PH, Cook DG, Colman S, Collins R (2004) Birth weight and subsequent cholesterol levels: exploration of the “fetal origins” hypothesis. JAMA 292:2755–2764

    PubMed  CAS  Google Scholar 

  93. Barker DJ (1998) Mother, babies, and health in later life. Churchill Livingstone, London

    Google Scholar 

  94. Basso O, Wilcox AJ, Weinberg CR (2006) Birth weight and mortality: causality or confounding? Am J Epidemiol 164:303–311

    PubMed  Google Scholar 

  95. Schisterman EF, Hernandez-Diaz S (2006) Invited commentary: simple models for a complicated reality. Am J Epidemiol 164:312–314

    PubMed  Google Scholar 

  96. Smith GD, Sterne J, Tynelius P, Lawlor DA, Rasmussen F (2005) Birth weight of offspring and subsequent cardiovascular mortality of the parents. Epidemiology 16:563–569

    PubMed  Google Scholar 

  97. Andersen AM, Osler M (2004) Birth dimensions, parental mortality, and mortality in early adult age: a cohort study of Danish men born in 1953. Int J Epidemiol 33:92–99

    PubMed  Google Scholar 

  98. Friedlander Y, Paltiel O, Manor O, Deutsch L, Yanetz R, Calderon-Margalit R, Siscovick DS, Harlap S (2007) Birthweight of offspring and mortality of parents: The Jerusalem Perinatal Study Cohort. Ann Epidemiol 17:914–922

    PubMed  Google Scholar 

  99. Jaquet D, Swaminathan S, Alexander GR, Abajian C (2005) Significant paternal contribution to the risk of small for gestational age. BJOG 112:153–159

    PubMed  Google Scholar 

  100. Clausson B, Lichtenstein P, Cnattingius S (2000) Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 107:375–381

    PubMed  CAS  Google Scholar 

  101. Svensson AC, Pawitan Y, Cnattingius S, Reilly M, Lichtenstein P (2006) Familial aggregation of small-for-gestational-age births: the importance of fetal genetic effects. Am J Obstet Gynecol 194:475–479

    PubMed  Google Scholar 

  102. Ha JC, Ha RR, Almasy L, Dyke B (2002) Genetics and caging type affect birth weight in captive pigtailed macaques (Macaca nemestrina). Am J Primatol 56:207–213

    PubMed  Google Scholar 

  103. Magnus P, Bakketeig LS, Hoffman H (1997) Birth weight of relatives by maternal tendency to repeat small-for-gestational-age (SGA) births in successive pregnancies. Acta Obstet Gynecol Scand Suppl 165:35–38

    PubMed  CAS  Google Scholar 

  104. Klebanoff MA, Meirik O, Berendes HW (1989) Second-generation consequences of small-for-dates birth. Pediatrics 84:343–347

    PubMed  CAS  Google Scholar 

  105. Wang X, Zuckerman B, Coffman GA, Corwin MJ (1995) Familial aggregation of low birth weight among whites and blacks in the United States. N Engl J Med 333(26):1744–1749

    PubMed  CAS  Google Scholar 

  106. Strauss RS, Dietz WH (1998) Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr 133:67–72

    PubMed  CAS  Google Scholar 

  107. Selling KE, Carstensen J, Finnstrom O, Sydsjo G (2006) Intergenerational effects of preterm birth and reduced intrauterine growth: a population-based study of Swedish mother-offspring pairs. BJOG 113:430–440

    PubMed  CAS  Google Scholar 

  108. La Batide-Alanore A, Tregouet DA, Jaquet D, Bouyer J, Tiret L (2002) Familial aggregation of fetal growth restriction in a French cohort of 7,822 term births between 1971 and 1985. Am J Epidemiol 156:180–187

    PubMed  Google Scholar 

  109. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA, Haefliger C, Horton R, Howe K, Jackson DK, Kunde J, Koenig C, Liddle J, Niblett D, Otto T, Pettett R, Seemann S, Thompson C, West T, Rogers J, Olek A, Berlin K, Beck S (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38:1378–1385

