The Epigenome and Developmental Origins of Health and Disease

Winner of 2016 BMA Medical Award for Basic and Clinical Sciences

The Epigenome and Developmental Origins of Health and Disease synthesizes the existing knowledge on how the in utero environment could be the most important environment in shaping later risk for various diseases or to conversely promote the health of the offspring.

The book mines the existing literature from a variety of disciplines from toxicology to nutrition to epigenetics to reveal how contrasting maternal in utero environmental changes might be leading to epigenetic convergence and the resulting deleterious phenotypic and physiological effects in our offspring.

It is increasingly becoming apparent that even subtle changes in the mother’s diet, stress, and exposure to low concentrations of toxic chemicals at levels deemed safe by the EPA and FDA, such as endocrine disrupting compounds (EDC), can dramatically impact the health of our children, possibly leading to metabolic, cardiovascular, immunological, neurobehavioral disorders, and increased risk for cancer to list but a few examples.

• Informs how everyday choices pregnant women make can impact child development
• Ties together how in utero environmental changes may be inducing epigenetic changes in the offspring leading to overlapping phenotypes regardless of the initial insult (toxic, nutrition, or stress)
• Includes a boxed-in area in each chapter for further references and resources to keep up with the field
• Features video interviews with the authors and other key leaders in the field

• Language: English
• Publisher: Academic Press
• Release date: Oct 10, 2015
• ISBN: 9780128016725

Book preview

The Epigenome and Developmental Origins of Health and Disease

Editor

Cheryl S. Rosenfeld

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Acknowledgments

Chapter 1. The Developmental Origins of Health and Disease (DOHaD) Concept: Past, Present, and Future

Introduction

The Origins of the Field

Conceptual Developments and Experimental Observations

DOHaD and Epigenetics

The Wider DOHaD Research Agenda

DOHaD and Public Policy

Chapter 2. Historical Perspective of Developmental Origins of Health and Disease in Humans

Introduction

Socioeconomic Stressors and Infant and Child Health

Allostasis and Allostatic Load

Weathering and African American Health Disparities

Acculturation and the Hispanic Paradox

A Life Course Approach and the Developmental Origins of Health and Disease

Epigenetic Regulation and Effects of Psychosocial Stress

Health Vulnerabilities Can be Heritable

Conclusions

Chapter 3. DOHaD and the Periconceptional Period, a Critical Window in Time

Introduction: DOHaD and the Periconceptional Perspective

The Periconceptional Period: A Summary of Key Events

In Vivo Maternal Nutritional Models of Periconceptional Programming

In Vitro Models of Periconceptional Programming Related to Assisted Reproductive Treatments

The Paternal Influence on Periconceptional Developmental Programming

Conclusions

Chapter 4. Introduction to Epigenetic Mechanisms: The Probable Common Thread for Various Developmental Origins of Health and Diseases Effects

Introduction

DNA Methylation

Posttranslational Histone Modifications

Noncoding RNA

Nucleosome Remodeling

Embryonic Epigenetic Reprogramming

Primordial Germ Cell Reprogramming

Conclusion

Chapter 5. Perinatal Neurohormonal Programming and Endocrine Disruption

Introduction

Effects of Sex Steroid Hormones on Brain Sexual Differentiation

Sex Steroid-induced Epigenetic Regulation of Brain Sexual Differentiation

Glucocorticoid and Maternal Stress Effects on Brain Development and Sexual Differentiation

Endocrine Disruption of Normal Brain Programming

Conclusions

Glossary

Chapter 6. Parental Nutrition and Developmental Origins of Health and Disease

Introduction

Overnutrition

Undernutrition

Epigenetics and Prenatal Programming by Malnutrition

Conclusions

Chapter 7. Maternal Prenatal Stress and the Developmental Origins of Mental Health: The Role of Epigenetics

Introduction

Epigenetics

Conclusions

Chapter 8. Epigenetics in the Developmental Origin of Cardiovascular Disorders

Introduction

Periods of Susceptibility to Developmental Programming

Programming Stimuli

Mechanisms of DOHaD in CVD

Concluding Remarks

Chapter 9. Developmental Effects of Endocrine-Disrupting Chemicals in the Ovary and on Female Fertility

Introduction

Ovarian Development and Function

Effects of Endocrine-Disrupting Chemicals on Female Reproduction and Ovary

Conclusions

Chapter 10. Developmental and Epigenetic Origins of Male Reproductive Pathologies

Introduction

Environmental Factors Known to Correlate with Male Reproductive Dysfunction

Developmental Environment and Establishment of Epigenetic Patterns

Developmental Exposures and the Incidence of Male Reproductive Abnormalities

Environmentally Induced Transgenerational Epigenetic Effects Related to Male Reproduction

Germ Line to Somatic Epigenetic Effects: Lesson from the Vinclozolin Transgenerational Model

Epigenetic Marks in Fertility: DNA Methylation and Histone Modifications

Epigenetic Marks and Fertility: Small Noncoding RNAs

Conclusions and Perspectives

Chapter 11. Developmental Origins of Childhood Asthma and Allergic Conditions—Is There Evidence of Epigenetic Regulation?

Introduction

Conclusions

Chapter 12. Immune Disorders, Epigenetics, and the Developmental Origins of Health and Disease

Introduction

Environmental Risk Factors Affecting Immune Function and Individual Vulnerability

The Immune System, Developmental Origins of Adult Health and Disease, and Public Health Implications

Immune Programming by the Microbiota

Interlinkage of Immune Disorders

Immune Disorders and Communicable Diseases

Immune Disorders and Noncommunicable Diseases

Autoimmune Disorders

Inflammatory Disorders

Conclusions

Chapter 13. Neurobehavioral Disorders and Developmental Origins of Health and Disease

Introduction

The Risk Associated with Early-Life Insults

Changes in the Stress System during Pregnancy

Organogenesis

Timing of Intrauterine Exposures

Emotional Regulation

Cognitive Regulation

Epidemiological Evidence for Programming Neurobehavioral Outcomes

Programming the Vulnerable Human Fetal Brain

Birth Phenotype and Neuronal Consequences

Neuronal Consequences of Intrauterine Exposures

Sex Differences and the DOHaD Model

Conclusions

Chapter 14. Metabolic Disorders and Developmental Origins of Health and Disease

Introduction

Intrauterine Growth Restriction

Gestational Diabetes in Pregnancy and Metabolic Programming of the Offspring

Obesity in Pregnancy and Metabolic Programming of the Offspring

Conclusion

Chapter 15. The Developmental Origins of Renal Dysfunction

Introduction

Impact of the Prenatal Environment on Renal Dysfunction and Chronic Kidney Disease

Kidney Development and Nephron Endowment

The Importance of Nephron Endowment: Links to Blood Pressure and Renal Disease

Exploring the Mechanisms of Renal Programming of Low Nephron Endowment: Evidence from Animal Models

Why is the Kidney Susceptible to Programming?

