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.
Introduction
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 organ systems) that may persist into adulthood (Fowden 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). 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.
Models of developmental programming (large animal and others) often exhibit compromised growth during embryonic, fetal, and(or) neonatal stages of development. As reviewed byCaton 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.
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.
Citation: Reproduction 165, 6; 10.1530/REP-22-0453
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.
Citation: Reproduction 165, 6; 10.1530/REP-22-0453
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.
Citation: Reproduction 165, 6; 10.1530/REP-22-0453
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 (NRC2007a,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 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 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 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.
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) 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 that IUGR, resulting from either maternal under- or 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, 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 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).
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 fromArnott 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).
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) | Sheep | Nutrition (overnutrition) | Altered growth and gene expression |
| Begum et al. (2013) | Sheep | Nutrition (undernutrition) | Altered body composition |
| Bellingham et al. (2016) | Sheep | Environmental (chemical exposure) | Altered neuroendocrine response |
| Bernhard et al. (2020) | Pigs | Environment (heat stress) | Altered reproductive development |
| Cogollos et al. (2017) | Pigs | Nutrition (undernutrition) | Altered growth and body composition |
| Copping et al. (2020) | Cattle | Nutrition (protein restriction) | Altered growth and gene expression |
| Davies et al. (2022) | Sheep | Environmental (exogenous steroid) | Altered muscle composition |
| Fisher et al. (2014) | Sheep | Nutrition (supplement) | Altered cortisol response |
| Fisher-Heffernan et al. (2015) | Sheep | Nutrition (supplement) | Altered immune response |
| Gionbelli et al. (2017) | Cattle | Nutrition (overnutrition) | Altered intestinal development |
| Gionbelli et al. (2018) | Cattle | Nutrition (overnutrition) | Altered muscle development |
| Hunter et al. (2015) | Sheep | Placental restriction | Altered growth and composition |
| Jaquiery et al. (2012) | Sheep | Nutrition (undernutrition) | Altered body composition |
| Keever-Keigher et al. (2021) | Pigs | Disease challenge | Altered gene expression |
| Lambermont et al. (2012) | Sheep | Disease challenge | Altered lung volume |
| Lansford et al. (2021) | Cattle | Nutrition (supplement) | Altered growth |
| Liu et al. (2021) | Sheep | Nutrition (over-nutrition) | Altered cellular signaling |
| Lugara et al. (2022) | Pigs | Nutrition (supplement) | Altered growth |
| Martin et al. (2012) | Sheep | Nutrition (under/overnutrition) | Altered growth |
| Ovilo et al. (2014) | Pigs | Nutrition (undernutrition) | Altered growth and gene expression |
| Peterson et al. (2021) | Sheep | Nutrition (under/overnutrition) | Altered gene expression |
| Rymut et al. (2021) | Pigs | Disease challenge | Altered blood chemistry parameters |
| Sales et al. (2020) | Sheep | Nutrition (supplement) | Altered behavior |
| Vonnahme et al. (2013) | Sheep | Nutrition (under/overnutrition) | Altered growth and cortisol |
| Wallace et al. (2020b) | Sheep | Nutrition (overnutrition) | Altered body composition and gene expression |
| Weller et al. (2016) | Cattle | Nutrition (overnutrition) | Altered gene expression |
| Zhao et al. (2022) | Pigs | Environment (heat stress) | Altered growth, muscle morphology, and gene expression |
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 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 (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 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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