    PubMed  CAS  Google Scholar 

  110. Rakyan VK, Hildmann T, Novik KL, Lewin J, Tost J, Cox AV, Andrews TD, Howe KL, Otto T, Olek A, Fischer J, Gut IG, Berlin K, Beck S (2004) DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PLoS Biol 2:e405

    PubMed  Google Scholar 

  111. Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T, Nagase H, Held WA (2005) Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci USA 102:3336–3341

    PubMed  CAS  Google Scholar 

  112. Enklaar T, Zabel BU, Prawitt D (2006) Beckwith–Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med 8:1–19

    PubMed  Google Scholar 

  113. Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y (2005) Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37(9):1003–1007

    PubMed  CAS  Google Scholar 

  114. Bliek J, Terhal P, van den Bogaard MJ, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, van der Smagt J, Kroes H, Mannens M (2006) Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. Am J Hum Genet 78:604–614

    PubMed  CAS  Google Scholar 

  115. Eggermann T, Schönherr N, Eggermann K, Buiting K, Ranke MB, Wollmann HA, Binder G (2008) Use of multiplex ligation-dependent probe amplification increases the detection rate for 11p15 epigenetic alterations in Silver-Russell syndrome. Clin Genet 73:79–84

    PubMed  CAS  Google Scholar 

  116. Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Demay MC, Danton F, Petriczko E, Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML, Gicquel C, Cabrol S, Le Bouc Y (2007) 11p15 ICR1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92:3148–3154

    PubMed  CAS  Google Scholar 

  117. Eggermann T, Eggermann K, Schonherr N (2008) Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome. Trends Genet 24:195–204

    PubMed  CAS  Google Scholar 

  118. Murrell A, Heeson S, Cooper WN, Douglas E, Apostolidou S, Moore GE, Maher ER, Reik W (2004) An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Mol Genet 13:247–255

    PubMed  CAS  Google Scholar 

  119. Heijmans BT, Kremer D, Tobi EW, Boomsma DI, Slagboom PE (2007) Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum Mol Genet 16:547–554

    PubMed  CAS  Google Scholar 

  120. Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C (2003) Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum Mol Genet 12:1569–1578

    PubMed  CAS  Google Scholar 

  121. Einstein F, Thompson RF, Bhagat TD, Fazzari MJ, Verma A, Barzilai N, Greally JM (2010) Cytosine methylation dysregulation in neonates following intrauterine growth restriction. PLoS One 5:e8887

    PubMed  Google Scholar 

  122. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (1996) Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460

    PubMed  CAS  Google Scholar 

  123. Casper RS, Sullivan EL, Tecott L (2008) Relevance of animal models to human eating disorders and obesity. Psychopharmacology 199:0033–3158

    Google Scholar 

  124. Bocock PN, Aagaard-Tillery KM (2009) Animal models of epigenetic inheritance. Semin Reprod Med 27:369–379

    PubMed  CAS  Google Scholar 

  125. Wu G, Bazer FW, Wallace JM, Spencer TE (2006) Intrauterine growth retardation: implications for the animal science. J Anim Sci 84:2316–2337

    PubMed  CAS  Google Scholar 

  126. Taylor PD, Poston L (2006) Developmental programming of obesity in mammals. Exp Physiol 92:287–298

    PubMed  Google Scholar 

  127. Barry JS, Anthony RV (2008) The pregnant sheep as a model for human pregnancy. Theriogenology 69:55–67

    PubMed  CAS  Google Scholar 

  128. Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N (1991) Molecular mapping of the mouse ob mutation. Genomics 11:1054–1062

    PubMed  CAS  Google Scholar 

  129. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    PubMed  CAS  Google Scholar 

  130. Church C, Lee S, Bagg EA, McTaggart JS, Deacon R, Gerken T, Lee A, Moir L, Mecinović J, Quwailid MM, Schofield CJ, Ashcroft FM, Cox RD (2009) A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet 5:e1000599

    PubMed  Google Scholar 

  131. Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, Mombaerts P, Friedman JM (2001) Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 108:1113–1121

    PubMed  CAS  Google Scholar 

  132. Surwit RS, Feinglos MN, Rodin J, Sutherland A, Petro AE, Opara EC, Kuhn CM, Rebuffe-Scrive M (1995) Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44:645–651