Mechanisms Leading to Impaired Renal Structure and Function

Conclusions

Chapter 16. Cancer and Developmental Origins of Health and Disease—Epigenetic Reprogramming as a Mediator

Introduction

Epigenetic Regulation in Cancer

Developmental Origin of Adult Disease

Developmental Origin of Adult Disease and Breast Cancer

Developmental Origin of Adult Disease and Prostate Cancer

Other Cancers

Epigenetically Active Agents Involved in Carcinogenesis

Exogenous Factors

Endogenous Factors

Conclusions

Glossary Terms, Acronyms, and Abbreviations

Chapter 17. Epigenetic Regulation of Gastrointestinal Epithelial Barrier and Developmental Origins of Health and Disease

Introduction

Epigenetics and GI Tract Development and Maturation

The Gut Microbiota and Programming

Developmental Origins of GI Diseases

Food and Epigenetics of the GI Epithelium

Conclusions and Future Directions

Abbreviations

Chapter 18. How the Father Might Epigenetically Program the Risk for Developmental Origins of Health and Disease Effects in His Offspring

Introduction

Sperm Epigenetics

Zygotic Epigenetic Reprogramming

Paternal Aging

Paternally Driven Environmental Effects

Transgenerational Epigenetic Inheritance

Conclusions

Chapter 19. Linkage between In Utero Environmental Changes and Preterm Birth

Introduction

Environmental Exposures

Chemicals

Particles/Air Pollution

Maternal Health

Conclusions

Glossary Terms

Chapter 20. Sexual Dimorphism and DOHaD through the Lens of Epigenetics: Genetic, Ancestral, Developmental, and Environmental Origins from Previous to the Next Generation(s)

Introduction

Complex Trajectories due to Sex Specificity to Both the Transmission and Inheritance of Susceptibility

Mechanisms of Unequal Expression of X- and Y-Chromosome-Linked Genes

Epigenetics and Gene Expression: Sex- Specific Marks, Mechanisms, and Dynamics

The Specific Epigenetic Features of Extraembryonic Tissues and Placenta

Differences between Male/Female Gametogenesis

Differences in Reprogramming of Maternal/Paternal Genome

What Levels of Evidence: The Limiting and Confounders Factors

Conclusions

Chapter 21. Transgenerational Epigenetic Inheritance: Past Exposures, Future Diseases

Introduction

A Crucial Role for the Germline in Epigenetic and Genetic Inheritance

Evidence for Transgenerational Epigenetic Inheritance in Animal Models

Evidence for Transgenerational Epigenetic Inheritance in Humans

Environmental Exposures Affecting the Male Germline: Adult versus Developmental Exposures

Conclusions and Perspectives

Chapter 22. The Placenta and Developmental Origins of Health and Disease

Introduction

Epidemiology and the Placenta

Placental Function

Environmental Influences on Placental Function

Epigenetics and the Placenta

The Placental Phenotype, Interventions, and Treatments

Concluding Remarks and Future Directions

Chapter 23. The Moral and Legal Relevance of DOHaD Effects for Pregnant Mothers

Introduction: Developmental Origins of Health and Disease Research and Legislative Interventions

The Legal Recognition of Fetal Rights

The Criminalization of the Bad Mother

Caring for Fetuses versus Caring for Future Persons

Beneficence, Nonmaleficence, and Future People

DOHaD Effects Are Not Deterministic

DOHaD and the Nonidentity Problem

Do Women Have a Duty to Abort in Order to Avoid Causing Developmental Origins of Health and Disease Harm to Future Persons?

Is the Criminalization of Mothers Justifiable?

Conclusions

Chapter 24. Introduction to Moms in Motion (MIM)

Abbreviations

Chapter 25. Reversing Harmful Developmental Origins of Health and Disease Effects

Introduction

Method

Discussion

Abbreviations

Chapter 26. Informational Resources for Developmental Origins of Health and Disease Research

Introduction

DOHaD-Related Scientific Organizations

DOHaD-Related Scientific Meetings

DOHaD-Related Journals, Databases, and Other Informative Resources

Social Media Resources Reporting Developmental Origins of Health and Disease Findings

Judging the Reliability of Developmental Origins of Health and Disease Informational Resources

Conclusions

Glossary

Index

Copyright

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Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

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ISBN: 978-0-12-801383-0

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Dedication

I dedicate this book to my father, Robert L. Rosenfeld, who passed away on February 5, 2005. From early childhood onwards, he encouraged me to pursue my interests in science and medicine and taught me that a good start and supportive environment can last a lifetime.

List of Contributors

Roger Brown,     School of Nursing, University of Wisconsin-Madison, Madison, WI, USA

Tatjana Buklijas,     Liggins Institute, The University of Auckland, Auckland, New Zealand

Douglas T. Carrell,     Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA

Mei-Wei Chang,     Michigan State University College of Nursing, East Lansing, MI, USA

Ana Cheong

Department of Environmental Health,University of Cincinnati College of Medicine,Cincinnati,OH,USA

Center for Environmental Genetics,University of Cincinnati Medical Center,Cincinnati,OH,USA

Quetzal A. Class,     Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

Jane K. Cleal,     Institute of Developmental Sciences, University of Southampton, Southampton, UK

James S.M. Cuffe,     School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia

Elysia Poggi Davis

Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA

Department of Psychology, University of Denver, Denver, CO, USA

Rodney R. Dietert,     Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

M Jean Brancheau Egan,     Michigan Department of Community Health, WIC Division, Lansing, MI, USA

