REPRODUCTION

REVIEW

Sex differences in developmental programming models

Catherine E Aiken1,2 and Susan E Ozanne2
1
Department of Obstetrics and Gynaecology, The Rosie Hospital and NIHR Cambridge Comprehensive Biomedical
Research Centre, University of Cambridge, PO Box 223, Cambridge CB2 0SW, UK and 2Metabolic Research
Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ,
UK
Correspondence should be addressed to C E Aiken at Department of Obstetrics and Gynaecology, The Rosie Hospital and NIHR
Cambridge Comprehensive Biomedical Research Centre, University of Cambridge; Email: cema2@cam.ac.uk

Abstract
The theory of developmental programming suggests that diseases such as the metabolic syndrome may be ‘programmed’ by exposure
to adverse stimuli during early development. The developmental programming literature encompasses the study of a wide range of
suboptimal intrauterine environments in a variety of species and correlates these with diverse phenotypic outcomes in the offspring.
At a molecular level, a large number of variables have been measured and suggested as the basis of the programmed phenotype. The range
of both dependent and independent variables studied often makes the developmental programming literature complex to interpret
and the drawing of definitive conclusions difficult. A common, though under-explored, theme of many developmental programming
models is a sex difference in offspring outcomes. This holds true across a range of interventions, including dietary, hypoxic, and surgical
models. The molecular and phenotypic outcomes of adverse in utero conditions are often more prominent in male than female offspring,
although there is little consideration given to the basis for this observation in most studies. We review the evidence that maternal energy
investment in male and female conceptuses may not be equal and may be environment dependent. It is suggested that male and female
development could be viewed as separate processes from the time of conception, with differences in both timing and outcomes.
Reproduction (2013) 145 R1–R13

Introduction outcomes, for example, male sensitivity to nephrogenic

The theory of the Developmental Origins of Health and
Disease (DoHaD) suggests that diseases such as the
metabolic syndrome may be ‘programmed’ during
development and early post-natal life. The theory
suggests that insults to the conceptus during develop-
ment, for example, suboptimal maternal nutrition, may
manifest as type 2 diabetes, heart disease or hyper-
tension in later life (Hales & Barker 1992, Stanner et al.
1997, Ravelli et al. 1998). Many developmental
programming studies have found that male and female
offspring exhibit different phenotypes following insults
in utero (Table 1). This observed difference in outcomes
between male and female offspring has led many
researchers to target their efforts exclusively on offspring
of one sex (Vieau et al. 2007). Despite wide recognition
of the importance of offspring sex in developmental
programming outcomes, the basis for the observed
sexual dimorphism in ‘programming’ of the metabolic
syndrome is not understood. It is unclear what aspects of
the differences between male and female development
give rise to the differential susceptibility to programming
insults. Table 1 demonstrates that although there are
patterns suggesting differential susceptibilities to certain
q 2013 Society for Reproduction and Fertility
ISSN 1470–1626 (paper) 1741–7899 (online)
insult (Woods et al. 2005, Loria et al. 2007) and female
sensitivity to placental disruption (Gallou-Kabani et al.
2010, Mao et al. 2010), these are not consistently
observed between different models and between
different species.
Sex differences in rodent models of developmental
programming
Sex differences in response to developmental program-
ming stimuli have been reported across a range of model
organisms. Direct comparisons between male and
female offspring have been made predominantly in rats
(Langley-Evans et al. 1996, Ozaki et al. 2001, Khan et al.
2003, Nivoit et al. 2009, Reverte et al. 2011), but
sex-specific differences are also reported in mice
(Gallou-Kabani et al. 2010, Vickers et al. 2011; see
Table 1). There is evidence that male rat offspring are
more susceptible to developmentally programmed
hypertension than female offspring in studies where the
sexes are directly compared (Langley-Evans et al. 1996,
Kwong et al. 2000, Dodic et al. 2002, Alexander 2003,
Woods et al. 2005, Maloney et al. 2011). This effect is
DOI: 10.1530/REP-11-0489
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R2 C E Aiken and S E Ozanne

Table 1 Selected studies demonstrating a sex difference in developmentally programmed outcome in various species.
