REPRODUCTION

SPECIAL REVIEW

DOHaD: A MENAGERIE OF ADAPTATIONS AND PERSPECTIVES

Large animal models of developmental programming:
sustenance, stress, and sex matter
CJ Hammer , JS Caton, CR Dahlen, AK Ward, PP Borowicz and LP Reynolds
Center for Nutrition and Pregnancy, and Department of Animal Sciences, North Dakota State University, Fargo,
ND, USA
Correspondence should be addressed to C J Hammer; Email: carrie.hammer@ndsu.edu
This article forms part of a special collection of review articles on DOHaD. The Guest Editor of this special collection was Dr
Pascale Chavatte-Palmer, INRAE, France.

Abstract
In brief: Developmental programming refers to the long-term programming of gene expression during fetal and postnatal
development, resulting in altered organ function even into adulthood. This review describes how maternal and paternal
sustenance and stress, as well as fetal sex, all matter in large animal models and affect developmental programming of
the offspring.
Abstract: Developmental programming is the concept that certain health outcomes throughout life can be linked to early fetal or
postnatal development. Progress in understanding concepts and mechanisms surrounding developmental programming is
heavily leveraged by the use of large animal models. Numerous large animal models have been developed that apply a host
of different maternal stressors and, more recently, paternal stressors. Maternal nutrition is the most researched maternal
stressor applied during gestation and includes both global nutrient supply and models that target specific macro- or micro-
nutrients. The focus of this review is to provide an overview of the many large animal models of developmental programming
and to discuss the importance of sex effects (including paternal contributions) in study design and data interpretation.
Reproduction (2023) 165 F1–F13

Introduction organ systems) that may persist into adulthood (Fowden

Developmental programming is the concept that certain
health outcomes throughout life can be linked to early
fetal or postnatal development (Barker 2004). We now
know that certain factors, or ‘stressors’, that occur during
gestation or postnatally can alter gene expression in the
developing fetus/neonate via epigenetic mechanisms.
These epigenetic alterations are thought to not only
‘program’ fetal and postnatal growth and development
but also cause long-term changes in organ structure (e.g.
altered number of nephrons in the kidney, remodeling of
the myocardium, altered pancreatic islet cell number or
structure, and altered number of skeletal myocytes) and
function (Du et  al. 2010, Reynolds et  al. 2010, Sutton
et  al. 2016, Chavatte-Palmer et  al. 2018, Caton et  al.
2020, Diniz et al. 2021). There is a large body of evidence
confirming the negative consequences of developmental
programming during the immediate perinatal period
(e.g. altered gestation length, reduced birth weight,
and poor survival of neonates) as well as a host of
chronic pathologies (e.g. altered body composition,
metabolic dysfunction, and dysfunction of numerous
et  al. 2005, Wu et  al. 2006, Reynolds & Caton 2012,
Coverdale et  al. 2015, Robles et  al. 2017, Odhiambo
et al. 2020, Bradbery et al. 2021, Reynolds et al. 2022a).
The focus of this review is to provide an overview
of the many large animal models of developmental
programming and to discuss the importance of
considering sex effects (including paternal contributions)
in study design and data interpretation. The use
of large animal models to explore the mechanisms of
developmental programming has helped to establish
the mechanisms involved, and these observations
have the potential to improve fetal development and
lifelong health outcomes.
Importance of large animal models
Research with large animal models has made significant
contributions to our current understanding of the
biomedical sciences in general (Carpenter 2003, Ireland
et al. 2008, Reynolds et al. 2009, Polejaeva et al. 2016,
Benammar et al. 2021, Nathanielsz 2021, Amat et al.
2022, Reynolds et  al. 2022b, Smith & Govani 2022).

© 2023 Society for Reproduction and Fertility https://doi.org/10.1530/REP-22-0453

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F2 C J Hammer and others
The reliance on and importance of animal models to
our knowledge of biological and clinical principles
is evident throughout the history of research. In fact,
early work in the area of energetics and micronutrients
helped foster development of the fields of biochemistry
and molecular biology (Nichols & Reeds 1991), and
work in placental development and reproductive
biology has long depended on animal models (Longo
& Reynolds 2010).