Kobra Eghtedary,     Michigan Department of Community Health, WIC Division, Lansing, MI, USA

Tom P. Fleming,     Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK

Sara Fneich,     INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France

Anne Gabory,     INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France

Jeffrey S. Gilbert,     Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA

Vivette Glover,     Institute of Reproductive and Development Biology, Imperial College London, London, UK

Peter D. Gluckman,     Liggins Institute, The University of Auckland, Auckland, New Zealand

Laura M. Glynn

Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA

Department of Psychology, Chapman University, Orange, CA, USA

Amrie C. Grammer,     University of Virginia Research Park, VA, USA

Carlos Guerrero-Bosagna,     Avian Behavioral Genomics and Physiology Group, IFM Biology, Linköping University, Linköping, Sweden

Mark A. Hanson,     Institute of Developmental Sciences, University of Southampton and NIHR Nutrition Biomedical Research Centre, University Hospital Southampton, Southampton, UK

Shuk-Mei Ho

Department of Environmental Health,University of Cincinnati College of Medicine,Cincinnati,OH,USA

Center for Environmental Genetics,University of Cincinnati Medical Center,Cincinnati,OH, USA

Cincinnati Cancer Center,Cincinnati,OH,USA

Cincinnati Veteran Affairs Medical Center, Cincinnati,OH,USA

Vinothini Janakiram

Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA

Timothy G. Jenkins,     Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA

Claudine Junien,     INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France

J.P. Lallès

Institut National de la Recherche Agronomique, UR1341 ADNC, Saint Gilles, France

Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France

Yuet-Kin Leung

Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA

Cincinnati Cancer Center, Cincinnati, OH, USA

Rohan M. Lewis,     Institute of Developmental Sciences, University of Southampton, Southampton, UK

Michele Loi,     Centro de Estudos Humanísticos, Universidade do Minho, Campus de Gualtar, Braga, Portugal

C. Michel

Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France

Institut National de la Recherche Agronomique/Université de Nantes, UMR1280, Nantes, France

Institut des Maladies de l’Appareil Digestif, Nantes, France

Karen M. Moritz,     School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia

Kristin E. Murphy,     Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA

Susan Nitzke,     Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA

Marianna Nobile,     Universita’ degli Studi di Milano-Bicocca, Dipartimento dei Sistemi Giuridici, Milano, Italy

Kieran J. O’Donnell,     The Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental University Institute, McGill University, Montreal, QC, Canada

Polina Panchenko,     INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France

Sara E. Pinney,     Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Ken Resnicow,     University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA

Lynette K. Rogers,     Center for Perinatal Research,The Research Institute at Nationwide Children’s Hospital,Columbus,Ohio

Cheryl S. Rosenfeld,     Department of Bond Life Sciences Center, Department of Biomedical Sciences, Genetics Area Program, Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, MO, USA

Lewis P. Rubin,     Department of Pediatrics, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School of Medicine, El Paso, TX, USA

Curt A. Sandman,     Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA

J.P. Segain

Centre de Recherche en Nutrition Humaine-Ouest, Nantes, France

Institut National de la Recherche Agronomique/Université de Nantes, UMR1280, Nantes, France

Institut des Maladies de l’Appareil Digestif, Nantes, France

Congshan Sun,     Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK

Martha Susiarjo,     Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Pheruza Tarapore

Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA

Cincinnati Cancer Center, Cincinnati, OH, USA

V. Theodorou,     Institut National de la Recherche Agronomique, UMR Toxalim, Toulouse, France

Sarah To,     Department of Environmental Health,University of Cincinnati College of Medicine,Cincinnati,OH,USA

Steve Turner,     Child Health, Royal Aberdeen Children’s Hospital, Aberdeen, UK

Mehmet Uzumcu,     Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

Miguel A. Velazquez,     Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK

Markus Velten,     Department of Anesthesiology and Intensive Care Medicine,Rheinische Friedrich-Wilhelms-University Bonn,Germany

Sarah Voisin,     INRA, UMR1198 Biologie du Développement et Reproduction, Jouy-en-Josas, France

Sarah L. Walton,     School of Biomedical Science, The University of Queensland, St Lucia, QLD, Australia

Aparna Mahakali Zama,     Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA

Acknowledgments

This book would not have been possible without all of the coauthors who kindly shared their knowledge and passion for the various areas. Ms Lisa Eppich and Ms Catherine A. Van Der Laan at Elsevier were integral in making this book come to life.

The concept of developmental origins of health and disease (DOHaD) was first clearly articulated by the late Sir David Barker. It was thus appropriate that it was originally termed the Barker hypothesis but subsequently changed to fetal origin of adult disease (FOAD), and most recently to developmental origins of adult health and disease. Since its conception, the DOHaD concept has gained currency and led to paradigm shifts in how scientists and clinicians view a variety of noncommunicable diseases. Correspondingly, it has paved the way for new avenues of diagnosis, prevention, and treatment strategies.

I am grateful to the many teachers, mentors, colleagues, and friends who along the way fostered my interests and curiosity in science and medicine. In particular, I am grateful to the late Mrs Patricia Murphy whose enthusiasm and wonderment for biology were contagious. My PhD mentor, Dr Dennis Lubahn, was incredibly supportive of me and my research ideas. The lessons I learned in his laboratory have stayed with me all of these years. Most of all, I am thankful to Dr R. Michael Roberts. For over 20  years, he has been a wonderful mentor, colleague, and friend.

I am thankful to Dr Deborah Wagner, my friend and former classmate, for allowing me over various holidays to serve as a relief veterinarian at her animal hospital. As veterinary students, we made a Forrest Gump pact that if she were to ever open her animal hospital, I would be her first mate. It has been rewarding to be able to indulge my veterinary interests and keep in touch with advances in clinical medicine. These experiences have helped shape my thinking and research directions.

Finally, I am grateful to my mother, sister, brother, nieces and nephews, and other family members who walk on two and four legs.