    PubMed  CAS  Google Scholar 

  133. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374:542–546

    PubMed  CAS  Google Scholar 

  134. Miltenberger RJ, Mynatt RL, Wilkinson JE, Woychik RP (1997) The role of the agouti gene in the yellow obese syndrome. J Nutr 127:1902S–1907S

    PubMed  CAS  Google Scholar 

  135. Salton SR, Hahm S, Mizuno TM (2000) Of mice and MEN: what transgenic models tell us about hypothalamic control of energy balance. Neuron 25:265–268

    PubMed  CAS  Google Scholar 

  136. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141

    PubMed  CAS  Google Scholar 

  137. Elmquist JK, Elias CF, Saper CB (1999) From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22:221–232

    PubMed  CAS  Google Scholar 

  138. Schroeder M, Zagoory-Sharon O, Lavi-Avnon Y, Moran TH, Weller A (2006) Weight gain and maternal behavior in CCK1 deficient rats. Physiol Behav 89:402–409

    PubMed  CAS  Google Scholar 

  139. Schroeder M, Shbiro L, Zagoory-Sharon O, Moran TH, Weller A (2009) Toward an animal model of childhood-onset obesity: follow-up of OLETF rats during pregnancy and lactation. Am J Physiol Regul Integr Comp Physiol 296:R224–R232

    PubMed  CAS  Google Scholar 

  140. Alexander J, Chang GQ, Dourmashkin JT, Leibowitz SF (2006) Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6J mice compared to control strains. Int J Obes (Lond) 30:50–59

    CAS  Google Scholar 

  141. Jimenez-Chillaron JC, Isganaitis E, Charalambous M, Gesta S, Pentinat-Pelegrin T, Faucette RR, Otis JP, Chow A, Diaz R, Ferguson-Smith A, Patti ME (2009) Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58:460–468

    PubMed  CAS  Google Scholar 

  142. Jones HN, Woollett LA, Barbour N, Prasad PD, Powell TL, Jansson T (2009) High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J 23:271–278

    PubMed  CAS  Google Scholar 

  143. Mueller BR, Bale TL (2006) Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. Physiol Behav 88:605–614

    PubMed  CAS  Google Scholar 

  144. Levin BE (1999) Obesity-prone and -resistant rats differ in their brain [3H] paramino-clonidine binding. Brain Res 512:54–59

    Google Scholar 

  145. Srinivasan M, Katewa SD, Palaniyappan A, Pandya JD, Patel MS (2006) Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 291:E792–E799

    PubMed  CAS  Google Scholar 

  146. Chang G-Q, Gaysinskaya V, Karatayev O, Leibowitz S-F (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

    PubMed  CAS  Google Scholar 

  147. Ericsson A, Säljö K, Sjöstrand E, Jansson N, Prasad PD, Powell TL, Jansson T (2007) Brief hyperglycaemia in the early pregnant rat increasing fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol 581:1323–1332

    PubMed  CAS  Google Scholar 

  148. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD (2000) Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 279:E83–E87

    PubMed  CAS  Google Scholar 

  149. Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, Burdge GC, Hanson MA (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104:12796–12800

    PubMed  CAS  Google Scholar 

  150. Morris TJ, Vickers M, Gluckman P, Gilmour S, Affara N (2009) Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental variations in metabolic traits. PLoS One 4:e7271

    PubMed  Google Scholar 

  151. Pinheiro AR, Salvucci ID, Aguila MB, Mandarim-de-Lacerda CA (2008) Protein restriction during gestation and/or lactation causes adverse transgenerational effects on biometry and glucose metabolism in F1 and F2 progenies of rats. Clin Sci (Lond) 114:381–392

    CAS  Google Scholar 

  152. Zambrano E, Bautista CJ, Deás M, Martínez-Samayoa PM, González-Zamorano M, Ledesma H, Morales J, Larrea F, Nathanielsz PW (2006) A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol 15:221–230

    Google Scholar 

  153. Drake AJ, Walker BR, Seckl JR (2005) Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 288:R34–R38

    PubMed  CAS  Google Scholar 

  154. Korotkova M, Gabrielsson BG, Holmäng A, Larsson B-M, Hanson LÅ, Strandvik B (2005) Gender-related long-term effects in adult rats by perinatal dietary ratio of n-6/n-3 fatty acids. Am J Physiol Regul Integr Physiol 288:R575–R579

