NATURE REVIEWS | ENDOCRINOLOGY VOLUME 5 | JULY 2009 | 401 REVIEWS Centre for Human Evolution, Adaptation and Disease, Liggins Institute, The University of Auckland, Auckland, New Zealand (P. D. Gluckman, T. Buklijas, F. M. Low, A. S. Beedle). Institute of Developmental Sciences, University of Southampton, Southampton, UK (M. A. Hanson). Correspondence: P. D. Gluckman, Liggins Institute, The University of Auckland, Private Bag 92019, Auckland 1023, New Zealand pd.gluckman@ auckland.ac.nz Epigenetic mechanisms that underpin metabolic and cardiovascular diseases Peter D. Gluckman, Mark A. Hanson, Tatjana Buklijas, Felicia M. Low and Alan S. Beedle Abstract | Cellular commitment to a specific lineage is controlled by differential silencing of genes, which in turn depends on epigenetic processes such as DNA methylation and histone modification. During early embryogenesis, the mammalian genome is ‘wiped clean’ of most epigenetic modifications, which are progressively re-established during embryonic development. Thus, the epigenome of each mature cellular lineage carries the record of its developmental history. The subsequent trajectory and pattern of development are also responsive to environmental influences, and such plasticity is likely to have an epigenetic basis. Epigenetic marks may be transmitted across generations, either directly by persisting through meiosis or indirectly through replication in the next generation of the conditions in which the epigenetic change occurred. Developmental plasticity evolved to match an organism to its environment, and a mismatch between the phenotypic outcome of adaptive plasticity and the current environment increases the risk of metabolic and cardiovascular disease. These considerations point to epigenetic processes as a key mechanism that underpins the developmental origins of chronic noncommunicable disease. Here, we review the evidence that environmental influences during mammalian development lead to stable changes in the epigenome that alter the individual’s susceptibility to chronic metabolic and cardiovascular disease, and discuss the clinical implications. Gluckman, P. D. et al. Nat. Rev. Endocrinol. 5, 401–408 (2009); published online 2 June 2009; doi:10.1038/nrendo.2009.102 Introduction Early evidence that the fetal environment influences sub- sequent susceptibility to chronic disorders came from experimental studies 1 and epidemiological research that showed increased rates of cardiovascular disease in his- torical cohorts that had experienced high infant mor- tality. 2 Further studies revealed an inverse relationship between birthweight and susceptibility to hypertension, cardiovascular morbidity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia and obesity. 2 These observations led to the hypothesis that fetal metabolic adjustments in nutritionally adverse circumstances that aim to restrict growth and thus safeguard brain develop- ment may result in an increased risk of chronic disorders in later stages of life. 3 Yet, some data, such as those from survivors of the Dutch ‘Hunger Winter’ (a short-term famine in 1944–45) indicate that individuals who were exposed to adverse conditions in utero need not have low birthweight to exhibit adverse effects subsequently. 4 This observation is consistent with the previous finding of a continuous relationship between birthweight and risk of cardiovascular disease 5 and with recent observations that demonstrated stronger correlations between metabolic dysfunction and neonatal adiposity, leptin concentra- tions in the umbilical cord and maternal nutrition than with birthweight. 6,7 Other studies focused on the role of excess nutrition and rapid weight gain in infants, 8 the risk of which is increased after impaired fetal growth. Whereas most research has involved pathways through Competing interests The authors and the Journal Editor V. Heath and the CME questions author D. Lie declare no competing interests. Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and Nature Publishing Group. MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. MedscapeCME designates this educational activity for a maximum of 0.75 AMA PRA Category 1 Credits TM . Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/ public/naturereviews; and (4) view/print certificate. Learning objectives Upon completion of this activity, participants should be able to: 1 Identify the window during which the epigenome is susceptible to environmental cues in mammals. 2 List growth factors that affect the risk for adult cardiovascular and metabolic diseases. 3 Describe the animal models used to explain the epigenetic basis of adult cardiovascular disease. 4 Describe the evidence for periconceptual influences on subsequent development in humans. © 2009 Macmillan Publishers Limited. All rights reserved