Cheryl S. Rosenfeld

Chapter 1

The Developmental Origins of Health and Disease (DOHaD) Concept

Past, Present, and Future

Peter D. Gluckman¹, Tatjana Buklijas¹,  and Mark A. Hanson²     ¹Liggins Institute, The University of Auckland, Auckland, New Zealand     ²Institute of Developmental Sciences, University of Southampton and NIHR Nutrition Biomedical Research Centre, University Hospital Southampton, Southampton, UK

Abstract

The developmental origins of health and disease (DOHaD) is a concept that has emerged over the past 50  years, linking the state of health and risk from disease in later childhood and adult life with the environmental conditions of the early life. Originally based on epidemiologic observations, the concept has given rise to a field that brings together clinical studies in a range of specialties, public and global health, experimental physiology, molecular biology (especially epigenetics), developmental biology, anthropology, the social sciences, and evolutionary biology. This chapter examines the evolution of thinking about the relationship between developmental influences and later-life health and disease; examines the establishment of DOHaD as a conceptual framework and a research field in its own right; discusses criticisms of DOHaD and barriers to its acceptance within the broader research community as well as to its recent integration into public health policy; and, finally, considers future directions that the field may take.

Keywords

Development; Developmental origins of health and disease; Disease; Epigenetics; Fetal physiology; History; Life course

Outline

Introduction 1

The Origins of the Field 2

Conceptual Developments and Experimental Observations 5

DOHaD and Epigenetics 8

The Wider DOHaD Research Agenda 9

DOHaD and Public Policy 10

References 11

Introduction

The overarching argument of the conceptual paradigm and the research field of developmental origins of health and disease (DOHaD) is that the state of health and risk from disease in later childhood and adult life is significantly affected by environmental factors acting during the preconceptional, prenatal, and/or early postnatal periods. The emphasis has been on obesity, type 2 diabetes mellitus, and cardiovascular disease, but a significant body of work has also been focused on endocrine cancers, osteoporosis and frailty in the elderly, mental health, cognitive function, respiratory disease, immune function, and allergy. While the field as currently constructed is just over two decades old, it is based on research that goes back to the 1930s. In this chapter, we bring together research traditions, concepts, and approaches that, over the last 80  years, have explored the question of prenatal and early postnatal environmental influences that impact health and disease in later life and look forward to emergent areas of attention and application of the concept.

The Origins of the Field

The idea that experiences in early life influence health in later life may be found throughout the history of Western medicine: well into the 1800s, it was believed that anything that a mother saw, touched, ate, or even imagined—collectively known as maternal impressions—had a capacity to permanently influence the developing organism [1,2]. In the early 1800s, the common view was that a new organism was created in a process called generation, out of maternal and paternal contributions as well as various experiences that the mother had during (and even before) pregnancy [3]. But in the nineteenth century, generation was replaced with reproduction, built on the new idea of heredity. The noun heredity was first used in the 1830s, to describe the transmission of parental qualities during conception, and at the same time to make a distinction between those inherited qualities and the properties that emerged during development [4]. Scientists studied where heredity resided within the cell; how hereditary particles were distributed among cells and their quantity was prevented from doubling in each successive generation; and to what extent were hereditary elements in the cells sensitive to developmental influences [5]. August Weismann’s work provided the conceptual basis for new thinking about heredity and development: while germ cells produced somatic cells, he argued, they were not affected by anything that somatic cells acquired or learned [6]. It followed that each individual was born with a certain predisposition toward disease; no environmental modifications could improve one’s outlook. The best one could do to improve one’s offspring’s chances was to reproduce with a person of better heredity.

The early 1900s were the heyday of hard heredity, exemplified by the emergence of genetics, an experimental discipline concerned with mechanisms of heredity, and the dominance of the social program of eugenics, seeking to reform society through rationalizing human reproduction [7]. But the deep economic crisis of the 1930s made it obvious that environmental conditions had a strong influence on the emergence and prevalence of disease [8]. New epidemiological work suggested that the conditions of early life played a role at least as important as heredity. A landmark paper by the Scottish epidemiologist William Ogilvy Kermack and colleagues in 1934 argued that the data behaved as if the expectation of life was determined by the conditions existing during the years 0–15 (…) the health of the man is determined preponderantly by the physical constitution which the child has built up [9]. The recognition of the importance of environmental conditions and the apparent demise of eugenics did not, however, mean the fall of the genetic model, which remained dominant through the twentieth century [8].

The Second World War was a pivotal event in the making of the developmental approach to the study of health and disease, conceptualized in the early twenty-first century as DOHaD. Even before the war, physiologists, teratologists, and agricultural scientists collected experimental evidence showing that manipulating the life conditions of pregnant animals permanently affected the patterns of growth and the phenotype of their offspring [10–12]. Interventions in humans were, for obvious reasons, too subtle to produce substantial differences, and they also focused on maternal mortality and morbidity rather than longer-term outcomes in the offspring [13]. But wartime famines provided rare natural experiments by exposing thousands of women to periods of severe undernutrition, in some cases sharply delineated [14,15]. The longest and the most severe famine took place in Leningrad under German siege (between September 1941 and January 1944) [14], but the clearest data came from Rotterdam and The Hague, two cities in northwestern Holland that had suffered food shortages during German reprisals from September 1944 to May 1945, in what became known as the Dutch Winter Famine [15,16]. Data collected showed that starvation in the last trimester of pregnancy caused a reduction in the birth weight of the offspring, while famine around conception increased the chance of miscarriage and malformation. Postwar Germany provided an opportunity for the British team working on the intersection of physiology, nutritional science, and pediatrics (Robert McCance, Elsie Widdowson, and Rex Dean) to study how low food rations and lack of food variety influenced lactation in new mothers, infant birth weight, and childhood growth [17]. Back in their Cambridge laboratories, Widdowson and McCance tested their clinical findings in animal experiments and demonstrated that the size of the litter and the rate of offspring growth depended on maternal nutrition. Interestingly, prenatal and early postnatal (preweaning) nutrition did not affect just the weight that the pups attained by adulthood: it also influenced susceptibility to infections, body proportions, and timing of reproductive maturation, as well as behavior [18]. Their results supported the theory of critical or sensitive periods, popular across disciplines as diverse as ethology (behavioral studies), linguistics, child psychology, and physiology, according to which each organ or tissue has a distinctive period of critical differentiation as well as a period of maximum growth, during which these organs and tissues are highly sensitive to injury [11].