Specifically relevant to this review, the area of
developmental programming has progressed rapidly
during the past 25 years, being heavily leveraged
by the use of large animal models. As a result, large
animal research has helped to refine and define the
concepts of developmental programming, resulting
in numerous published works and reviews (Reynolds
et al. 2010, Reynolds & Caton 2012, Coverdale et al.
2015, Chavatte-Palmer et  al. 2017, Reynolds et  al.
2017, Caton et  al. 2020, Amat et  al. 2022, Reynolds
et  al. 2022a,b, Robles et  al. 2022). Recently, the
journals ‘Animal Frontiers‘ dedicated two issues and
‘Veterinary Clinics of North America: Food Animal
Practice’ dedicated one issue entirely to large animal
models: ‘Developmental Programing; What Mom
Eats Matters’ (Zinn et  al. 2017), ‘Farm Animals are
Important Biomedical Models’ (Hamernik 2019), and
‘Developmental Programming in Livestock Production’
(Funston & Mulliniks 2019), respectively. Clearly, the
use of large animal models to study developmental
programming is well established and has contributed
significantly to both our practical and mechanistic
understanding of these processes.
Large animal models present unique advantages
when compared with rodents or other more laboratory-
based approaches. Specifically, large animal models (i)
exhibit pregnancies with a similar physiology to that
of humans; swine are an exception as they are litter-
bearing animals, but cattle in particular have a similar
gestation length as humans and also most often have
singleton pregnancies, making them particularly
well suited for investigations of pregnancy, including
developmental programing; (ii) provide an abundance
of tissues for multiple lines of investigation using the
same experimental protocol; (iii) can be chronically
instrumented for sampling over time, for example, with
blood flow probes or catheters for blood sampling; (iv)
can be used in experimental protocols that would be
unethical in humans; and (v) often provide the dual
efficiencies of having applications both to agriculture
and to biomedicine and therefore have contributed
substantially to our understanding of both the short-
and long-term consequences of developmental
programming. For these reasons, large animal models
have historically been and will continue to be employed
to address critical questions in both biomedical and
agricultural sciences, and this is particularly relevant in
the area of developmental programming.
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 (2023) 165 F1–F13
Models of developmental programming (large
animal and others) often exhibit compromised growth
during embryonic, fetal, and(or) neonatal stages of
development. As reviewed by Caton et  al. (2019),
compromised offspring exposed to maternal stressors,
including inappropriate nutrition, can exhibit ‘1)
increased neonatal morbidity and mortality; 2) altered
postnatal growth; 3) altered body composition (e.g.,
increased fat, reduced muscle growth); 4) metabolic
disorders (e.g., poor glucose tolerance and insulin
resistance); 5) cardiovascular disease; and 6) altered
structure and function of organs and/or organ systems,
including adipose, cardiovascular, digestive (including
pancreas), endocrine, gastrointestinal, immune, kidney,
liver, mammary gland, muscle, neural, placenta,
and reproductive’. Research with animal models of
developmental programming can have significant
implications for the development and eventual
dysfunction of multiple organ systems, and such models
have helped define the mechanisms responsible for
altered metabolic and growth outcomes, even when
perturbations occur during early pregnancy (Reynolds
et  al. 2010, 2019, 2022b, Reynolds & Caton 2012,
Caton et al. 2019, 2020).
Large animal models of developmental
programming: maternal stressors matter
The largest body of research in developmental
programming has been focused on the dam, and
numerous large animal models have been developed to
study a wide range of stressors (Fig. 1). The importance of
paternal contributions to developmental programming
is only just beginning to be realized and is addressed
later in this review.
Maternal stressors: sustenance
Maternal sustenance, or nutrient supply to the dam,
is a major contributor to developmental programming
and consequently health and productivity of the fetal,
neonatal, and adult offspring (Wallace et al. 1999, 2001,
Wu et al. 2006, Reynolds et al. 2010, Funston et al. 2012,
Reynolds & Caton 2012, Robinson et  al. 2013, Meyer
& Caton 2016, Caton et  al. 2019, 2020, Robles et  al.
2021, Reynolds et al. 2022a,b). The fact the fetal growth
trajectory is such that the largest fetal body weight gain
occurs during the last half of gestation led to the concept
that maternal nutrient supply during early gestation is
relatively unimportant. This concept was bolstered over
time with nutrient requirement estimates from the US
National Academies of Science (NRC 2007a,b, 2012,
2016). However, earlier work (Robinson et al. 1999) had
indicated that the fetal growth trajectory was responsive
to nutrient supply from the very early stages of gestation.