Reference Main result Species
Animal models
Male-specific outcomes
Langley-Evans et al. (1996) Low-protein diet gives elevated blood pressure in male offspring relative to females Rat
Kwong et al. (2000) Low-protein diet increases blood pressure in male offspring Rat
Ozaki et al. (2001) Nutrient restriction (30% reduction) increases blood pressure and vascular dysfunction Rat
more in male offspring
Dodic et al. (2002) Dexamethasone exposure gives increased blood pressure more in male offspring Sheep
Franco Mdo et al. (2002) Nutrient restriction (50%) reduces eNOS expression in aorta of male offspring Rat
Alexander (2003) Reduced uterine perfusion causes sustained increase in blood pressure in male offspring Rat
Ortiz et al. (2003) Antenatal dexamethasone injection persistently elevates blood pressure in male offspring Rat
Hemmings et al. (2005) Hypoxia gives increased myogenic tone in male offspring Rat
McMullen & Langley-Evans Low-protein diet gives elevated blood pressure, which is glucocorticoid dependent only Rat
(2005) in male offspring
Woods et al. (2005) Low-protein diet gives elevated blood pressure and reduced nephron number in Rat
male offspring
Zambrano et al. (2005) Isocaloric low-protein diet during lactation affects insulin sensitivity more in second- Rat
generation male offspring
Gilbert et al. (2007) Nutrient restriction impairs nephrogenesis in male offspring Sheep
Loria et al. (2007) Early post-natal ANGII blockade increases proteinuria and impairs urine concentrating Rat
ability in male offspring
Mueller & Bale (2007) Chronic variable stress exposure in early gestation decreases learning ability in Mouse
male offspring
Sinclair et al. (2007) Periconceptual reduction in methionine and B vitamins gives impaired blood pressure Sheep
in male offspring
Nivoit et al. (2009) High-fat and sugar diet increases insulin resistance in male offspring Rat
Tang et al. (2009) Prenatal betamethasone exposure decreased glomerular filtration rate and sodium Sheep
excretion in male offspring
Micke et al. (2010) Low-protein diet in the first trimester gives heavier male offspring in young adult life Cow
Reverte et al. (2011) Early post-natal ANGII blockade followed by high-protein diet leads to renal insufficiency Rat
in male offspring
Maloney et al. (2011) Methyl-deficient maternal diet periconceptually impairs glucose homoeostasis in Rat
male offspring
Female-specific outcomes
Lee & Rivier (1996) Ethanol exposure leads to exaggerated HPA stress response in young female offspring Rat
Khan et al. (2003) High-fat diet increases blood pressure in female offspring Rat
Wilcoxon et al. (2003) Ethanol exposure leads to decreased placental 11b-hydroxysteroid dehydrogenase-2 Rat
levels and left ventricular hypertrophy in female offspring
Manikkam et al. (2004) Prenatal testosterone exposure provokes post-natal catch-up growth in female Sheep
offspring only
Porter et al. (2007) High-salt diet preconceptually increases stress response in female offspring Rat
Padmavathi et al. (2009) Maternal zinc deficiency impairs glucose-induced insulin secretion in male but not Rat
female offspring
Mao et al. (2010) High-fat and low-fat diet produce up-regulation of placental genes more marked in Mouse
female offspring
Gallou-Kabani et al. (2010) High-fat diet leads to DNA hypomethylation in female placenta only Mouse
Rodriguez et al. (2011) Betamethasone exposure reduces associative learning more in female offspring Baboon
Vickers et al. (2011) Fructose exposure gives decreased placental weight, increased plasma leptin and Rat
glucose in female offspring
Epidemiology
Male-specific outcomes
Zaren et al. (2000) Maternal smoking decreases birth weight and head circumference proportionally more Human
in male offspring
Goldenberg et al. (2006) Placentas from preterm deliveries showed more lymphohistiocytic infiltration in Human
male offspring
Haley et al. (2006) Prenatal exposure to alcohol increases the heart rate of female infant offspring more than Human
males, but with the males showing a greater increase in plasma cortisol
Mingrone et al. (2008) Male offspring of obese mothers have higher levels of insulin secretion in response to GTT Human
Female-specific outcomes
Roseboom et al. (2001) Higher rates of obesity in female offspring conceived during famine Human
Clifton (2005) Maternal asthma in pregnancy causes altered placental glucocorticoid metabolism Human
and growth in female offspring
Stark et al. (2009) Antenatal betamethasone administration increased placental 11b-hydroxysteroid Human
dehydrogenase-2 activity in female offspring and this was positively correlated with
mean arterial blood pressure
Studies were included only if the results of both sexes were reported in the original paper. Studies were included if the effect of a developmental
programming insult was of greater statistical significance in one sex or was seen only in one sex. For animal models, only papers that specified an
intended developmental programming intervention were included.

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seen in rats with a range of interventions including
antenatal dexamethasone administration (Alexander
2003, Ortiz et al. 2003), prenatal low-protein diet
(Langley-Evans et al. 1996, Kwong et al. 2000, Woods
et al. 2005) and uterine hypoperfusion (Alexander 2003).
The effect is not entirely consistent, however, as a
maternal high-fat diet has been reported to elevate blood
pressure in female offspring only (Khan et al. 2003). The
attenuation of the endothelial response to acetylcholine
induced by this model was, however, present in both
male and female offspring. In keeping with the
predominantly male hypertensive effects of prenatal
insults on development, studies have found more
impaired renal function in male than in female rat
offspring (Woods et al. 2005, Gilbert et al. 2007, Loria
et al. 2007, Reverte et al. 2011). Focusing on studies
where the sexes are compared directly within the same
model, it has been suggested that an anatomical basis for
impaired renal function can be seen in a direct reduction
of the number of nephrons in male offspring (Woods
et al. 2005). The greater susceptibility of male renal
development to adverse stimuli is also demonstrated
with post-natal intervention, when exposure to angio-
tensin II receptor antagonists causes decreased nephron
number in both male and female rats but decreased
glomerular filtration rate and papillary volume only in
males (Saez et al. 2007).
