Review of Fetal Programming: Implications to Horse Health

IN-DEPTH: REPRODUCTION

M. Carey Satterﬁeld, PhD; Josie A. Coverdale, PhD; and Guoyao Wu, PhD

Available evidence strongly suggests that the fetal and early neonatal periods of development are sensitive to environmental cues, which have long-lasting consequences to growth, health, and likely performance of the foal. The recent adoption of the horse as a companion animal has been associated with an increased incidence of obesity and a wide array of associated diseases including insulin resistance, Cushing’s disease, equine metabolic syndrome, diabetes mellitus, hyperlipaemia, laminitis, endotoxaemia, osteochondrosis dissecans, and equine motor neuron disease.1 The experiences of the mare during gestation and the foal immediately after birth may affect the foal’s behavior into adulthood. A paucity of information exists regarding this phenomenon in the horse, highlighting a need for extensive future research in this area. Authors’ address: 442 Kleberg MS2461, Department of Animal Science, Texas A&M University, College Station, Texas 77843; e-mail csatterﬁeld@ tamu.edu. © 2010 AAEP.

1. Introduction Famine occurred near the end of World War II, An emerging body of evidence has established a link spanning the winter of 1944–1945, because a food between the fetal environment in utero and subse- embargo and destruction of communications stopped quent adult health and disease. The foundation of the supply of food to areas of the Netherlands under this concept, sometimes referred to as the “Barker German occupation. It ended abruptly with the Hypothesis,” is rooted in two studies conducted by end of the war. The relatively short, defined period Dr. David Barker. The first study, conducted in of famine coupled with impeccable birth and medical Britain and Wales, established a link between low records provided a large and unique population to birth weight and development of coronary heart dis- study. These studies suggested that not only re- ease in adulthood.2,3 Indeed, the relative risk of duced growth rate and stature in adulthood but also death because of coronary heart disease is 50% adult obesity, diabetes, hypertension, and schizo- greater when birth weight of the individual was less phrenia were linked to reduced nutrient availability than 5.5 lbs compared with a birth weight of over 8.5 in utero.4 Importantly, the time of exposure during lbs.3 Poor maternal nutrition is a major contribu- gestation plays a central role in determining disease tor to low birth weight; armed with this knowledge, type and susceptibility (Table 1). As an example, Dr. Barker studied people born immediately before 2-h glucose concentrations (a predictor of insulin or during the Dutch famine of World War II to test resistance) are elevated in adulthoods exposed to his hypothesis that a poor fetal environment results famine during the second and third trimesters of in susceptibility to disease later in life. The Dutch development but not the first trimester.5 In con-

NOTES

AAEP PROCEEDINGS ր Vol. 56 ր 2010 207 IN-DEPTH: REPRODUCTION

Table 1. Birth and Adult Characteristics According to Timing of Exposure to Famine

Exposure to Famine

Born In Late In Mid- In Early Conceived Before Gestation Gestation Gestation After n

Birth weight (g) 3,372 3,137* 3,236* 3,481 3,425 912 Adult characteristics BMI (kg/m2) 26.6 26.7 26.4 27.9 27.2 736 LDL/HDL cholesterol 2.9 2.8 2.7 3.3* 2.9 704 2-h plasma glucose concentrations (mmol/l) 5.7 6.3* 6.1* 6.1 5.9 702 Doctors diagnosis of airways disease 15.5 15.0 24.8* 23.0* 17.3 912

BMI, body mass index; LDL, low density lipoprotein; HDL, high density lipoprotein. Adapted from Roseboom TJ, Van Der Meulen JH, Ravelli AC, et al. Perceived health of adults after prenatal exposure to the Dutch famine. Paediatr Perinat Epidemiol 2003;17:391–397. *p Ͻ 0.05.