The discrepancies between these two paradigms can be
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explained by the use of traditional approaches to assess
nutrient requirements in gestating animals and the
relatively small amounts of nutrients required during the
early stages of conceptus development.
Put another way, as the conceptus grows from
two cells to an embryo and then to a fetus with fully
recognizable organ systems early in pregnancy (e.g. the
first 30–35 days in sheep and 45–50 days in cattle), the
demand of the conceptus for transport of nutrients and
respiratory gases to support cellular processes of growth
and differentiation, while relatively large, is small
compared with the total maternal nutrient demand.
Consequently, mismatches in maternal and conceptus/
early fetal nutrient supply and demand during this
critical developmental window create opportunities
for perturbed developmental outcomes. Recent work
from our laboratories (Crouse et al. 2017, 2019, 2020,
2022a,b, McLean et  al. 2017a,b, 2018, Caton et  al.
2020, Diniz et al. 2021, 2022) has clearly demonstrated
that even moderate changes in maternal nutrient supply
during early pregnancy can have profound effects
on the developing offspring. Clearly, inappropriate
maternal nutrition is one of the most studied maternal
factors impacting developmental outcomes in offspring,
particularly when considering large animal models and
defining critical periods of development.
Maternal undernutrition, or nutrient restriction,
leads to decreased nutrient supply to the fetus during
development (Reynolds & Caton 2012). Much of
the published work with large animal models on
developmental programming has focused on maternal
undernutrition because of its implications for livestock
production, and especially ruminants, as well as for the
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Developmental programming: large animal models F3
Figure 1 Large animal models of
developmental programming. Figure is not
meant to be all inclusive but is provided as a
general overview of published large animal
models. Created with BioRender.com.
many human populations that are food insecure and in
poverty. However, decreased fetal nutrient supply can
result from numerous events, including poor maternal
nutrient supply, maternal metabolic dysfunction,
placental dysfunction, environmental extremes, and
low forage supply or quality (especially in ruminant
species) (Reynolds & Caton 2012, Reynolds et  al.
2017, 2022a,b). Most of the published data with
sheep indicate that maternal undernutrition during the
last two-thirds of gestation reduces fetal growth and
birth weight (Reed et  al. 2007, Swanson et  al. 2008).
Conversely, beef cattle present with more plasticity
when faced with nutrient restriction during the last
two-thirds of gestation, and thus the data are mixed,
with some reports showing no differences and others
reporting reduced birth weights (Taylor et  al. 2018,
Sletmoen-Olson et  al. 2000). In mares, moderate
nutrient restriction during pregnancy often results in
little change in placental measurements or foal birth
weights; however, placental tissues from restricted
mares had increased transcript abundance for genes
associated with transport of a diverse array of nutrients
(Robles et al. 2022). Interestingly, in sheep, first-parity
ewe lambs are more likely to exhibit reduced fetal birth
weight than mature ewes, which is likely explained
by a combination of reduced placental function and
the nutrient demands associated with continued body
growth of first-parity ewes (Wallace et al. 1996, 2001,
2000, 2011).
Birth weights are important as they are easily
recorded and serve as a proxy for reduced fetal
growth and compromised pregnancies, even though
programmed changes in metabolism and organ function
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F4 C J Hammer and others
have been reported in the absence of reduced fetal
birth weights (Reynolds & Caton 2012, Reynolds et al.
2017, Reynolds et  al. 2022a,b, Robles et  al. 2022).
Neonates that are growth restricted at birth, often termed
intrauterine growth restriction (IUGR), are at greater risk
of postnatal complications resulting in increased disease
susceptibility, poor productivity, and complications
later in life, including premature aging and reduced
longevity (Wu et al. 2006, Funston et al. 2012, Reynolds
& Caton 2012, Reynolds & Vonnahme 2017, Reynolds
et al. 2022a,b) as well as decreased efficiency of growth
and altered body composition (Greenwood et al. 1998,
Greenwood et  al. 2000, Wu et  al. 2006, Larson et  al.
2009, Robinson et  al. 2013, Caton et  al. 2019). IUGR
also occurs in swine as a result of compromised maternal
nutrition; however, piglet placement within the placenta
among other maternal and intrauterine stressors often
contributes to IUGR (Almeida & Dias 2022, Chand et al.