Impaired glucose tolerance and insulin resistance are
also a common finding in rat offspring in developmental
programming studies. This feature has been noted in
both male and female offspring in various models
(Vickers et al. 2000, Petry et al. 2001, Simmons et al.
2001, Seckl 2004, Ozanne et al. 2005). Where the sexes
are directly compared, the effect is observed in either the
male (Nivoit et al. 2009) or the female (Vickers et al.
2011) offspring. It has further been suggested that
impaired insulin sensitivity is a male-specific finding in
second-generation rat offspring when the dams of the F0
generation are exposed to isocaloric low-protein diet
during lactation (Zambrano et al. 2005). Conflicting
results on offspring outcomes may be an effect related to
the precise nature and timing of the intervention.
Variations in the type of exposure, developmental age
at which it was applied and age at which outcomes were
measured could all contribute to the differences in
outcomes observed. In the absence of further studies
directly comparing offspring outcomes, systematic
conclusions cannot be drawn. Despite the preponder-
ance of developmental programming papers measuring
outcomes related to hypertension, renal development
and impaired glucose tolerance, other sex-specific
differences in rodent studies specifically linked to
developmental programming are reported including
learning ability (Mueller & Bale 2007), myogenic tone
(Hemmings et al. 2005) and endothelial function (Franco
Mdo et al. 2002). Studies of mouse models that have
measured effects of developmental programming on the
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Sex differences in developmental programming R3
placenta in both male and female offspring have reported
that the placentas of female offspring are more readily
affected by prenatal insults (Wilcoxon et al. 2003,
Gallou-Kabani et al. 2010, Mao et al. 2010). It may be
hypothesised that female offspring are more protected
from in utero insults by the relative ease with which
the placenta adapts in the face of adverse conditions.
The relative malleability of the female placenta is
also observed in other species, including the rat,
where ethanol exposure in utero leads to decreased
11b-hydroxysteroid dehydrogenase-2 activity in female
offspring (Wilcoxon et al. 2003), and in human studies,
where placental up-regulation of 11b-hydroxysteroid
dehydrogenase-2 activity in response to antenatal steroid
administration occurs specifically in female offspring
(Stark et al. 2009). 11b-Hydroxysteroid dehydrogenase-2
is associated with improved physiological stability,
particularly in infants born preterm, and it is therefore
unsurprising to note that levels are decreased by a
physiological insult such as alcohol consumption
and increased by antenatal steroid administration
(which confers advantage in neonatal outcome; Stark
et al. 2009).
Sex differences in larger mammals and humans
Sex-specific differences in offspring outcomes from
developmental programming models are also demon-
strated in farm animals, mainly sheep (Dodic et al. 2002,
Manikkam et al. 2004, Gilbert et al. 2007, Sinclair et al.
2007, Tang et al. 2009) and cows (Micke et al. 2010).
A male offspring-predominant hypertensive effect,
similar to that demonstrated in rat models, has been
observed in sheep exposed to excess steroids in utero
(Dodic et al. 2002) and in sheep fed a low-methionine
and vitamin B diet in the periconceptual period (Sinclair
et al. 2007). In keeping with rodent data suggesting a
greater sensitivity of the developing renal system to
developmental insult in males than in females (Woods et
al. 2005, Saez et al. 2007), studies in sheep have also
demonstrated that prenatal steroid exposure reduces
glomerular filtration rate in male offspring (Tang et al.
2009) and nephrogenesis is impaired in male offspring
exposed to nutrient restriction (Gilbert et al. 2007).
Growth patterns are addressed in larger mammals
with the phenomenon of catch-up growth observed in
young adult male cows when exposed to low-protein
diet in the third trimester, with no significant difference
in the carcass weights of females with the same exposure
(Micke et al. 2010). However, prenatal testosterone
exposure in sheep caused intrauterine growth retar-
dation (IUGR) in both sexes, but catch-up growth was
reported in female offspring only (Manikkam et al. 2004).
Human studies in developmental programming are
by necessity limited to observational and epidemio-
logical data; however, these do suggest that adverse
conditions during pregnancy have sexually dimorphic
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effects. The developmental insults studied are wide-
ranging, including maternal smoking (Zaren et al. 2000),
antenatal steroid administration (Stark et al. 2009),
famine (Roseboom et al. 2001), asthma (Clifton 2005)
and obesity (Mingrone et al. 2008). These reflect the
results of animal models in showing effects on placental
function more in female offspring (Roseboom et al. 2001,
Clifton 2005, Stark et al. 2009), but growth restriction,
increased insulin secretion and plasma cortisol prefer-
entially in males (Zaren et al. 2000, Haley et al. 2006,
Mingrone et al. 2008).
In attempting to explain the difference in outcomes for
male and female offspring, parallels may be drawn from
fields other than developmental biology and molecular
biology, such as evolutionary biology. Evolutionary
biology traditionally views mammalian males as the
more ‘costly’ sex, and it may therefore not be energy-
efficient for a mother to invest heavily in long-term
protection of male conceptuses (Rickard et al. 2007,
Mathews et al. 2008). This type of effect may explain a
number of apparently anomalous results; for instance,
female infants of mildly asthmatic mothers demonstrate
a degree of IUGR, but this is ‘rescued’ after maternal
exposure to inhaled steroids. The growth of male infants
on the other hand is unaffected by mild asthma, but
males have a high rate of in utero mortality and
severe IUGR if an acute exacerbation of asthma occurs
(Clifton 2005).
