Abstract
There is now considerable evidence that elements of the heritable or familial component of disease susceptibility are transmitted by nongenomic means, and that environmental influences acting during early development shape disease risk in later life. The underlying mechanisms are thought to involve epigenetic modifications in nonimprinted genes induced by aspects of the developmental environment, which modify gene expression without altering DNA sequences. These changes result in life-long alterations in gene expression. Such nongenomic tuning of phenotype through developmental plasticity has adaptive value because it attempts to match an individual's responses to the environment predicted to be experienced. When the responses are mismatched, disease risk increases. An example of such mismatch is that arising either from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socioeconomic conditions, which contribute substantially to the increasing prevalence of type-2 diabetes, obesity, and cardiovascular disease. Recent evidence suggests that the effects can be transmitted to more than the immediately succeeding generation, through female and perhaps male lines. Future research into epigenetic processes may permit us to develop intervention strategies.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- Dnmt:
-
DNA methyltransferase
- CpG:
-
cytosine and guanine adjacent to each other in the genome, linked by a phosphodiester bond
- GR:
-
glucocorticoid receptor
- HDAC:
-
histone deacetylase
- HMT:
-
histone methyltransferase
- PPAR:
-
peroxisome proliferator-activated receptor
- RNS Pol:
-
RNA polymerase
- TF:
-
transcription factor
References
Godfrey KM 2006 The “Developmental Origins” hypothesis: epidemiology. In: Gluckman PD, Hanson MA (eds) Developmental Origins of Health and Disease—A Biomedical Perspective. Cambridge University Press, pp 6–32
Huxley R, Owen C, Whincup P, Cook D, Rich-Edwards J, Smith G 2007 Is birthweight a risk factor for coronary heart disease in later life? J Epidemiol (in press)
Hanson MA, Gluckman PD 2005 Developmental processes and the induction of cardiovascular function: conceptual aspects. J Physiol 565: 27–34
Gluckman PD, Hanson MA 2006 Mismatch; How Our World No Longer Fits Our Bodies. Oxford University Press, Oxford
Promoting Optimal Fetal Development: Report of a Technical Consultation. World Health Organization. Available at: http://www.who.int/nutrition/topics/fetal_dev_report_EN.pdf
Waterland RA, Jirtle RL 2003 Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC 2005 Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135: 1382–1386
Pham TD, MacLennan NK, Chiu CT, Laksana GS, Hsu JL, Lane RH 2003 Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol 285: R962–R970
Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ 2004 Epigenetic programming by maternal behavior. Nat Neurosci 7: 847–854
Laird PW 2005 Cancer epigenetics. Hum Mol Genet 14: R65–R76
West-Eberhard MJ 2003 Developmental Plasticity and Evolution. Oxford University Press, New York
Bateson P, Barker D, Clutton-Brock T, Deb D, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Mirazón Lahr M, Macnamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE 2004 Developmental plasticity and human health. Nature 430: 419–421
Gluckman PD, Hanson MA, Spencer HG, Bateson P 2005 Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies. Proc Biol Sci 272: 671–677
Gluckman PD, Hanson MA 2004 Living with the past: evolution, development and patterns of disease. Science 305: 1733–1736
Gluckman PD, Hanson MA, Beedle AS 2007 Early life events and their consequences for later disease; a life history and evolutionary perspective. Am J Hum Biol 19: 1–19
Van Speybroeck L 2002 From epigenesis to epigenetics. The case of C.H. Waddington. Ann N Y Acad Sci 981: 61–81
Schmalhausen I 1949 Factors of Evolution; the Theory of Stabilizing Selection. Blakiston, McGraw-Hill, New York
Applebaum SW, Heifetz Y 1999 Density-dependent physiological phase in insects. Annu Rev Entomol 44: 317–341
Schlichting CD, Pigliucci M 1998 Phenotypic evolution: a reaction norm perspective. Sinauer Associates Inc., Sunderland, MA
Waddington CH 1957 The Strategy of the Genes: A Discussion of Some Aspects of Theoretical Biology. Macmillan, New York
Mayr E 2001 What Evolution Is. Basic Books, New York
Jablonka E, Lamb MJ 2005 Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral and Symbolic Variation in the History of Life. MIT Press, Cambridge, MA
Maynard Smith J 1990 Models of a Dual Inheritance System. J Theor Biol 143: 41–53.