But, as the world recovered from the wartime trauma, in the 1960s and 1970s interest in the relationship between prenatal and perinatal influences and later health and disease waned. In this period, fetal physiologists largely focused on questions that emphasized fetal autonomy rather than interplay between the environment and the developing organism. They studied, for example, fetal respiratory movements, fetal endocrine growth mechanisms, or fetal control of the onset of labor [19]. It was mostly researchers with a strong interest in socioeconomic determinants of health inequalities who pursued questions of the interaction between environment and development. At the University of Birmingham’s Department of Social Medicine, under Professor Thomas McKeown, a young David Barker completed his PhD thesis on Prenatal influences and subnormal intelligence (1966) [20]. He found that children of all levels of subnormal intelligence (classified as IQ under 75) had a birth weight lower than expected. Interestingly, the normal siblings of all but the most severely subnormal children (IQ less than 50) were born at low birth weight too. These low birth weights of both normal and subnormal children, Barker suggested, reflected influences which affect the intra-uterine lives of all children in their families.

At the same time, a pair of South African political immigrants to the United States (via the University of Manchester’s Department of Social Medicine), the Columbia University epidemiologists Zena Stein and Mervyn Susser, undertook a large program of study of the influence of maternal nutrition on mental competence [21,22]. One part of their research was an intervention study of providing food supplements to pregnant women drawn from a population with a high frequency of low birth weight; the other, an observational study based on the Dutch Winter Famine cohort. While both of these studies produced negative results, they rekindled interest in the Dutch Winter Famine cohort, which from then onwards would play a key role in the study of developmental, as well as transgenerational, influences upon adult health.

The first study (by Stein, Susser, and the Amsterdam researcher Anita Ravelli) to associate undernutrition during gestation in the Dutch Winter Famine cohort with manifestations of metabolic disease was published in 1976, showing that young men exposed in early pregnancy had significantly higher rates of obesity, while men exposed in late pregnancy (and first months of infancy) had lower obesity rates [23]. Women who suffered famine during first and second trimester in utero had offspring whose birth weight was lower than the birth weight of offspring born to women who had not been exposed to famine as fetuses; but the offspring of women exposed during the third trimester showed no reduction in birth weight [24]. Overall, from the mid-1970s onwards multiple historical and prospective epidemiological studies studied the relationship between maternal morbidity, infant mortality and birth weight, and morbidity and mortality from cardiovascular disease [25–28]. In North America, Millicent Higgins was the first to employ a long-term formal birth cohort to examine later-life outcomes, reporting in 1980 that the male offspring of women with toxemia developed significantly higher blood pressures by 20  years of age. By the mid-1980s, reports linking low birth weight and later hypertension started to merge [27,28].

Innovative conceptual developments took place in Eastern Germany, where the Berlin endocrinologist Günther Dörner studied differences in phenotypes between men born before, during, and after the Second World War and showed association between nutrition and later prevalence of metabolic and cardiovascular disease [29–31]. He became particularly interested in the effects of maternal stress and gestational diabetes on the offspring [32,33]. Dörner argued that the concentrations of hormones, neurotransmitters, and metabolites during the early development preprogrammed feedback loops control reproduction and development [34,35]. Inappropriately set feedback loops could then trigger disease. Dörner’s "functional teratology," as he termed it, may be compared to the proposal by another endocrinologist in this period, Norbert Freinkel, who spoke of metabolic teratogenesis when describing the effect of gestational diabetes on the next generation [36]. Around the same time, Frans Van Assche and colleagues used experimental models of gestational diabetes (in which part of the pancreatic β cells were chemically destroyed) to show that prenatal diabetogenic conditions permanently affected the adult offspring’s ability to handle situations stressing their glucose metabolism, such as pregnancy, and also had similar transgenerational effects [37].

It was, however, the work of David Barker in the 1980s, by then at the University of Southampton’s MRC Environmental Epidemiology Unit, that prompted this diverse collection of observations to coalesce into a field. In 1985, Barker’s unit produced a compendium of maps that used color gradation to show differences in mortality from selected diseases across the counties of England and Wales [38]. The mortality from cardiovascular disease appeared highest in poor and lowest in rich areas, a finding that opposed the view established by the Framingham Heart Study, according to which affluence caused the modern epidemic of heart diseases [39]. Barker, who since his Birmingham days with McKeown had been interested in prenatal influences especially nutrition, observed a strong geographical relationship between the areas of high infant mortality in the early twentieth century and the areas of high cardiovascular mortality between 1968 and 1978 [40]. Barker’s best-known study used the largest and most detailed set of records on infant welfare that could be found in the United Kingdom, those from the county of Hertfordshire from 1911 onwards. These records contained information about birth weight and early growth and development, and became the basis of a large study cohort. The follow-up of the Hertfordshire infants showed that death rates for cardiovascular disease fell progressively from those weighing 2.5  kg or less at birth to those weighing 4.3  kg, with a slight increase in the heaviest group (above 4.3  kg) [41]. Blood pressure and cholesterol levels showed equivalent trends.

Barker’s work attracted wide interest. The Southampton team began collaboration with the Amsterdam group studying the Dutch Winter Famine cohort. Other studies, both retrospective and prospective, followed worldwide. Early on, Barker’s work came to the attention of the doyen of fetal physiology Geoffrey Dawes, who was near retirement [42]. In Dawes’s view, Barker’s findings opened up new research opportunities. Dawes introduced Barker to his colleagues working in fetal physiology at a workshop meeting near La Spezia, Italy, in 1989. The proceedings, published under the title Fetal Autonomy and Adaptation, make interesting reading: the physiologists were clearly skeptical about Barker’s observations, but resolved to test them experimentally. The first workshop on fetal origins of adult disease took place in Sydney in 1994, and it brought a broader group of perinatal scientists in contact with Barker’s group [43]. This meeting launched a fast-growing series of annual workshops. Under David Barker’s leadership, foremost investigators of that period created the Council for the Fetal Origins of Adult Disease (FOAD) with John Challis as its first chair. The first global congress on FOAD was held in Mumbai, India, in 2001. At the second congress, in Brighton, UK, in 2003, it was decided the council would be reformed into an academic society, Developmental Origins of Health and Disease (DOHaD), with Peter Gluckman as the founding president and Mark Hanson as secretary.