2022, Farmer & Edwards 2022).
IUGR has major impacts on human health and
livestock production in both the short and long term.
In the short term, low birth weights are associated with
increased rates of morbidity and mortality in livestock
and are more pronounced during adverse environmental
conditions such as high environmental temperatures/
humidity or drought, which are often experienced in
production systems (Mellor 1983, Azzam et al. 1993, Van
Rens et al. 2005, Caton et al. 2019). For example, low-
birth-weight lambs (Greenwood et  al. 1998, Hammer
et  al. 2011), calves (Bellows et  al. 1971, Corah et  al.
1975) and piglets (Quiniou et al. 2002, Van Ginneken
et  al. 2022) exhibit greater neonatal mortality and are
slower to adjust to the postnatal environment compared
with offspring considered to be within the normal birth
weight range for the species and breed. Importantly
the long-term, hidden costs of IUGR are the impacts
on postnatal growth and body composition, nutrient
utilization, reproductive efficiency, metabolism and
organ dysfunction, and other detrimental consequences
(e.g. reduced longevity), which all are highly relevant to
animal production and human health but are less easily
discerned and therefore less often documented. that IUGR, resulting from either maternal under- or
Postnatal growth rates and reproductive efficiencies
are reduced in offspring experiencing IUGR (Greenwood
et  al. 1998, 2000, Meyer et  al. 2010, Reynolds &
Vonnahme 2017). While low-birth-weight offspring
generally have lower absolute growth rates to weaning
(Cundiff et  al. 1986), the most perturbed individuals
exhibit greater fractional growth rates from birth to
weaning yet remain stunted with respect to height in
adolescence (Wallace 2011).
Maternal nutrient excess, or over-nutrition, is also
a model that has been examined in large animals.
The elegant overnourished, adolescent ewe model
developed by Jacqueline Wallace and colleagues at
the Rowett Research Institute in Aberdeen, Scotland
(Wallace et al. 1996, 2001, 2014, 2017, 2020a, 2021a,b)
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 (2023) 165 F1–F13
has contributed significantly to our understanding of the
consequences of overfeeding/overeating in adolescent
pregnancies. Using this model, Da Silva et  al. (2001)
reported that reduced neonatal growth in IUGR lambs
was more pronounced in males than females up to
weaning, and both sexes continued to experience
reduced growth compared with controls up to 25 weeks
of age. These authors (Da Silvia et al. 2001, 2002, 2003)
also reported delayed puberty and reduced testicular
growth in male offspring as well as fewer ovarian
follicles in female fetuses. Similarly, heifers born to non-
supplemented, grazing cows (presumably exhibiting
fetal malnutrition) demonstrated delayed puberty
(Funston et al. 2008) and had lower pregnancy rates and
a lower percentage calving within the first 21 days of the
calving season compared with supplemented controls
(Martin et  al. 2007). In contrast, female offspring
from undernourished ewes exhibited altered ovarian
function (reduced progesterone production and reduced
proliferation of ovarian tissues) postnatally but with no
effects on uterine function or attainment of puberty
(Grazul-Bilska et al. 2014a).
In sheep, body composition is often altered in
IUGR fetuses and has variously been associated with
small and thin or small and fat phenotypes at birth
depending on the nutritional paradigm that resulted in
the growth restriction (Matsuzaki et  al. 2006, Luther
et al. 2007). In addition, low birth weight in lambs has
been associated with decreased percentages of carcass
muscle and bone and increased percentages of fat at
slaughter (Makarechian et al. 1978). Furthermore when
low birth weight lambs are artificially reared to achieve
contrasting postnatal growth rates, they have more
fat and less body minerals than normal-birth-weight
controls, independent of the postnatal growth trajectory
achieved (Greenwood et  al. 1998). At slaughter, steers
from non-supplemented, grazing cows had lower body
weight and hot carcass weight, reduced marbling scores,
and a lower percentage grading choice compared with
supplemented controls (Larson et al. 2009). These data
combined with other evidence presented above indicate
overnutrition, probably has both short- and long-term
impacts on production and sustainability of animal
agriculture.