    CAS  Google Scholar 

  155. Franko KL, Forhead AJ, Fowden AL (2010) Differential effects of prenatal stress and glucocorticoid administration on postnatal growth and glucose metabolism in rats. J Endocrinol 204:319–329

    PubMed  CAS  Google Scholar 

  156. Ford SP, Hess BW, Schwope MM, Nijland MJ, Gilbert JS, Vonnahme KA, Means WJ, Han H, Nathanielsz PW (2007) Maternal undernutrition during early to mid-gestation in the ewe results in altered growth, adiposity, and glucose tolerance in male offspring. J Anim Sci 85:1285–1294

    PubMed  CAS  Google Scholar 

  157. Costine BA, Inskeep EK, Wilson ME (2005) Growth hormone at breeding modifies conceptus development and postnatal growth in sheep. J Anim Sci 83:810–815

    PubMed  CAS  Google Scholar 

  158. Smith NA, McAuliffe FM, Quinn K, Lonergan P, Evansa ACO (2009) Transient high glycaemic intake in the last trimester of pregnancy increases offspring birthweight and postnatal growth rate in sheep: a randomised control trial. BJOG 116:975–983

    PubMed  CAS  Google Scholar 

  159. Campion DR, Hausman GJ, Stone RT, Klindt J (1988) Influence of maternal obesity on fetal development in pigs. J Anim Sci 66:28–33

    PubMed  CAS  Google Scholar 

  160. Kind KL, Clifton PM, Grant PA, Owens PC, Sohlstrom A, Robinson RCT, JS OJA (2003) Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig. Am J Physiol Regul Integr Comp Physiol 284:R140–R152

    PubMed  CAS  Google Scholar 

  161. Sullivan TM, Micke GC, Perkins N, Martin GB, Wallace CR, Gatford KL, Owens JA, Perry VEA (2009) Dietary protein during gestation affects maternal insulin-like growth factor insulin-like growth factor binding protein, leptin concentrations, and fetal growth in heifers. J Anim Sci 87:3304–3316

    PubMed  CAS  Google Scholar 

  162. Génin F, Perret M (2000) Photoperiod-induced changes in energy balance in gray mouse lemurs. Physiol Behav 71:315–321

    PubMed  Google Scholar 

  163. Farley D, Tejero ME, Comuzzie AG, Higgins PB, Cox L, Werner SL, Jenkins SL, Li C, Choi J, Dick EJ Jr, Hubbard GB, Frost P, Dudley DJ, Ballesteros B, Wu G, Nathanielsz PW, Schlabritz-Loutsevitch NE (2009) Feto-placental adaptations to maternal obesity in the baboon. Placenta 30:752–760

    PubMed  CAS  Google Scholar 

  164. Sullivan EL, Koegler FH, Cameron JL (2006) Individual differences in physical activity are closely associated with changes in body weight in adult female rhesus monkeys (Macaca mulatta). Am J Physiol Regul Integr Comp Physiol 291:R633–R642

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN, USA

    Natalia E. Schlabritz-Loutsevitch MD, PhD

Authors
  1. Natalia E. Schlabritz-Loutsevitch MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gene B. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald Adkins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natalia E. Schlabritz-Loutsevitch MD, PhD .

Editor information

Editors and Affiliations

  1. UT Health Science Center at Memphis, Division of Pediatric Endocrinology and, Le Bonheur Children's Hospital, North Dunlap Street 50, Memphis, 38103, Tennessee, USA

    Robert J. Ferry, Jr.

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Schlabritz-Loutsevitch, N.E., Hubbard, G.B., Adkins, R. (2011). Fetal Origins of Obesity and Diabetes. In: Ferry, Jr., R. (eds) Management of Pediatric Obesity and Diabetes. Nutrition and Health. Humana Press. https://doi.org/10.1007/978-1-60327-256-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-256-8_2

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-255-1

  • Online ISBN: 978-1-60327-256-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation