The epigenome and developmental origins of health and disease

THE EPIGENOME AND
DEVELOPMENTAL
ORIGINS OF HEALTH
AND DISEASE
Edited by

Cheryl S. Rosenfeld

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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

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

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

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

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

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

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

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

xiii


xiv

LIST OF CONTRIBUTORS

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


LIST OF CONTRIBUTORS

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 FriedrichWilhelms-University Bonn, Germany

xv

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.

xvii

Cheryl S. Rosenfeld


C H A P T E R

1

The Developmental Origins of Health
and Disease (DOHaD) Concept: Past,
Present, and Future
Peter D. Gluckman1, Tatjana Buklijas1, 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

O U T L I N E
Introduction1

The Wider DOHaD Research Agenda

The Origins of the Field

DOHaD and Public Policy

2

Conceptual Developments and Experimental
Observations5
DOHaD and Epigenetics

10

References11

8

INTRODUCTION

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

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

The Epigenome and Developmental Origins of Health and Disease


9

1

Copyright © 2016 Elsevier Inc. All rights reserved.


2

1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT

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

The Origins of the Field

“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

3

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.


4

1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT

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


Conceptual Developments and Experimental Observations

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

5

“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


6

1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT

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


Conceptual Developments and Experimental Observations

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

7

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


8

1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT

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 mid1990s 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 mid2000s, 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


THE WIDER DOHaD RESEARCH AGENDA

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

9

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


10

1.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT

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


References

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

11

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 ( />.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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C H A P T E R

2

Historical Perspective of Developmental
Origins of Health and Disease in Humans
Lewis P. Rubin
Department of Pediatrics, Texas Tech University Health Sciences Center El Paso, Paul L. Foster School
of Medicine, El Paso, TX, USA

O U T L I N E
Introduction17

A Life Course Approach and the Developmental
Origins of Health and Disease
24

Socioeconomic Stressors and Infant and Child
Health19
Allostasis and Allostatic Load

20

Weathering and African American Health
Disparities21
Acculturation and the Hispanic Paradox

25

Health Vulnerabilities Can be Heritable

27

Conclusions28

22

References28

INTRODUCTION

wealth of prospective clinical data, experimental models, and an emerging appreciation of
the underlying molecular and developmental
mechanisms, most recently epigenetic regulation of gene expression. This paradigm is now
known as the developmental origins of health
and disease (DOHaD) [1]. A central tenet of this
framework is that early life psychosocial stress
has an indirect lasting impact on physiological
wear and tear via health behaviors, adiposity,
and socioeconomic factors in adulthood [2,3].

Adverse social and psychosocial circumstances, including exposure to social, economic,
and psychological stressors, have been associated with a variety of poor health outcomes
in different parts of the world and in a range
of ethnic and age groups. During the last two
decades, epidemiological evidence that early
life stressors increase susceptibility to disease later in life has become supported by a
The Epigenome and Developmental Origins of Health and Disease


Epigenetic Regulation and Effects
of Psychosocial Stress

17

Copyright © 2016 Elsevier Inc. All rights reserved.


18

2.  DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IN HUMANS

Psychosocial stress may also lead to preterm
birth by altering immune system function either
independently or in interaction with neuroendocrine dysfunction.
The association between birth weight and
development of traditionally adult-onset diseases, such as type 2 diabetes mellitus and cardiovascular diseases, was first demonstrated
25 years ago by Hales [4]. In the decades since,
the hypothesis that environmental factors act
on the genome to create differences in vulnerability or resilience has become a central concept
in health-related research, especially maternal
child health [5,6]. One underlying biological
mechanism for effects of fetal deprivation and
stress is environmentally inducible epigenetic
change.
Correspondingly, investigation of biological
mechanisms of health and disease has increasingly emphasized the environmental context
of the individual. A “critical period” refers to a
time window when developmental changes in
the organism (or subsystems) toward increasing
complexity, greater plasticity, and more efficient
functioning occur rapidly and may be most easily modified either in favorable or unfavorable
directions. Also known as “biological programming” or as a “latency model,” these critical,
environmentally sensitive periods underlie the

developmental origins of adult disease. The critical developmental period model also includes
the possibility that effects of an exposure in
development may be dramatically changed by
later physiological or psychological stressors.
This expansion of critical period (fetal) effects
with later-life effect modifiers provides a plausible framework to approach the interactions
between early and later-life risk factors [7].
A related concept, the “thrifty phenotype”
hypothesis [8], states that the thrifty aspects of
adaptation to a nutrient-limited environment
can induce later unhealthy permanent changes.
These include reduced capacity for insulin
secretion and insulin resistance that, combined
with obesity, aging, and physical inactivity, are