Conceptual Developments and Experimental Observations

A major conceptual development in the DOHaD field took place in 1992 when David Barker and Nicholas Hales proposed their thrifty phenotype hypothesis [44]. Thrifty phenotype was a developmental alternative to the thrifty genotype explanation of the modern epidemic of noncommunicable diseases (NCDs), proposed in the 1960s by a medical geneticist James Neel [45,46] interested in the evolution of contemporary human populations. Neel argued that in the past thrifty genes had been selected because they provided advantage in the time of famine; but in the affluent contemporary world they only increased disease risk. The thrifty phenotype, by contrast, placed an emphasis on development, arguing that nutritionally inadequate conditions in pregnancy not only affected fetal growth but also induced permanent changes in insulin secretory capacity and in glucose metabolism. While well adapted for famine, in a nutritionally rich postnatal environment the individual would have a higher risk of metabolic disease.

The initial focus of the field—in David Barker’s work and in studies of the Dutch Winter Famine cohort, as well as, earlier, in postwar undernutrition studies—was on the consequences of low birth weight. For this reason, experimental studies induced intrauterine growth restriction (IUGR) in animal models, while clinical studies compared the outcomes of normal-weight and IUGR offspring [47–50]. The centrality of low birth weight to Barker’s hypothesis, however, became a problem. First, the supposed link between low birth weight and adult NCD contradicted the observed ecological trends: post–Second World War, the incidence of NCDs increased precisely in those countries that also had high average birth weights, such as Norway, Finland, and Scotland [51]. Second, disciplinary divisions hindered recognition of this problem. Most early epidemiological work studied processes associated with suboptimal nutritional conditions or excessive maternal stress and later disease risk; at the same time, the class of phenomena highly relevant for the modern, developed world, associated with gestational diabetes, maternal obesity, and infant overfeeding, was being studied by endocrinologists and obstetricians. The relative importance of these pathways clearly differed in different populations and at different stages of the nutritional transition. Yet the two disciplinary groups, epidemiologists and clinicians, presented their results at different venues and rarely talked to each other. Third, many epidemiological studies produced data inconsistent with or even contrary to Barker’s hypothesis [52]. Some even argued that the observed differences did not exist, i.e., that they were results of errors, confounding, and inappropriate study design [53]. Even the studies of historical famines did not at all support the thrifty phenotype: for instance, studies on survivors of the Leningrad siege found no difference in glucose tolerance, lipid concentrations, hypertension, or cardiovascular disease rates between those groups exposed and those who were not exposed to famine during development [54]. A Finnish historical study found no effect of famine exposure upon survival in adulthood [55]. Even studies based on the Dutch Winter Famine cohorts produced results that contradicted previous findings and the main hypothesis: for example, that glucose tolerance was lower in participants exposed in mid- to late gestation rather than early to mid-gestation [56,57]. Critics maintained that Barker’s hypothesis was neither precisely formulated nor consistent, with regard to the timing of critical events at the stage of gestation when undernutrition might have been expected to produce the specific impact [58]. They emphasized the need to move from epidemiological to mechanistic studies, because retrospective studies rarely provided sufficiently detailed data, prospective studies took too long, and neither could explain how, for example, a modification in nutrition in mid-gestation may lead to a change in blood pressure decades later [57].

Rather than undermining the field, these challenges to the DOHaD concept encouraged further research and inspired conceptual thinking. Researchers recognized that there was indeed an excessive emphasis on birth weight, while in reality early life events informed later disease outcomes in multiple ways, depending on the type and timing of the insult [59]. Birth weight was only one of many possible proxies for variable intrauterine effects [60]. Programming (a term introduced by Alan Lucas [61], a decade and a half after Dörner’s preprogramming [34,35], which, while popular, is problematic for its inference of a predetermined developmental course rather than a plastic one) [62] could, and did, operate in the absence of effects on birth weight. For example, one study showed that variation in maternal nutrition influenced childhood carotid intima media thickness independently of birth weight [63]. Insulin resistance, predicted by the thrifty phenotype hypothesis to be a major adaptation to adverse prenatal nutritional conditions, only appeared some years after birth. In fact, growth-retarded babies tended to have greater insulin sensitivity [64]. A more sophisticated understanding of the developmental events was therefore required.

In the early 2000s, the Cambridge ethologist Patrick Bateson, first alone [65] and then together with the authors and others [66], proposed a comprehensive hypothesis that placed the DOHaD phenomenon firmly within the evolutionary framework of developmental plasticity and allowed for multiple pathways of induction. We argued that, within the normal range, environmental cues received during development influenced the developmental path taken by the organism. The path was adaptive if the later postnatal environment matched the prenatal one, but if the environment changed or the prediction proved to be wrong, it would turn out to be pathological. The model was gradually refined to take into account the observations that the environments that mattered were those of later childhood, after weaning and up to the age of peak reproductive fitness at the end of the second decade of life [62,67]. This concept, termed the predictive adaptive response, could account for findings previously deemed paradoxical or inexplicable [68,69]. For instance, infants born during the Leningrad famine grew up in a nutritional environment much poorer than the Dutch Winter Famine babies; because their nutritional forecast was correct, the lack of increase in the incidence of cardiovascular or metabolic disease was not surprising. In Jamaica, children born small were more likely to respond to malnutrition with marasmus/wasting, while those born larger responded with kwashiorkor (syndrome characterized by altered protein, amino acid, and lipid metabolism in addition to wasting). Kwashiorkor is a more severe condition, associated with higher mortality than marasmus, so it may be argued that larger babies forecast a more plentiful nutritional environment during their development and were maladapted to low nutritional planes [70]. Although this heuristic model has received criticisms, these have largely been addressed [67].

We now argue that there are two categories of pathways by which developmental factors induce later disease risk [62,71]. The induction by normative exposures involving maternal stress or reduced fetal nutrition could be interpreted using the predictive adaptive model and is thus best framed in terms of an evolved adaptive response, ultimately disadvantageous in the mismatched modern obesogenic environment. However, maternal obesity, gestational diabetes, and infant overfeeding could be interpreted as evolutionary novel exposures, likely inducing long-term effects through alternative mechanisms including the adipogenic effect of fetal hyperinsulinemia [72].