Sexual dimorphism in terms of energy expenditure
and investment in conceptuses may be viewed as a
species-level survival advantage to preserve precious
resources at times of environmental stress in order to
gain maximum chance of overall species survival.
Adaptations in the offspring somatic tissues to environ-
mental stresses that are costly in terms of energy
investment would therefore be made preferentially to
female offspring, whose overall physiology and repro-
ductive tracts must be protected to ensure that they can
reproduce and withstand the stresses of pregnancy and
lactation, whereas the male has only to protect his
germ cells and be fit to mate. This kind of adaptive
mechanism could be manifested in the changes
described in rat models in Table 1, i.e. lack of protection
for male offspring in terms of renal tract development,
and susceptibility to hypertensive disease (Langley-Evans
et al. 1996, Kwong et al. 2000, Ozaki et al. 2001,
Alexander 2003, Woods et al. 2004, Loria et al. 2007),
where the somatic development of the male offspring is
‘killed’ to save maternal resources. Female offspring on
the other hand seem to have more placental adaptations
to adverse conditions (Wilcoxon et al. 2003, Vickers
et al. 2011), which might reflect attempts to buffer
and adapt to stressors, in order to preserve female
conceptuses in optimal condition and maximise the
chances of successful pregnancy and raising of a litter.
The adaptive response to some interventions may not
be clear-cut, for example to maternal hyperglycaemia,
Reproduction (2013) 145 R1–R13
where this may reflect a nutritionally replete environ-
ment or a maternal pathology that would compromise
the well-being of the pregnancy. It is clear that for
propagation of the species, there must be survival of both
male and female offspring to reproductive years, but
developmental programming could reflect subtle
differences in the long-term investment in each sex.
Nonetheless, male conceptuses do survive in utero and
post-natally despite harsh conditions, and there is clearly
capacity to postulate that counter-mechanisms have
evolved to ensure survival of both sexes. On this basis,
we propose that females may be more sensitive and
adaptable to the intrauterine environment, whereas
males may only be vulnerable and respond to the
harshest of pre- and post-natal environments. The
evidence for the basis of a sex difference is examined
on both a species and an individual conceptus level, in
an attempt to gain insight into the phenomenon.
Evolutionary aspects of sexual dimorphism in
developmental programming
Mammalian sex differences may be considered on three
levels – primary reproductive characteristics; secondary
differences in males and females not directly linked to
reproduction (for example differences in muscle mass;
Wells et al. 2010); and species-level differences in
behaviours, hierarchies and mating strategies (Bouissou
1983, Mank 2009). The first and second of these
differences are the areas with which developmental
biology is primarily concerned; however, it may be
illuminating to additionally consider the third. Sexual
dimorphism is observed throughout the animal kingdom
and is dependent on sex-limited gene expression
(Williams & Carroll 2009). Patterns of sex-limited gene
expression and sex determination transcription factors
are broadly similar in mammalian species but diverge
across other classes and phyla (Williams & Carroll 2009).
From an evolutionary biology point of view, the energy
invested by parents in male vs female offspring is thought
to be influenced by the condition of the parents and
the post-natal environment faced by the offspring (Trivers
& Willard 1973, Koskela et al. 2009).
The Trivers–Willard hypothesis (Trivers & Willard
1973) states that in a species where there is a sex-
based difference in reproductive success, mothers with
plentiful resources will be able to invest in the sex
with a reproductive disadvantage, whereas mothers
facing an adverse environment will preferentially
produce offspring of the sex with a greater chance of
reproductive success. If developmental programming is
considered as the molecular mechanism by which this
differential investment in offspring sex can be realised,
then the sexually dimorphic results of the various
animal models of developmental programming may be
better understood.
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The application of the underlying principles of the
Trivers–Willard hypothesis to the developmental pro-
gramming hypothesis has several attractive elements.
In particular, the inherent assumptions in both models
are remarkably similar: first that maternal ‘condition’
relates to fetal ‘condition’, secondly that the effects
‘programmed’ by the in utero environment persist into
adult life and thirdly that the effects of advantageous
conditions should be greater in the more reproductively
variable sex (Trivers & Willard 1973). Detecting a sex
ratio skew in laboratory models of developmental
programming is not straightforward, as many models
cull litters to a standardised number of males and
females, or a set low number of single sex offspring in
order to maximise the plane of nutrition (Khan et al.
2003, Loria et al. 2007, Chen et al. 2008, Tarry-Adkins
et al. 2010) but do not report pre-culling litter size or
gender distributions. Interestingly, however, a few
studies have shown that the sex ratio in rodent models
can be altered by changing maternal diet (Rosenfeld
et al. 2003, Rosenfeld & Roberts 2004), and a similar
effect has been noted with calorie restriction (Meikle &
Drickamer 1986) and increased fats in the maternal diet
(Fountain et al. 2008). It has been demonstrated that a
mouse model utilising a maternal high-fat diet, which
may be taken as a proxy for a nutrient-rich plentiful
environment, produced litters skewed towards excess
males (male fraction 0.67) whereas a low-fat diet in the
same animals skewed the ratio towards excess female
offspring (male fraction 0.39) (Rosenfeld et al. 2003).