Much of the data discussed above have been from
models of global maternal under- or overnutrition,
which means that the plane of maternal nutrition
was achieved by modulating dietary intake and not
dietary composition. However, numerous studies
have investigated the effects of specific nutrients on
developmental outcomes. Both macronutrients (energy,
protein, and fat) and micronutrients (specific amino
acids, fatty acids, vitamins, and minerals) have been
assessed. A detailed review of the effects of all specific
nutrients in the maternal diet that affect offspring
outcomes is beyond the scope of this review. However,
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in each case, examples exist in which maternal dietary
supply of a specific nutrient class affects offspring
outcomes (Swanson et  al. 2017, Menezes et  al. 2021,
2022, Crouse et al. 2022a).
In some cases, no differences have been observed,
perhaps either because dietary requirements were met
or due to biological plasticity – i.e. a compensatory
response that protected the fetus and offspring from
adverse developmental outcomes. As an example,
increased maternal dietary protein intake has been
shown to decrease (Sletmoen-Olsen et al. 2000) or have
no effect (Martin et al. 2007, Larson et al. 2009) on calf
birth weight. However, Funston and colleagues (2012)
reported that protein supplementation of beef cows
during gestation had long-term positive effects on the
offspring, including improved carcass characteristics,
reproductive traits in females, and weaning weights,
even in the absence of changes in birth weight. Others
(Radunz et al. 2012, Lan et al. 2013) have reported that
dietary energy source in beef cows can alter offspring
adipose development, glucose metabolism, and DNA
methylation and gene expression.
Meyer et  al. (2012), Wang et  al. (2015), Reynolds
et  al. (2017), and Chavatte-Palmer et  al. (2018) have
clearly shown that epigenetic mechanisms are key to
developmental programming, which has been recently
explored by our laboratories (Crouse et al. 2022b, Diniz
et  al. 2022). Interestingly, individual micronutrients,
including folic acid, vitamin B12, methionine, choline,
vitamin B6, sulfur, and selenium, are associated with
epigenetic status and represent opportunities for novel
investigations into maternal/fetal nutrient supply and its
effects on epigenetic mechanisms, gene expression, and
developmental outcomes (Dahlen et  al. 2021, Crouse
et al. 2022a, Diniz et al. 2022).
In summary, numerous studies using animal models
have shown that maternal nutrient supply has major
effects on fetal development, many of which may
originate early in pregnancy, resulting in poor postnatal
outcomes, with both short- and long-term consequences
for health and productivity.
Maternal stressors: environment, disease, and toxins
In addition to models examining the effects of maternal
sustenance, large animal models have also focused
on environmental and other stressors during gestation.
Much of the published work has focused on heat stress,
high altitude stress/hypoxia, and the stress associated
with transportation and has been reviewed previously
(Arnott et  al. 2012, Papamatheakis et  al. 2013, Tao &
Dahl 2013, Gonzalez-Candia et  al. 2020, Johnson
et  al. 2020, Ghaffari 2022). Other maternal stressors
include disease challenges, toxin/chemical exposure,
and exogenously administered drugs and/or toxins.
For example, administration of steroids, especially
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Developmental programming: large animal models F5
synthetic ones, is a common medical intervention
aimed at manipulating the fetal hypothalamic–pituitary
axis and improving fetal lung/organ maturation prior
to parturition; interestingly, this protocol was initially
developed in a sheep model (Liggins 1969). Exogenous
steroid administration improves immediate postnatal
outcomes but also has lasting effects on programming
of organ systems postnatally (Molnar et al. 2003, Long
et  al. 2013, Schiffner 2017). A detailed review of all
maternal stressors is outside the scope of this review,
but each of the stressors potentially affects embryo/
fetal development and placentation as well as postnatal
growth and development (Reynolds et al. 2014, Ouellet
et al. 2021, Cattenao et al. 2022, Ghaffari 2022).
Maternal stressors: advanced reproductive techniques
Advanced reproductive techniques (ARTs), including
embryo transfer, in vitro fertilization, in vitro production of
embryos, intracytoplasmic sperm injection, and cloning,
are all utilized in large animals. Maternal oocyte quality,
uterine environment, and embryonic development all
can be influenced by several of the stressors mentioned
previously (Reynolds et  al. 2010, Caton & Reynolds
2012, Grazul-Bilska et  al. 2012, Moussa et  al. 2015).