Theoretical work has both fed off and inspired further expansion and refinement of molecular human and experimental animal research. Experimental studies demonstrated how intrauterine challenges could lead to metabolic disease in adult animals [73,74]. The early models used a variety of maternal nutritional challenges in rodents [75,76]. In general, these models showed that maternal undernutrition led to offspring obesity, hypertension, and insulin resistance. A feature of these studies is that they induced an integrated, relatively stereotypic phenotype in the offspring, with common features including hyperphagia, altered energy expenditure [77], fat preference in the diet [78,79], and altered timing of puberty [80], as well as the endothelial dysfunction, hypertension, insulin resistance, and obesity [73]. Importantly, Vickers, then others, showed that long-term effects of maternal undernutrition could be reversed by neonatal leptin treatment [81]. This finding was interpreted as experimental support of the predictive adaptive response model, a conclusion reinforced when other approaches to reversal were also demonstrated to be effective [82]. As it became clear clinically that there were at least two major pathways to long-term developmental effects, researchers started to study offspring of experimental animals exposed to high fat [83,84] or high fructose concentrations [85,86]. These experiments confirmed that the offspring of mothers under such exposures developed obesity and insulin resistance as adults. A limited amount of work was also done in large-animal models [87,88].

At the same time, a considerable number of experimental studies examined the impact of maternal stress and care on the offspring phenotype. Pregnant animals were exposed to dexamethasone, to mimic maternal stress; their offspring exhibited phenotypic outcomes similar to those seen with maternal nutritional manipulation [89]. Jonathan Seckl, Michael Meaney, Frances Champagne, and colleagues examined the impact of maternal care upon their offspring’s neuroendocrine and behavioral development using the highly influential model of rat dams that exhibited either high licking/grooming (LG) or low LG behavior [90,91]. Importantly, they showed that the maternal behavior changed the expression of a glucocorticoid receptor gene (through epigenetic modification), and thus the offspring’s response to stress, and that the difference persisted into adulthood, yet could be eliminated by cross-fostering, to high from a low-LG or to low from a high-LG mother [91]. The phenotype produced by different levels of stress exposure could also be reversed by manipulation of the epigenetic change (in the glucocorticoid receptor gene) using a histone deacetylase inhibitor. Together, these studies pointed to the long-term effects of maternal nutritional and hormonal signals upon the offspring phenotype.

DOHaD and Epigenetics

The success of DOHaD over the past decade was in no small part related to the application of epigenetics to explain the relationship between developmental exposure and later risk from disease in molecular terms. Epigenetics is today usually defined as the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA section [92]. Although the name epigenetics goes back to the mid–twentieth century and the work of Conrad Waddington (who used it to describe the study of causal mechanisms by which the genes bring about phenotypic effects), the discipline started growing from the mid-1990s onwards [93]. Today the discipline is well established though somewhat controversial: while mitotic heritability of epigenetic marks is widely accepted, the existence and role of transgenerational epigenetic inheritance, well documented in some species and especially in plants [94], remains contentious, with some experts doubting its significance.

Paradoxically, it was the publication of the human genome and the rise of genomics in the 1990s and 2000s that gave epigenetics a boost. Throughout the century of the gene [95], it was believed that once the DNA sequence was revealed, the variation in disease risk at the population level would be explained. But a decade later and following many genome-wide association studies as well other genomic and genetic studies, it is clear that, while some single nucleotide polymorphisms are indeed associated with the risk of NCDs, those linked to large effects in individuals are rare in the population [96,97]. The quest for common variants that contribute smaller effects continues, but the interest in other explanations of disease causation—in particular, developmental ones—has increased.

Epigenetics provided DOHaD with tools to show precisely how the developmental environment modulates gene transcription, producing a long-term effect on gene expression and on phenotypic outcome. For epigenetics, DOHaD offered a repository of clinically important research problems. While DOHaD studies in the 1990s largely focused on explaining the effects of modifications in developmental environment in functional terms (e.g., reduced renal nephron number [98], altered hormonal sensitivity [99], altered endothelial function [100], or altered hepatic metabolic activity [101]), by the mid-2000s, and particularly after the seminal work on the LG/HG mice [91], attention shifted to molecular epigenetics.

While there is a large range of epigenetic modifications, DNA methylation and histone modification are the best studied. The exposures that received the most research attention have been maternal stress and maternal nutrition. Studies in rats have shown, for example, that a change in the maternal diet altered DNA methylation and histone modification in the 5′ regulatory regions of specific nonimprinted genes [102–105]. Induced changes could be prevented by nutritional interventions in pregnancy [102] or changed by hormonal modifications in the juvenile period [106].

In contrast to good experimental evidence from animal models, data supporting this argument for humans have been scarcer. Perhaps the most definitive and influential study was that of Godfrey and colleagues [107] on two independent cohorts of children aged 6 or 9  years. Using DNA obtained from the umbilical cord at birth and taking a relatively unbiased discovery approach, the authors found a strong association, consistent across cohorts, between the methylation of a particular site in the RXRα promoter region and the degree of adiposity 6–9  years later. They also demonstrated that this epigenetic change was associated with maternal carbohydrate intake in early pregnancy: mothers with lower carbohydrate intake had higher methylation in the RXRα promoter region. Later, the group showed in vitro that epigenetic changes induced nutritionally at this region of the promoter did not affect adipocyte differentiation, but they did alter insulin sensitivity and glucose metabolism in these same adipocytes when they were fully differentiated [108]. Since then, others, e.g., Harvey et al. [109], have linked other epigenetic changes at birth to other later phenotypic effects. The discussed two studies have suggested that, independent of birth weight, a sizable portion of phenotypic variance in body composition in late childhood is determined by normative in utero exposures, especially those operating in early pregnancy. Such observations, together with epidemiological analysis of periconceptional nutrition [110] and experimental observations [87,111] of periconceptional undernutrition, are shifting attention to the periconceptional and preconceptional period.