Calorie restriction in a mouse model gave results,
consistent with the idea of a sex ratio skewed towards
female offspring by acute dietary stress (Meikle &
Drickamer 1986), but the sex ratio is not significantly
different after a long period of calorie restriction. This
adds weight to the idea of an adaptive process in
response to environmental stress.
The idea of maternal enhancement of the fitness of
one sex over the other depending on the post-natal
environment that the offspring will face is consistent with
the differences observed in developmental programming
models. Some of the sex differences described in the
developmental programming literature may be more
easily explained if viewed with respect to the evolution-
ary basis rather than focusing on the molecular
mechanism. If the Trivers–Willard hypothesis is
re-written in terms more usually accessible to develop-
mental biologists, it postulates that the external environ-
ment is signalled to the conceptus by the mother via
the uterine environment. This signalling influences the
phenotype of offspring produced to maximise chances
of species survival. This theory equates to the DoHaD
hypothesis and is a useful framework for considering the
apparent complexity of the observed sex differences in
developmental programming phenotypes. More particu-
larly, the Trivers–Willard hypothesis specifies sexual
dimorphism as a key feature of the changes produced by
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Sex differences in developmental programming R5
environmental pressures. The weight of evidence for
such an effect in the developmental programming
literature implies that a similar import should be
attached to considering offspring sex when reviewing
and designing developmental programming studies.
Evidence for the Trivers–Willard effect is controversial
in epidemiological studies of human populations, but
several studies have found evidence of skewed sex ratios
linked to environmental conditions (Andersson &
Bergstrom 1998, Kanazawa 2007, Cameron & Dalerum
2009). The situation for monotocous as opposed to
polytocous mammals may differ substantially. If a
Trivers–Willard effect does exist for monotocous mam-
mals, including humans, it may also be more difficult to
detect in population studies, as there is no scope for a
subtle shift in sex ratio within a single pregnancy.
Mechanistic aspects of sexual dimorphism in
developmental programming
While it is useful to consider developmental program-
ming at a species level, and to gain insight from an
evolutionary perspective into the reasons behind the
utility of a developmental programming effect, it is also
necessary to consider how sex-specific differences in
development occur at an individual level.
Three major factors give rise to sex differences in
development: differences in patterns of development
(genetic, transcriptional and morphological), differences
in timing of development and the influence of steroid
hormone exposure during life in utero and post-natally.
These factors combine to produce mature adult organ-
isms that are sexually dimorphic in terms of anatomy,
physiology, reproductive capacity and behaviour (Fig. 1).
Genetic and morphological differences
in development
Evidence from rodent models
From the earliest stages of preimplantation development,
the sex of the embryo influences both growth patterns
and survival. In the mouse, cultured individual blas-
tomeres from the two-cell embryo yield a higher rate of
successful male than female conceptuses (Sato et al.
1995). Cultured preimplantation murine male embryos
show a faster rate of growth in vitro than do female
embryos (Valdivia et al. 1993). Fetal sex is determined by
the presence or absence of a Y chromosome bearing the
Sry gene. In the mouse, this gene is responsible for the
onset of sexual dimorphism between embryonic (E) days
10.5–12.5. Sexual differentiation in the male initially
involves the interaction of SRY with SF1 to stimulate (via
SOX9) Sertoli cell development in the genital ridges,
which subsequently differentiate into testes (Sekido &
Lovell-Badge 2008). However, there are other important
central and peripheral regions expressing SRY, which
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R6 C E Aiken and S E Ozanne
Zygote
Preimplantation embryo
Post-implantation
Sexually dimorphic adults Early post-natal life
Male sex is a significant risk factor
for adverse neonatal outcome
contribute to the development of a phenotypically male
or female neonate, including heart, liver and kidneys,
but particularly the brain and adrenal glands (Kopsida
et al. 2009). Cells derived from day 10.5 mouse embryos
and grown in culture show similar patterns and rates of
cell division irrespective of chromosomal sex but differ
in their sensitivity to applied insults (e.g. ethanol) with
female lineages showing higher rates of cell death
(Penaloza et al. 2009).
It is possible that female feto-placental units are more
responsive to adverse uterine environments at an early
stage. For instance, maternal high-fat diet during
pregnancy appears to directly influence placental
methylation patterns only in female murine offspring
(Gallou-Kabani et al. 2010). This finding is consistent
with the increased sensitivity of gene expression profiles
in female placentas to a maternal high-fat diet (Mao et al.
2010). The decreased incidence of adverse outcomes in
female fetuses compared with males could be the
consequence of a greater environmental adaptability,
and hence protection, by placental physiology.