trast, the development of airway disease in adult- availability will be scarce later in life and develop an hood is more prevalent in people exposed to famine extremely efficient metabolism. If, in fact, the nu- during the first and second trimesters of develop- trient availability is high later in life, this metabolic ment but not the third trimester. efficiency would result in the deposition of fat. In- “Barker’s Hypothesis” has been experimentally deed, some horses are described as “easy-keepers”—a tested in a number of species, including non-human “condition” that may result from the metabolic pro- primates, rats, mice, cattle, and sheep, with many gramming of the fetus in utero. similarities shown between these species and hu- When environmental cues during prenatal life in- mans. It has been found that not only maternal correctly predict the postnatal environment, the off- undernutrition but also overnutrition during preg- spring is inappropriately programmed to the nancy can adversely affect the offspring’s health as environment, leading to an increased prevalence of an adult. Interestingly, the civilization of the horse disease later in life. This disparity between pre- has been associated with the increased incidence of dicted (programmed) and actual environment cre- obesity and a wide array of associated diseases in- ates a mismatch that has been observed in the wild, cluding insulin resistance, Cushing’s disease, equine in society, and under experimental conditions. For metabolic syndrome, diabetes mellitus, hyperlipaemia, example, vascular cholesterol buildup in pigs receiv- laminitis, endotoxaemia, osteochondrosis dissecans, ing a diet high in saturated and trans fatty acids is and equine motor neuron disease.1 prevented when their mothers were fed the same Although experimental evidence regarding the diet during gestation.6 In sheep, a mismatched developmental origins of disease in the horse are prenatal and postnatal diet leads to cardiovascular lacking, given the observed incidence of metabolic dysfunction and altered renal function as adults.7 disorders in equine veterinary practice, it is likely that similar mechanisms of fetal programming exist 3. Maternal Undernutrition in the horse. These mechanisms necessitate fur- In livestock production, drought during gestation is ther study. This review will aim to provide a broad the most common cause of a mismatched prenatal understanding of fetal programming as it is affected and postnatal environment. Thus, the preponder- by the fetal and neonatal environment—not only ance of available literature regarding maternal nu- nutrition but also early postnatal care. Evidence tritional status and its effects on fetal programming provided from other species may serve to guide fu- is derived from studies of maternal undernutrition. ture experimental work in the horse. From a livestock perspective, insufficient nutrient supply is common across all species because of poor 2. Fetal Programming forage quality and/or availability, excessive temper- Fetal programming can be summarized as the pro- atures resulting in heat stress that deprives the fetus cess whereby the fetus adapts to its uterine envi- of nutrients, poor management practices, and even ronment. This adaptation occurs in response to twinning in typically monotocous species. nutrition and other environmental stimuli. Impor- In both clinical and agricultural settings, birth tantly, an identical stimulus can have a vastly dif- weight is the predominant indicator of prior nutrient ferent effect depending on the stage of fetal availability in utero. However, to complicate mat- development (i.e., first versus third trimester) dur- ters, in the horse, experimentally induced maternal ing which it occurs. The adaptive process is rooted undernutrition, as well as undernutrition induced in evolution and likely intended to provide an ad- by maternal illness, showed no influence on birth vantage to the fetus after birth. For example, a weight.8,9 There are questions regarding the level poorly nourished fetus would predict that nutrient of undernutrition and weight loss in these studies.