The Wider DOHaD Research Agenda

When thinking about the present and future DOHaD research, three major research avenues come to mind: (1) broadening and refining the epigenetic approach: studying a range of epigenetic marks; studying epigenetic inheritance through the male line as well as inheritance across multiple generations; (2) considering preventative interventions, targeted at epigenetic modifications; (3) expanding the range of studied exposures from nutrition and stress to include a variety of environmental variables. These avenues are based on recent research. For example, nongenetic inheritance through the male line has become an intense area of study. A limited number of experimental [112,113] and epidemiological [114] studies suggest that paternal factors may influence offspring health too [115]. Such studies are in their infancy, but there is growing evidence showing that epigenetic marks are transmitted across generations via the sperm. Intergenerational maternal effects have been more clearly documented and there are multiple mechanisms by which such transduction might occur [116]. Epigenetic marks can be induced de novo (under persisting environmental influences) in each generation [117] or can be transmitted directly to the offspring [118].

The experimental data and, particularly, recent human data linking maternal state to the offspring’s epigenetic state [119] have allowed investigators to consider preventative interventions before and during pregnancy. An increasing number of clinical studies have commenced in which maternal nutrition is manipulated to explore the impact of nutritional variations on the offspring. Animal studies continue to explore potentially applicable techniques to reverse conditioning in human infants. The applicability of such interventions will rely heavily on validation of epigenetic biomarkers to monitor effects, given the time it will take for the phenotype to emerge.

Such studies are all highly experimental and preliminary, but they point to the direction in which DOHaD research will progress. There will be ongoing expansion of epigenetic methodologies to inform both experimental studies and clinical human studies. The skill set of investigators engaged in DOHaD research is thus likely to shift significantly in the next decade.

Regarding the range of the studied exposures, DOHaD had its early origins in the study of teratogenesis; more recently, environmental toxicologists have embraced the DOHaD paradigm [120]. They, too, have seen that subtle levels of toxins such as air pollutants, or endocrine disruptors such as bisphenol A, can affect fetal epigenetic states and, at least experimentally, induce longer-term phenotypic change not dissimilar to that found in the more traditional DOHaD domain [121]. The interaction between epigenetic processes and the environment is of much current interest [122].

Globally, concern has been increasing over the effects of air pollution, as well as many industrial and agricultural chemicals, on the fetus. While their effects on the fetal epigenetic state are undisputed, the clinical significance of such observations is less clear. This lack of clarity stresses the importance of new prospective clinical cohorts, preferably starting before conception, providing biological samples to measure the exposome of mother and infant, measuring the epigenetic state of the infant as well as its emergent phenotype over time. Such studies are complex and expensive but important [123,124].

DOHaD and Public Policy

From its origins, DOHaD was focused on the causes of NCDs, especially cardiovascular and metabolic disease. Today NCDs—especially diabetes, cardiovascular disease, chronic lung disease, and common forms of cancer—account for around 60% of all deaths worldwide [125]. A high proportion of these diseases occurs in Asia, especially China and India, but a rise in the near future in parts of the world poorly equipped to deal with them—e.g., sub-Saharan Africa—has been predicted [126]. While the rise in prevalence has to do with the Western lifestyle, urbanization, and greater economic prosperity, the newly emerging epidemic is caused not by these factors as such, but by the magnitude of the recent change in behavior and environment. Scholars in DOHaD from Barker [127] onward [128] have long argued that a life course approach is important in understanding both the origins and prevention of the obesity and NCD epidemics.

However, despite the wealth of experimental, epidemiological, and clinical data supporting the DOHaD concept, the latter has gained essentially no traction within the public health community. The reasons for this failure have been discussed above and in other articles [62], and they include the overemphasis on low birth weight, lack of a conceptual framework, and a lack of underlying mechanisms. But the evidence of multiple pathways, operating independently of birth weight; the construction of a conceptual framework; and the elaboration of the epigenetic mechanisms have all addressed these concerns. Perhaps the most difficult problem was obtaining an estimate of the weight of the developmental effect. But the calculations of Barker and colleagues suggest that, using the proxy of low birth weight as a marker of a poor developmental environment, the risk of cardiovascular disease is increased by a factor of about sevenfold in adults with birth weight at the low end of the range. However, studies such as Godfrey’s showed that this pathway was not pathological and exceptional but rather normative and ubiquitous, operating in uncomplicated pregnancies across the normal developmental range. The rising rates of maternal obesity and gestational diabetes point to the prevalence of nonadaptive responses, no longer restricted to the developed world, but of high importance in the developing world, where the double burden of unbalanced nutrition is a growing concern. The normative nature of the exposures pointed to the overlap with the reproductive–maternal–neonatal child health agenda, which the World Health Organisation (WHO) and other organizations recognize as linked to the millennium development goals [129].

In 2011, a landmark event occurred when the United Nations General Assembly adopted the resolution titled Political declaration of the high-level meeting of the General Assembly on the prevention and control of non-communicable diseases (document A/66/L.1). For the first time, the influence of early life course events was recognized by the international community and a specific clause explained the DOHaD concept (see Box 1). This declaration led the WHO and its regional divisions to start considering life course biology and its import in greater depth. With an increased attention, nongovernmental organizations interested in NCDs have started taking notice. Private- as well as public-sector research is increasingly engaged.

In 2014, the Director General of the WHO announced the establishment of a Commission to End Childhood Obesity. The background paper made it clear that the life course approach, of which DOHaD forms a part, made an important basis of this initiative. The announcement recognized the longer-term benefits of the primary prevention of childhood obesity. The commission and its working groups include many members with a depth of experience in DOHaD-related research. The DOHaD research is at last poised to influence public health.

Box 1

Clause 26 of the Political Declaration of the High-Level Meeting of the General Assembly on the Prevention and Control of Noncommunicable Diseases (Document A/66/L.1). UN General Assembly, 66th Session, Follow-Up to the Outcome of the Millennium Summit, September 16, 2011 (http://www.un.org/ga/search/view_doc.asp?symbol=A/66/L.1)

(We) note also with concern that maternal and child health is inextricably linked with NCDs and their risk factors, specifically as prenatal malnutrition and low birth weight create a predisposition to obesity, high blood pressure, heart disease and diabetes later in life; and that pregnancy conditions, such as maternal obesity and gestational diabetes, are associated with similar risks in both the mother and her offspring.

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