Evidence from large mammal and human studies
There is evidence that development of male and female
bovine conceptuses may be differently influenced by
early culture conditions. In bovine blastocysts, the
expression of antivirals in culture medium is twice as
high in female conceptuses as in males, due to increased
interferon t levels (Larson et al. 2001). This difference
has been postulated to give survival advantage to female
embryos (Walker et al. 2009). In bovine conceptuses
cultured in vitro, increasing glucose concentrations in
the culture medium led to an increased proportion of
male vs female blastocysts surviving in culture to the
blastocyst stage (Gutierrez-Adan et al. 2001, Larson et al.
2001). Thus, in the bovine preimplantation embryo,
Reproduction (2013) 145 R1–R13
Culture more successfully
Higher levels of antivirals
expressed
Transcriptional differences
More susceptible to insults in culture
media, e.g. Ethanol
Increased rate of growth and higher
birth weight
Figure 1 Sex differences arising in male and female
development from conception to the sexually
dimorphic adult.
before expression of any overt sex-specific morphology,
survival may already be influenced in a sex-dependent
manner by the interaction of genetic factors and
environmental conditions. By contrast, however, a
study of in vitro development of murine embryos in
elevated glucose concentrations failed to demonstrate
any sex-specific effects, although total and trophecto-
derm cell numbers were reduced in all conceptuses
(Bermejo-Alvarez et al. 2012). There is insufficient data
available to draw conclusions on whether glucose
concentrations may influence development in vitro in a
sex-specific manner in other species, but given the
difference in the findings of bovine and murine studies, it
may be expected that this will prove to be a species-
specific effect.
In humans, male sex is a significant risk factor for
adverse motor and cognitive outcomes in premature
infants and for survival in neonatal intensive care units
(Stevenson et al. 2000), with 20% reduced survival of
male preterm infants relative to females (Vatten &
Skjaerven 2004). Recent evidence regarding the differing
outcomes of male and female premature births suggests
that feto-placental immune function may be sexually
dimorphic and may play a key role in influencing
survival. Premature (!32 weeks) male neonates are
more likely to have a placenta showing evidence of
chronic inflammation and decidual lymphoplasmacytic
cell infiltration (Ghidini & Salafia 2005, Goldenberg
et al. 2006), whereas female placentas appear better
protected from inflammatory insult. The other major
difference influencing early life survival, and highlighted
in many studies, is the degree of peripheral vasodilata-
tion of the microvasculature, which is considerably
lower in female neonates (Stark et al. 2008). This
difference confers a considerable survival benefit as it
enables better cardiovascular stability and may be
linked to the observations on immune function, via
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levels of circulating cytokines. These adaptations in the
female fetus require increased energy expenditure on
the feto-placental unit, which may be proportionally
more costly to the mother in keeping with the Trivers–
Willard hypothesis.
Timing of development
Human males and females are known to undergo
development at different rates, both in utero and post-
natally up until the post-pubertal stage (Pedersen 1980,
Davis et al. 1993, de Onis et al. 2009). Growth velocity
may be critical to the extent to which an individual is
affected by an insult at any particular time point. A fetus
growing faster in utero can be considered to have a
greater effective exposure to a given insult than one that
undergoes fewer cell cycles during the period of
exposure. This may be the basis for the observation
from human studies that male infants of diabetic mothers
show an increased incidence of fetal macrosomia
(weight at birth O4000 g, leading to increased risk of
adverse events at delivery and neonatal outcomes;
Di Renzo et al. 2007), despite being exposed to the
same level of hyperglycaemia for the same absolute
time period as their female counterparts.
Sex differences in temporal development have been
postulated from the time of conception itself, with the
proposition that human male conceptuses are more
likely to result at the extremes of the fertile period (James
2001, 2008). However, the empirical evidence for this
proposition is contentious (Gray et al. 1998). The theory
has been advanced that conception at either end of the
fertile window results in less ‘fit’ embryos, purporting to
explain why a higher number of spontaneously aborted
conceptuses are male and advances an idea of male
‘fragility’ extending through life (Kraemer 2000). Sexual
dimorphism is also a feature of early post-implantation
growth in mammalian conceptuses (Pedersen 1980).
Later post-morphogenesis in utero growth is also faster in
human males with an average higher birth weight and
also a greater spread of birth weights (Clifton 2010);
however, levels of b human chorionic gonadotrophin,
which are responsible for maternal recognition and
response to the pregnancy, are greater with a female than
a male fetus (Cowans et al. 2009). Ultrasonographic
measurements of human growth in utero shows that the
slower rate of growth of the female fetus becomes
significant at 28 weeks of gestation and increases
towards term (Parker et al. 1984).
Timing of sexual development
Sexual maturity is reached earlier in females than in
males, an effect that is preserved across a range of
species from mice to humans, and may be correlated
with expression of kisspeptin in the hypothalamus
(Clarkson & Herbison 2006, Kauffman 2010). There is
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Sex differences in developmental programming R7
a marked difference in developmental programming of
offspring phenotypes when measured before and after
puberty. For example, in prenatal exposure to maternal
ethanol consumption (Lee & Rivier 1996), immature rat
males and females show a dimorphic hypothalamo-
pituitary axis (HPA) response to immune stimuli, but
post-puberty, both show exaggerated ACTH release to
the same stimuli. Spurious results may be obtained using
experimental protocols that take measurements at an
absolute time point after birth in young adult animals
and which consequently fail to take account for the later
sexual maturation of males, thereby observing an effect
that reflects pubertal status rather than primarily a sex
difference.