Additionally, ARTs in general (and independent of
oocyte quality and uterine environment) have large
effects on embryonic development, organogenesis, and
placentation, with much of this occurring very early in
pregnancy, at least in sheep models (Grazul-Bilska et al.
2013, Grazul-Bilska et al. 2014b, Reynolds et al. 2014,
Siqueira et al. 2019).
Maternal stressors: developmental windows
The timing and duration of the particular stressor can
greatly impact developmental outcomes. Pre-breeding
and periconceptually, as well as early, mid, and late
gestation, are all periods when maternal stressors can
have profound, and differing, developmental effects
(Caton et al. 2019, Reynolds et al. 2022b). In addition, the
duration can be short or occur across multiple timepoints,
for example periconceptually. These observations have
resulted in the concept of developmental ‘windows’
of programming. For example, feeding ewes a globally
restricted diet from 60 days before until 30 days after
mating results in premature birth of their lambs as
well as reduced postnatal survival (Bloomfield et  al.
2003, Kumarasamy et  al. 2005). As another example,
heat stress applied during the periconceptual period
impaired cellular function, caused DNA fragmentation,
and resulted in an increase in reactive oxygen species,
leading to decreased embryo survival, but when initiated
during late gestation, heat stress altered placental
structure and function and resulted in reduced calf birth
weight (Ouellet et al. 2021).
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Large animal models of developmental
programming: sex matters
Many investigations of developmental programming
in large animals did not address the impacts of fetal
sex on pre- and postnatal outcomes; yet, all the major
large animal model species have reported differences
in the development of female and male conceptuses/
fetuses, including placental development, ranging
from differences in the rate of development to altered
endocrine and metabolic gene expression (Gutierrez-
Adan et  al. 1996, Zeng et  al. 2019, Claes et  al. 2020,
Chavatte-Palmer et  al. 2022, Drum et  al. 2022). More
recently, there has been a surge in work reviewing sexual
dimorphism and placental development in humans,
rodents, and large animals (Rosenfeld 2015, Kalisch-
Smith et  al. 2017, Christians 2022, Stenhouse et  al.
2022), further highlighting the importance of accounting
for sex effects in developmental programming models.
We conducted a search in Web of Science covering
the last 10 years (January 1, 2012, to January 1, 2023) to
identify developmental programming studies reporting
sex effects. Search terms were adapted from Arnott et al.
(2012) and were designed to combine words related to
prenatal stress and the different large animal species. The
initial searches generated a list of articles for cattle (91),
sheep (144), horses (19), and pigs (57). The initial lists were
screened and duplicates, irrelevant articles (e,g. human
trials looking at bovine milk and guinea pig studies), and
review articles were removed. Additionally, studies that
specifically administered testosterone/estrogen to affect
reproductive development or were designed to examine
only one offspring sex were removed. The final reference
list contained 81 articles (cattle, 19; sheep, 49; horses, 2;
and pigs, 11). The references were reviewed for inclusion
of sex effects in the analysis. Of those, 60% included
offspring sex in the statistical model, with the majority
(72%) reporting sex-affected outcomes (Table 1).
Effects of sex include alterations in behavior, organ
and whole-body growth, body composition, and gene
expression across multiple species and maternal models.
Offspring effects have been noted during prenatal and
postnatal development as well as into adulthood. Most
strikingly, Jaquiery et  al. (2012) reported that brief
periconceptual undernutrition in sheep resulted in
increased body fat and smaller hearts and lungs in male
offspring compared to females when examined later in
adulthood (3–4 years of age).
Dad matters too!
Though the vast majority of research in the area of
developmental programming has been focused on
the impacts of maternal stressors, there also is clear
evidence in several species that the environment of
the male during spermatogenesis and/or spermatocyte

Table 1  Large animal models reporting fetal or offspring sex effects published in the last 10 years. This table does not include studies designed
to examine developmental programming effects on reproductive performance specifically targeting male or female reproductive organs nor does
it include studies specifically examining only one offspring sex.