208 2010 ր Vol. 56 ր AAEP PROCEEDINGS IN-DEPTH: REPRODUCTION More nutritionally defined studies are needed in the result in reduced growth performance, including horse. Nonetheless, subsequent observations that both whole-body and skeletal muscle-growth rates low birth weight is correlated with adult onset dis- and reduced nutrient use. Given the combined ef- eases such as cardiovascular disease and metabolic fects of impaired vascular function and suboptimal syndrome highlight the importance of this simple skeletal muscle and whole-body growth, it has been measure on predicting and potentially managing po- hypothesized that the athletic performance of horses tential health risks. For example, children born with may be highly susceptible to fetal programming.23 low birth weight had elevated levels of glucose and insulin in response to glucose challenge at 4 yr of 4. Maternal Overnutrition age.10 Thus, although foals born to mares with nu- Among livestock species, obesity is most often en- tritional deficiencies or excesses may seem normal at countered in horses as views shift from one of a birth, studies are needed to monitor them for prob- primarily livestock species to one of recreation and lems, especially metabolic problems, later in life. companionship. The civilization of the horse in the Experimental evidence in a variety of species and mod- Western culture has followed a similar trend to that els has provided a wealth of knowledge regarding the of humans and has increased the incidence of obe- mechanisms by which reduced nutrient availability sity and its associated metabolic disorders in both in utero gives rise to adult disease. In rats, maternal species.24,25 There is little experimental evidence protein restriction induces hypertension and vascular to predict the long-term consequences of maternal dysfunction in adult female offspring.11 Interestingly, obesity in the horse. However, maternal obesity these effects were maintained in the F2 generation.12 has been linked to obesity and metabolic perturba- In parallel, women born to mothers exposed to the tions in the offspring of a number of species. In Dutch Famine grew up to give birth to infants that non-human primates, a maternal high-fat diet has were smaller than babies born to women not exposed been shown to alter the fetal hepatic metabolome to the famine in utero. These observations highlight and promote the development of non-alcoholic fatty the heritable aspect of these developmental adapta- liver.26–28 tions. These adaptations do not alter the DNA se- In rats, feeding a high-fat diet during pregnancy quence (are not genetic alterations) but instead, alter or during suckling induces cardiovascular dysfunc- the way that the DNA is used, and thus, they are tion characterized by elevated systolic blood pressure termed “epigenetic” alterations. Although many epi- and impaired endothelium-dependent relaxation.29 genetic alterations are reset when sperm and eggs are Importantly, response to maternal dietary treatment produced, these data show that some may be passed on differed between male and female offspring, with to the next generation. From a selection/performance female offspring being more susceptible to elevated standpoint, the heritability of these factors compli- systolic and diastolic blood pressure in response to cates investigation into the effects of environment ver- high-fat diet during gestation and/or lactation. sus genetics and likely contributes to some observed Feeding the high-fat maternal diet altered renal phenotypic differences between siblings from the same function but not weight of the kidney or glomerular genetic background. number.30 Notably, in application to the horse, in Studies in a number of species have shown that addition to altered cardiovascular function, a ma- maternal undernutrition during pregnancy alters ternal high-fat diet during pregnancy also resulted the pattern of fetal organ development, resulting in impaired glucose homeostasis in offspring, char- in impaired organ function later in life. In sheep, acterized by elevated plasma insulin levels at 1 yr maternal undernutrition induces left ventricular hy- of age.31 Similar observations have been made in pertrophy and alters gene expression in the fetal offspring of pregnant mice fed a high-fat diet, in- left ventricle.13,14 These cardiac perturbations re- cluding increased adiposity, hypertension, and insu- main at 1 yr of age and are associated with deposi- lin resistance.32,33 tion of lipid in the heart and whole-body obesity.15 In sheep, maternal overnutrition has an array Maternal nutrient restriction in sheep has also been of consequences on fetal organ development. Ma- shown to impair renal function.16,17 Clinically, per- ternal overnutrition results in an increase in fetal turbation of the cardiac and renal systems would weight at mid-gestation, with a number of fetal or- likely result in the development of hypertension and gan and tissue weights increased proportionally susceptibility to heart failure. with the increase in overall weight.34 However, at The consequences of intrauterine growth re- term, birth weights of lambs from overnourished striction (IUGR), defined as impaired growth and dams are not different compared with normally fed development of the fetus or its organs, have been ewes.35,36 These findings suggest that although investigated in a number of livestock species18 and maternal obesity does not affect birth weight, the go well beyond animal health to factors that could pattern of development is altered by maternal over- potentially affect performance. In both pigs and nutrition. To this end and again, directly rele- sheep, IUGR results in decreased skeletal muscle- vant to the horse, subsequent studies have indicated fiber number, increased deposition of adipose tissue, that maternal obesity down-regulates genes in- and increased connective-tissue content.19–22 Col- volved in the development of skeletal muscle and liver lectively, these alterations in normal development metabolic function in the fetus.37,38 Importantly,