In considering the applicability of these results to
a human population, a further level of complexity is
added by the suggestion that a prenatal insult may
itself influence the timing of puberty, for example
children born at very low birth weight, whether at
term or prematurely, show early puberty, up to 2 years in
advance of their normal birth weight peers (Wehkalampi
et al. 2011). Hence, not only may the measured
phenotype be influenced by the timing of the
measurement but also by the nature and extent of the
insult applied.
Reproductive aging in developmental programming
In comparing phenotypes during later life, very few
developmental programming studies address ambient
sex steroid levels at the time of sampling, yet a very
different outcome may be observed depending on
whether females still have the cardioprotective effect of
oestrogen. Female rodents demonstrate cycle irregula-
rities at around 9–12 months of age (Sokol et al. 1999,
Spencer et al. 2008), eventually becoming acyclic and
entering ‘estropause’ at 12–18 months of age (Van
Kempen et al. 2011). The key differences between
menopause and estropause may be understood in
terms of circulating oestrogen levels, which fall dramati-
cally in human menopause, but are maintained at a
higher ambient level in rodents (Maffucci & Gore 2006).
Many developmental programming studies have
sampling time points at around estropause (9–12
months; Remmers et al. 2008) and yet do not consider
whether the effects of sex steroids on female tissues are
consistent at this age, or indeed whether the results
would have relevance to a human population.
At the later extreme of life, aging and longevity have
been studied in the developmental programming
literature, particularly with respect to telomere length
(Jennings et al. 1999, Tarry-Adkins et al. 2008). It is
known that telomere length in both the renal cortex and
the medulla of male rats is shorter than in females and
that telomere shortening is associated with increased
markers of cellular senescence (Tarry-Adkins et al.
2006). In male rats, it has also been shown that prenatal
Reproduction (2013) 145 R1–R13
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R8 C E Aiken and S E Ozanne
exposure to a maternal low-protein diet in rats shortens
telomeres prematurely in a number of organs
(Tarry-Adkins et al. 2008), but the effect is less well
studied in females.
In humans, differences in the lifespan of males and
females are well recognised, despite the lack of a
demonstrated difference in telomere length at birth
(Okuda et al. 2002). Women have greater telomere
lengths in later life than men in peripheral blood
leukocytes (Benetos et al. 2001), and this difference
may be linked to oestrogen-dependent promotion of
telomerase activity (Kyo et al. 1999). European women
undergo menopause at a median age of 54 years (Dratva
et al. 2009) and thereafter their general propensity to
diseases of the metabolic syndrome changes consider-
ably. A sex difference in developmental timing thus
extends throughout life and is worthy of consideration in
the design of developmental programming studies when
planning both exposure and measurement of phenotypic
outcomes. Spurious results may be obtained when
comparing males and females at the same absolute
time from conception, but failing to take account of the
different maturational stage that this represents. Particu-
larly in obtaining tissue samples from young adult
animals around the advent of sexual maturity, a sex
difference in pubertal stage is not often considered.
Similarly, in studies that involve senescent tissue, the
normal rate of tissue aging in male and female tissues
and hence differences in for example telomere length
and markers of oxidative damage should be considered.
Exposure to sex steroids
Increased steroid exposure in utero has been demon-
strated to affect fetal and placental metabolism, nutrient
transfer and endocrine function (Milley 1996, Timmer-
man et al. 2000, Challis et al. 2002). Fetal glucocorticoid
exposure is a strong candidate for involvement in
programming of the metabolic syndrome and has been
shown to affect development in a range of organisms
(Seckl 2008). It is unclear whether exposure to sex
steroids may have similar adverse effects. Evidence from
human populations suggests that the prevalence of
insulin insensitivity and polycystic ovarian syndrome is
higher in the presence of excess androgen hormones
(Veiga-Lopez et al. 2008, Moulana et al. 2011), and it
has been suggested that exposure to excess androgen in
childhood influences the development of the metabolic
syndrome and polycystic ovarian syndrome (Idkowiak
et al. 2011). In adult humans, male subjects show
an increased propensity to at least some aspects of the
metabolic syndrome compared with females, possibly
as a primary effect of ambient sex steroid levels
(Regitz-Zagrosek et al. 2006). Epidemiological evidence
shows that the sex difference in risk for cardiovascular
disease narrows considerably after the menopause and
Reproduction (2013) 145 R1–R13
that oophorectomy in rats can narrow this gap in
incidence at an earlier age (Ojeda et al. 2007, 2008).
From a developmental point of view, male fetuses are
exposed to higher levels of androgens in utero compared
with female fetuses (Barry et al. 2010). In the human
fetus, it has been demonstrated that the testes can
synthesise androgens from LDL-cholesterol by gesta-
tional week 10 (Carr et al. 1983). It is difficult to
determine with accuracy fetal testosterone levels,
particularly in the human where fetal and maternal
testosterone serum levels are poorly correlated (Scott
et al. 2009). The essential ‘masculinisation programming
window’ – when androgen levels become significant in
fetal serum – occurs shortly before the time at which
definitive male fetal phenotypic characteristics appear,
corresponding to E15.5–17.5 in the rat (Welsh et al.