Holliday R 1991 Mutations and Epimutations in Mammalian Cells. Mutat Res 250: 351–363
Gluckman PD, Hanson MA, Beedle AS 2007 Non-genomic transgenerational inheritance of disease risk. Bioessays 29: 145–154
Li E, Beard C, Jaenisch R 1993 Role for DNA methylation in genomic imprinting. Nature 366: 362–365
Walsh CP, Chaillet JR, Bestor TH 1998 Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20: 116–117
Waterland RA, Jirtle RL 2003 Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300
Bird A 2002 DNA methylation patterns and epigenetic memory. Genes Dev 16: 6–21
Reik W, Dean W, Walter J 2001 Epigenetic reprogramming in mammalian development. Science 293: 1089–1093
Yoder JA, Soman NS, Verdine GL, Bestor TH 1997 DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol 270: 385–395
Gidekel S, Bergman Y 2002 A unique developmental pattern of Oct-3/4 DNA methylation is controlled by a cis-demodification element. J Biol Chem 277: 34521–34530
Hershko AY, Kafri T, Fainsod A, Razin A 2003 Methylation of HoxA5 and HoxB5 and its relevance to expression during mouse development. Gene 302: 65–72
Grainger RM, Hazard-Leonards RM, Samaha F, Hougan LM, Lesk MR, Thomsen GH 1983 Is hypomethylation linked to activation of delta-crystallin genes during lens development?. Nature 306: 88–91
Benvenisty N, Mencher D, Meyuhas O, Razin A, Reshef L 1985 Sequential changes in DNA methylation patterns of the rat phosphoenolpyruvate carboxykinase gene during development. Proc Natl Acad Sci U S A 82: 267–271
Reik W, Walter J 2001 Genomic imprinting: parental influence on the genome. Nat Rev Genet 2: 21–32
Arnaud P, Feil R 2005 Epigenetic deregulation of genomic imprinting in human disorders and following assisted reproduction. Birth Defects Res C Embryo Today 75: 81–97
Brook JS, Whiteman M, Brook DW 1999 Transmission of risk factors across three generations. Psychol Rep 85: 227–241
Kaati G, Bygren LO, Edvinsson S 2002 Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10: 682–688
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding J, ALSPAC Study Team 2006 Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14: 159–166.
Lumey LH, Stein AD 1997 Offspring birth weights after maternal intrauterine undernutrition: a comparison within sibships. Am J Epidemiol 146: 810–819
Painter RC, Roseboom TJ, Bleker OP 2005 Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20: 345–352
Baird DD, Newbold R 2005 Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reprod Toxicol 20: 81–84
Hatch EE, Troisi R, Wise LA, Hyer M, Palmer JR, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Adam E, Noller KL, Herbst AL, Robboy S, Hartge P, Hoover RN 2006 Age at natural menopause in women exposed to diethylstilbestrol in utero. Am J Epidemiol 164: 682–688
Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Herbst AL, Noller KL, Hyer M, Hoover RN 2006 Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 15: 1509–1514
Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N 2006 Hypospadias: a transgenerational effect of diethylstilbestrol?. Hum Reprod 21: 666–669
Burdge GC, Phillips ES, Dunn RL, Jackson AA, Lillycrop KA 2004 Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator–activated receptors in the liver and adipose tissue of the offspring. Nutr Res 24: 639–646
Bertram C, Trowern AR, Copin N, Jackson AA, Whorwood CB 2001 The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142: 2841–2853
Burdge GC, Hanson MA, Slater-Jefferies JL, Lillycrop KA 2007 Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr ( in press)
Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R 2001 Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr Res 49: 460–467
Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ 2006 Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147: 2909–2915
Lillycrop KA, Slater-Jefferies JL, Hanson MA, Godfrey KM, Jackson AA, Burdge GC 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 ( in press)
Han HC, Austin KJ, Nathanielsz PW, Ford SP, Nijland MJ, Hansen TR 2004 Maternal nutrient restriction alters gene expression in the ovine fetal heart. J Physiol 558: 111–121
Oliver MH, Hawkins P, Harding JE 2005 Periconceptional undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep. Pediatr Res 57: 591–598