Reference Species Maternal model Sex effect

Adam et al. (2013)
Begum et al. (2013)
Bellingham et al. (2016)
Bernhard et al. (2020)
Cogollos et al. (2017)
Copping et al. (2020)
Davies et al. (2022)
Fisher et al. (2014)
Fisher-Heffernan et al. (2015)
Gionbelli et al. (2017)
Gionbelli et al. (2018)
Hunter et al. (2015)
Jaquiery et al. (2012)
Keever-Keigher et al. (2021)
Lambermont et al. (2012)
Lansford et al. (2021)
Liu et al. (2021)
Lugara et al. (2022)
Martin et al. (2012)
Ovilo et al. (2014)
Peterson et al. (2021)
Rymut et al. (2021)
Sales et al. (2020)
Vonnahme et al. (2013)
Wallace et al. (2020b)
Weller et al. (2016)
Zhao et al. (2022)
Sheep Nutrition (overnutrition) Altered growth and gene expression
Sheep Nutrition (undernutrition) Altered body composition
Sheep Environmental (chemical exposure) Altered neuroendocrine response
Pigs Environment (heat stress) Altered reproductive development
Pigs Nutrition (undernutrition) Altered growth and body composition
Cattle Nutrition (protein restriction) Altered growth and gene expression
Sheep Environmental (exogenous steroid) Altered muscle composition
Sheep Nutrition (supplement) Altered cortisol response
Sheep Nutrition (supplement) Altered immune response
Cattle Nutrition (overnutrition) Altered intestinal development
Cattle Nutrition (overnutrition) Altered muscle development
Sheep Placental restriction Altered growth and composition
Sheep Nutrition (undernutrition) Altered body composition
Pigs Disease challenge Altered gene expression
Sheep Disease challenge Altered lung volume
Cattle Nutrition (supplement) Altered growth
Sheep Nutrition (over-nutrition) Altered cellular signaling
Pigs Nutrition (supplement) Altered growth
Sheep Nutrition (under/overnutrition) Altered growth
Pigs Nutrition (undernutrition) Altered growth and gene expression
Sheep Nutrition (under/overnutrition) Altered gene expression
Pigs Disease challenge Altered blood chemistry parameters
Sheep Nutrition (supplement) Altered behavior
Sheep Nutrition (under/overnutrition) Altered growth and cortisol
Sheep Nutrition (overnutrition) Altered body composition and gene expression
Cattle Nutrition (overnutrition) Altered gene expression
Pigs Environment (heat stress) Altered growth, muscle morphology, and gene expression

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residence in the epididymis can elicit programming
responses in the offspring. For semen, the mechanisms
of programming of offspring are likely a combination
of classic epigenetic mechanisms such as DNA
methylation, histone modification, and various RNA
alterations (Kretschmer & Gapp 2022), oxidative stress
inducing DNA damage (Billah et  al. 2022), and/or the
microbiome of the semen (Luecke et al. 2022). A portion
of the cargo carried with semen as it enters the female
reproductive tract originated within the developing
sperm, a portion is contributed during residence in the
epididymis (e.g. epididymosomes), and a portion is
contributed from secretions of the accessory sex glands
upon ejaculation. Interestingly, contributions from the
sperm and seminal plasma both result in alterations of
offspring phenotype (Watkins et al. 2018).
For small non-coding RNA, the most likely mode
of action is that signals from the perturbed male
environment are packaged into epididymosomes, then
loaded into sperm during residence in the epididymis,
carried with the sperm to the oocyte at fertilization,
and then either act in the zygotic cytoplasm to regulate
maternally derived RNAs or act in the zygotic nucleus
to influence transcription in the early embryo (Hur et al.
2017). As a proof of concept, isolating and injecting
sncRNAs from males exposed to various stressors into
untreated oocytes elicited behavioral and phenotypic
changes in the resultant offspring similar to those
observed with natural mating (Duffy et al. 2021).
The experimental paradigms that have been reported
include paternal exposure to under- and overnutrition,
high fat or low protein diets, supplementation of
epigenetic modifiers (folic acid, vitamin B12, and
methionine), acute or chronic stress, exercise, and drug/
alcohol/endocrine disruptor exposure, all of which
have demonstrated altered development of the offspring
(Billah et al. 2022). Depending on the specific research
paradigm, perturbations to a sire during spermatogenesis
have resulted in changes in offspring body weight,
muscle mass, adiposity, bone density, metabolic
responses, temperament, and/or reproductive outcomes.
Another important concept is that the effects of
stressors to which a sire (F0 generation) is exposed are
not limited to the first-generation (F1) offspring. In rodent
models (Aiken & Ozanne 2014) and in sheep (Braz et al.