2008). If the molecular-level sex differences in rat
developmental programming models are ascribed to
the difference in fetal testosterone exposure, it would be
reasonable to expect that sex differences should also
become detectable at around E15.5–17.5, or at least not
detectable significantly before this time in the rat model.
In female sheep offspring, it has been demonstrated that
in utero administration of testosterone to the mother
produces pancreatic dysregulation and changes in liver
metabolism (Hogg et al. 2011).
A further consideration in polytocous organisms is the
effect of differing levels of intrauterine sex steroid
exposure in the female offspring, dependent on intra-
uterine position. Those females that developed in utero
between two male fetuses are known as ‘2M females’
and have higher testosterone exposure than ‘0M
females’, which develop between two female fetuses
(vom Saal & Bronson 1980). Testosterone exposure of
2M females has been shown to affect their subsequent
reproductive function (Vom Saal & Moyer 1985) and
sexually dimorphic preoptic area development (Pei et al.
2006). The consideration of intrauterine position applies
much less frequently to larger mammal and human
populations that are not litter-bearing, but the differences
in physiology observed in 2M females adds weight to
the hypothesis that in utero exposure to sex steroids may
profoundly influence developmental programming.
Much less work has gone into understanding the
effects of female sex hormone exposure in utero, but it
has been shown that sex differences in insulin sensitivity
may be influenced by the effect of oestrogen as a leptin
sensitiser on the fetal brain (Clegg et al. 2003, 2006).
Sex-specific differences in epigenetic regulation
Sex-specific differences in epigenetic modulations are
associated with developmentally programmed pheno-
types in animal models (fully reviewed in Dunn et al.
(2011)). These effects are proposed to extend to second
generations of offspring in rats (Morgan & Bale 2011)
and can be induced by a variety of adverse stimuli,
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including maternal dietary and stress interventions
(Dunn et al. 2011).
In the female preimplantation embryo, there exists a
period during which transcription occurs from both X
chromosomes, between the start of transcription from
the embryonic genome and X inactivation. The absolute
extent of this window is species specific, lasting in the
mouse between the eight-cell and blastocyst stages
(Gardner et al. 2010). The result of a period of expression
from both X chromosomes is a proteome considerably
different from that of the male (Epstein et al. 1978).
Differential expression of over 600 X-linked genes has
been shown in the mouse (Kobayashi et al. 2006),
including dose-dependent up-regulation of hypoxan-
thine–guanine phosphoribosyltransferase (Kratzer &
Gartler 1978) and glucose 6-phosphate dehydrogenase
(Williams 1986). Persistence of these proteomic
changes after X inactivation could account for ongoing
differences in male and female growth patterns, as
well as potentially determining their responsiveness to
developmental insults.
Applying these considerations to larger mammals and
humans is more challenging – the timing and mechanism
of X inactivation is not well conserved across mamma-
lian species (Okamoto & Heard 2009). The precise
timing of X inactivation in human embryos is yet to be
fully determined (van den Berg et al. 2009). It remains
uncertain how the contribution of X inactivation to
developmental programmed offspring phenotypes
should be interpreted, particularly in view of the fact
that not all genes on the X chromosome are silenced at
X inactivation (Brown & Greally 2003). In humans, up
to 15% of genes carried on the X chromosome appear
to escape inactivation and hence a gene dosage effect
remains a plausible explanation for sex differences in
developmental programming even after X inactivation
has occurred (Brown & Greally 2003).
Conclusions
In the foregoing discussion, it is assumed that the sex
differences in developmental programming models are
the result of the differential ability of the male and female
fetus to respond to a particular stress; however, a further
question, which is difficult to address experimentally,
is whether the mother’s response to a given stress is
influenced by the sex of fetus she is carrying. Develop-
mental programming stresses are not normally applied to
the fetus directly, but particularly in the case of dietary
interventions are mediated by the maternal physiology.
It could therefore be postulated that all fetuses respond
identically to the same insult, but the insult is buffered
by the mother in a way that depends on the sex of the
fetus. This is a major point requiring clarification via
further experimental work.
In view of the major temporal, spatial and biochemical
differences between male and female development, both
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Sex differences in developmental programming R9
pre- and post-natally, it may be argued that the sexes
should be treated by researchers as separate models.
In designing experiments, it is the goal of most
researchers to use the fewest animals and least resources
practicable to fully address their question. This leads to a
paucity of studies in which sexual dimorphism is built
into the model, and yet this is a pertinent issue when
applying the results of developmental programming
studies to designing diagnostic, preventative and thera-
peutic measures.
Declaration of interest
The authors declare that there is no conflict of interest that
could be perceived as prejudicing the impartiality of the review
reported.
Funding
S E Ozanne is a British Heart Foundation Senior Fellow.
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Received 21 December 2011
First decision 2 February 2012
Revised manuscript received 1 October 2012
Accepted 15 October 2012
Reproduction (2013) 145 R1–R13
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