AAEP PROCEEDINGS ր Vol. 56 ր 2010 209 IN-DEPTH: REPRODUCTION these changes in gene and protein expression in re- lighter than a Thoroughbred foal born to a Thor- sponse to maternal overnutrition result in increased oughbred mare. The genetic contribution was evi- fetal and/or neonatal adiposity.34,39,a Therefore, al- dent also in that the birth weights of foals from the though birth weight in the overnourished offspring between-breed transfers were intermediate to those does not change, the body composition is signifi- of either within-breed transfer offspring. Thor- cantly altered to more fat and less muscle, likely oughbred foals born to pony mares grew at a faster having considerable impacts on growth and perfor- rate than Thoroughbred foals born to Thoroughbred mance. We have found that maternal overnutrition mares, whereas the opposite was true in foals born results in impaired glucose uptake and diminished to pony mares.45 At 36 mo, Thoroughbred foals growth rate to postnatal day 210 compared with carried in ponies had significantly smaller canon controls growing in an identical nutritional environ- bone circumference, elbow-to-knee length, and knee- ment from birth.b to-fetlock length than did control Thoroughbred Although little information is available in the foals, whereas in ponies carried in Thoroughbreds, horse, the data available support similar effects of these values, as well as body weight at 36 mo, were maternal overnutrition in this species. Feeding all significantly greater than those in control ponies. mares a high-starch diet during late gestation pro- Evaluation of cardiovascular and metabolic func- duced a trend to reduced insulin sensitivity of foals tion in early postnatal life indicates that providing a from postnatal day 5 to postnatal day 160.40 Ma- luxurious uterine environment (pony embryo in a ternal overnutrition during late gestation also reduced Thoroughbred mare) results in an increased basal colostrum immunoglobulin G (IgG) content, whereas arterial blood pressure and baroreflex threshold, de- levels of protein and fat in colostrum were un- creased baroreflex sensitivity, and altered response changed.41 The long-term consequences of these ob- to stress46 as well as elevated basal insulin and servations require further study. Additionally, given insulin secretion in response to glucose infusion.47 that the preponderance of evidence regarding obesity In contrast, Thoroughbred foals gestated in pony in non-livestock species involves the feeding of high mares exhibited normal basal arterial pressure and levels of fat, which are fed at low to moderate levels in baroreflex threshold but exhibited enhanced baro- the horse, studies are needed to determine the effects reflex sensitivity and increased production of cate- of high-caloric diets consisting of high levels of starch cholamines in response to acute stress. These data on the consequences of maternal obesity to the devel- support the conclusion that intrauterine environ- oping equine offspring. ment may alter cardiovascular function and postnatal insulin secretion as well. Further studies are 5. Uterine Capacity needed to determine if these physiologic changes The uterine versus fetal (i.e., genetic) contribution to continue into adulthood. fetal growth has been of interest in a number of species, including the horse. Indeed, ovum dona- 6. Mechanisms of Fetal Programming tion and embryo-transfer studies in humans indi- How is a permanent alteration in the function of a cate that birth weight is highly correlated with metabolic system induced during fetal life? The weight of the recipient but not the weight of the genetic code established by the DNA sequence es- ovum donor, indicating that the uterine environ- sentially does not change after fertilization. It has ment in which the embryo develops is more impor- long been questioned how the known miniscule rate tant than the genetic contribution to birth weight.42 of change to the genetic code could account for the Similarly, the mare is famous for her ability to con- array of phenotypic variation among genetically trol the size of the foal that she carries, first shown similar individuals. Indeed, this question led to a by crossing Shetland ponies with shire stallions and search for mechanisms of differential regulation of vice versa.43 gene function within animals of a given genetic Over the past decade, a series of studies conducted makeup. This investigation resulted in the now by Dr. Twink Allen’s group in Cambridge has used widely accepted observation that changes in gene embryo transfer to determine some effects of the expression can be modified without any change in uterine environment on fetal and postnatal growth the DNA sequence.48 These changes in expression and development in the horse. This group per- (i.e., whether a gene is being used (transcribed) and formed within-breed embryo transfer in either Thor- how often and under what circumstances) can be oughbred or pony mares as well as the reciprocal heritable—either mitotically (i.e., to the daughter crosses—transfer of a Thoroughbred embryo to a cells after mitotic cell division) or more rarely, mei- pony mare and its reciprocal. Data from these otically (i.e., to the next generation through the eggs studies clearly indicate that the maternal uterine and sperm). The study of this phenomenon has environment plays a role in regulating not only fetal been termed “epigenetics,” derived from the Greek but also postnatal development. Transfer of a pony prefix epi that means over or above. embryo into a Thoroughbred mare resulted in a At present, three mechanisms have been identi- greater than 50% increase in birth weight compared fied that serve to regulate gene expression: DNA with a pony foal born to a pony mare.44 Reciprocally, methylation, modifications of the histones (the a Thoroughbred foal born to a pony mare was 37% proteins around which the DNA is wrapped), and