McMillen IC, Robinson JS 2005 Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85: 571–633
Gardner DS, Tingey K, Van Bon BW, Ozanne SE, Wilson V, Dandrea J, Keisler DH, Stephenson T, Symonds ME 2005 Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition. Am J Physiol Regul Integr Comp Physiol 289: R947–R954
Poore KR, Cleal JK, Newman JP, Boullin JP, Noakes D, Hanson MA, Green LR 2007 Nutritional challenges during development induce sex-specific changes in glucose homeostasis in the adult sheep. Am J Physiol Endocrinol Metab 292: E32–E39
Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, Jackson AA, Poston L, Hanson MA 2006 Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47: 982–987
Jackson AA, Dunn RL, Marchand MC, Langley-Evans SC 2002 Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clin Sci (Lond) 103: 633–639
Brawley L, Torrens C, Anthony FW, Itoh S, Wheeler T, Jackson AA, Clough GF, Poston L, Hanson MA 2004 Glycine rectifies vascular dysfunction induced by dietary protein imbalance during pregnancy. J Physiol 554: 497–504
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
Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA 2007 Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97: 435–439
Gluckman PD, Hanson MA, Spencer HG 2005 Predictive adaptive responses and human evolution. Trends Ecol Evol 20: 527–533
Lister AM 2004 The impact of Quaternary Ice Ages on mammalian evolution. Philos Trans R Soc Lond B Biol Sci 359: 221–241
Jablonka E, Oborny B, Molnar I, Kisdi E, Hofbauer J, Czaran T 1995 The adaptive advantage of phenotypic memory in changing environments. Philos Trans R Soc Lond B Biol Sci 350: 133–141
Moran NA 1992 The evolutionary maintenance of alternative phenotypes. Am Nat 139: 971–989
Sultan SE, Spencer HG 2002 Metapopulation structure favors plasticity over local adaptation. Am Nat 160: 271–283
Gluckman PD, Hanson MA 2004 Maternal constraint of fetal growth and its consequences. Semin Fetal Neonatal Med 9: 419–425
Kuzawa CW 1998 Adipose tissue in human infancy and childhood: an evolutionary perspective. Am J Phys Anthropol 27: 177–209
Popkin BM 2001 Nutrition in transition: the changing global nutrition challenge. Asia Pac J Clin Nutr 10: S13–S18
Bhargava SK, Sachdev HS, Fall CH, Osmond C, Lakshmy R, Barker DJ, Biswas SK, Ramji S, Prabhakaran D, Reddy KS 2004 Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 350: 865–875
Prentice AM, Moore SE 2005 Early programming of adult diseases in resource poor countries. Arch Dis Child 90: 429–432
Gluckman PD, Hanson MA 2004 The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15: 183–187
Anway MD, Cupp AS, Uzumcu M, Skinner MK 2005 Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469
Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJ 1997 Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ 315: 837–840
Silverman BL, Purdy LP, Metzger BE 1996 The intrauterine environment: implications for the offspring of diabetic mothers. Diabetes Rev 4: 21–35
Aerts L, Van Assche FA 2006 Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol 38: 894–903
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102: 10604–10609
Silva AJ, White R 1988 Inheritance of allelic blueprints for methylation patterns. Cell 54: 145–152
Acknowledgements
The authors thank Dr. Alan Beedle for his assistance with the literature search and editing of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Godfrey, K., Lillycrop, K., Burdge, G. et al. Epigenetic Mechanisms and the Mismatch Concept of the Developmental Origins of Health and Disease. Pediatr Res 61, 5–10 (2007). https://doi.org/10.1203/pdr.0b013e318045bedb
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/pdr.0b013e318045bedb
This article is cited by
-
Effect of lipotoxicity on mitochondrial function and epigenetic programming during bovine in vitro embryo production
Scientific Reports (2023)
-
Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures
Clinical Epigenetics (2022)
-
Newborn screen metabolic panels reflect the impact of common disorders of pregnancy
Pediatric Research (2022)
-
Infant feeding practices associated with adiposity peak and rebound in the EDEN mother–child cohort
International Journal of Obesity (2022)