2022), paternal programming has been shown to persist
until at least the F2 generation and in those cases can
therefore be termed transgenerational programming.
In addition to the stressors already mentioned, the age
of the male affects the cargo carried by sperm and has
the potential to cause developmental programming of
the resultant offspring. For example, as bulls increased
in age through the peripubertal period (10–16 months),
the miRNA content (Wu et  al. 2020) and DNA
methylation patterns (Lambert et al. 2018) of their sperm
changed. In fact, changes in the cargo carried by sperm
occur throughout the reproductive life span of a male
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Developmental programming: large animal models F7
(Ashapkin et  al. 2022) and are likely the mechanism
linking advancing age of the father with increased
incidence of health disorders in their children (Phillips
et al. 2019).
An additional and important observation is that
dimorphic sex effects arise in response to challenging
paternal environments, and these effects are already
exhibited by the pre-implantation embryo. In mice,
for example, male blastocysts had more pronounced
transcriptome changes in response to obesity of the
sire than female blastocysts (Hedegger et  al. 2020).
Some of these effects are exhibited by the placenta
(Claycombe-Larson et  al. 2020) and persist even into
later postnatal timepoints.
Sometimes, the sex effects are quite striking and seem
to be working in opposite directions. For example, in
an obesity model in mice, the female offspring gained
less body fat, but male offspring had greater body weight
gains (Dahlhoff et al. 2014). In other instances, however,
it seems the same pathways are affected in an attempt
to achieve homeostasis in response to sire programming.
For example, male offspring from male mice exposed to
a dexamethasone challenge during spermatogenesis had
decreased systemic concentrations of glucose, whereas
female offspring exhibited impaired glucose tolerance
(Gapp et al. 2021). In addition, a model of rodent exercise
revealed increased cognitive ability in male offspring
from exercised fathers, but females responded with
decreased neurodegeneration (Kusuyama et  al. 2020),
which may culminate in a similar end point over time.
Transgenerational paternal inheritance of weaning and
postweaning body weight phenotype in a sheep model
also acted in a sex-specific manner, such that dietary
supplementation of only F0 males with methionine from
weaning to puberty altered not only the methylome of
their sperm but also affected the sperm methylome of
F1 and F2 male offspring (Braz et al. 2022). Moreover,
testicular size of male offspring was reduced in both the
F1 and F2 generations. Interestingly, however, weaning
weight and postweaning weight were reduced only in
the F2 generation females, whereas reduced loin muscle
depth was observed only F2 generation males (Braz
et  al. 2022). Clearly, more work needs to be done to
understand the complex interactions between the sire’s
environment and sex-specific impacts on their offspring.
In addition, a majority of current work in developmental
programming has focused on human epidemiology
and rodent research models. Because of the advantages
mentioned above, however, we believe that more work
is required using large animal models to determine the
extent to which paternal programming is present under
‘normal’ management paradigms.
Conclusion/future directions
Large animal models of developmental programming
fulfill a crucial need for studying the perinatal
Reproduction (2023) 165 F1–F13
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F8 C J Hammer and others
development, as evidenced by the multiple models
available. It is clear that sex effects may occur and
influence outcomes during fetal/neonatal development,
growth, and performance. More studies that
investigate sex-dependent mechanisms and epigenetic
modifications in models of developmental programming
are needed, as is research designed to examine paternal
and transgenerational contributions. Finally, it must
be noted that epigenetic changes do not always imply
negative consequences and that some alterations in fetal
development are potentially positive and may serve an
adaptive benefit (Bateson et al. 2014). The use of large
animal models to identify mechanisms that cause or
contribute to developmental programming (whether
negative or positive) will continue to address critical
questions in both biomedical and agricultural sciences,
with the ultimate goal of improving both neonatal
survival and lifelong productivity and health.
Declaration of interest
The authors have no conflicts of interest to declare.
Funding
Preparation of this review did not receive any specific
grant from any funding agency in the public, commercial, or
not-for-profit sector.
Author contribution statement
All authors contributed to the conception and structure
of the manuscript. CH, JC, CD, and LR wrote the manuscript.
CH, JC, PB, and LR edited the final manuscript.
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Received 4 December 2022
Accepted 23 March 2023
Available online 23 March 2023
Version of Record published 21 April 2023
Reproduction (2023) 165 F1–F13
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