important factors in determining type 2 diabetes in a nutritionally rich environment. Indeed,
a key tenet of the developmental/fetal origins
paradigm is that fetal undernutrition in midto-late gestation impairs fetal growth and can
program later-life deleterious health outcomes
including disturbed somatic growth, metabolic
stress, aberrant glucose tolerance and type 2
diabetes mellitus, and cardiovascular disease.
In the 1960s, Widdowson and McCance [9] were
among the first to demonstrate that brief periods
of undernutrition during critical developmental
times are not necessarily followed by “catch-up
growth.” They showed that the earlier in life rats
were exposed to malnutrition, the more serious
and permanent were later effects [9].
Although different models invoked to

describe and explain biopsychosocial stress significantly overlap, some have been developed
to understand conditions or effects in specific
populations and communities. The underlying
biological mechanisms involve environmentally
induced epigenetic changes in gene expression,
which may be passed transgenerationally. This
chapter addresses some complexities inherent
in stress assessment and reviews the historical
evolution of molecular, especially epigenetic,
mechanisms that mediate effects of physical,
nutritional, psychological, and social stress.
Cotemporal with the recognition that epigenetics is the fundamental mechanism of an
organism’s adaptation, several biopsychosocial frameworks have advanced understanding
of developmental origins of health and disease. Allostasis, which incorporates hormonal
responses to predictable environmental changes,
provides an integrative framework. Geronimus’s
concept of “weathering” [10] aims to explain
how socially structured, repeated stress can
accumulate and increase disease vulnerability
in African Americans. Weathering emphasizes
the importance of internalized/interpersonal
racism as a driver of racial outcome disparities.
Similarly, for Mexican immigrants and Mexican Americans, an “acculturation” framework


Socioeconomic Stressors and Infant and Child Health

has proven to be especially useful for exploring
health disparities, including preterm birth and
neuropsychiatric risk in childhood [11].

Although traditional theory and methods
have focused separately on how social and
physical environmental factors affect children’s
health, evolving research has underscored the
importance of integrated approaches [12]. Fundamentally, socioeconomic and physical/chemical environmental dimensions interact, stress
being a permissive factor for susceptibility to
certain immunological and toxic insults. In addition, unhealthy residential environments and
psychosocial stress can covary [13], potentiating
adverse effects on health and development. As
an example, prenatal stress and environmental
metal exposures synergistically alter maternal
diurnal cortisol during pregnancy and stress
responses in the offspring [14], although these
interactions remain poorly understood. Environmental pollutants, such as pesticides and
endocrine disruptors, can produce birth defects,
impaired fecundity, infertility, and altered
somatic growth and neurodevelopment [15].
This chapter considers the development of
contemporary concepts of the biopsychosocial underpinnings of later health and disease.
It then reviews the development of the current
understanding of epigenetics as one of the fundamental biological mechanisms of plasticity
and adaptation.

SOCIOECONOMIC STRESSORS
AND INFANT AND CHILD HEALTH
The American psychologist James Garbarino coined the term socially toxic environments
to describe conditions of poverty and violence
[16]. This heuristic is particularly germane for
examining adverse effects on maternal and
child health. Despite improvements in maternal

health care, socioeconomic differences in birth
outcomes remain pervasive, show substantial
variation by racial or ethnic subgroup, and are

19

associated with disadvantage measured at multiple levels (individual/family, neighborhood)
and time points (childhood, adulthood), and
with adverse health behaviors that are themselves socially patterned [17]. The ongoing longitudinal Adverse Childhood Experiences Study
of adults has uncovered significant associations
among chronic conditions, quality of life and life
expectancy in adulthood, and trauma and stress
associated with adverse childhood experiences.
The latter include physical or emotional abuse
or neglect, deprivation, or exposure to violence
[18]. A growing body of evidence indicates
that there exists a stepwise gradient in health
according to socioeconomic status (SES); that
is, people in each class commonly have poorer
health outcomes than those just above them and
have better outcomes than those below [19,20].
The shape of this relationship between SES and
health actually may be curvilinear, decreasing
health outcomes becoming more common at
even higher SES levels [21]. Socioeconomic gradients, and their implications for relative social
status, therefore, inform explanations of how
economics interacts with psychosocial stress
and, thereby, epigenetic pathways.
Wilkinson and Picket have argued that relative deprivation is the core mechanism of how
income impacts health in societies, i.e., why

many problems associated with relative deprivation are more prevalent in more unequal
societies [22,23]. Specific associated deleterious health outcomes include preterm birth, low
birth weight (LBW), and child mortality. In economics, social science, and policy, a commonly
utilized measure of statistical dispersion representing the income distribution of a country’s
population is the Gini Index [24] developed by
the statistician and sociologist Corrado Gini in
1912. Modifications of the Gini Index recently
have begun to be utilized as an indicator of
income or wealth inequality in health research.
Theoretically, health effects of income inequality, measured by the Gini Index, could result
from inequalities in access to opportunities and