210 2010 ր Vol. 56 ր AAEP PROCEEDINGS IN-DEPTH: REPRODUCTION RNA-based mechanisms such as non-coding RNA or which may enhance the neonates’ ability to combat inhibitory RNAs.49 These epigenetic modifications cold exposure at birth. Restriction of essential B can alter the magnitude of the expression of that vitamins, folate, and methionine during the peri- particular gene. The addition of a methyl group to conceptual period in sheep resulted in altered DNA the cytosines in a particular DNA sequence results methylation, insulin resistance, and elevated blood in suppression of gene expression (the transcription pressure, observed most notably in adult male off- machinery fails to bind to it) and thus, causes sup- spring.55 Given the myriad of functions that amino pressed function of that gene.49 Conversely, removal acids play in physiology, it is not surprising that a of methyl groups will increase the activity of a gene. group of amino acids plays a critical role in mainte- These methylation events occur at discrete locations nance and regulation of epigenetic status. Specifi- within genes, and some genes are more susceptible cally, methylation of DNA requires donation of a than others to this process. For example, the glu- methyl group derived from S-adenosylmethionine.18 cocorticoid receptor gene is a methylation-sensitive S-adenosylmethionine is synthesized from the amino gene. Is there a specific example of the impact of acid methionine. In addition to its role as a methyl this? donor, methionine is also required for the synthe- Histone modifications cause these proteins to sis of other amino acids and non-protein products. either tighten or loosen their hold on the DNA Synthesis and metabolism of the amino acids are wrapped around them, thus making genes more or interdependent; thus, it is not surprising that over- less available for transcription.50 all amino acid and micronutrient availability may Non-coding RNAs can bind to DNA and RNA hav- alter the epigenetic code through changes in DNA ing the complementary nucleotide sequence. They methylation as well as by histone modifications.56 have been recently found to regulate both transcrip- Although extremely complex, these data highlight tion of genes, by binding to areas on the DNA, and the delicate nutritional balance regulating devel- the function of mRNAs already transcribed from the opment. The bounty of supplements that are cur- genes, either inhibiting protein production from the rently available for equine use is overwhelming. It mRNA or actually causing destruction of the mRNA. is imperative that we use caution when giving nutri- This is an active area of research. tional supplements to pregnant mares, because using Environmental cues, such as nutrient availability, an inappropriate type, dose, or combination may have stress, or environmental pollutants and toxins, seem permanent consequences on the developing fetus. to be primary triggers to induce changes in the epigenome (the epigenetic pattern regulating DNA 8. Behavioral Programming function).51 The extent to which cells are able to In addition to programming various aspects of respond to these cues lies in large part with the health and disease, the prenatal and early postnatal plasticity of the cells in question. Thus, the devel- environment can also give rise to behavioral pro- oping embryo and fetus are prime targets for epi- gramming. Among livestock species, the benefits genetic modifications. Studies are now directly or consequences of behavioral programming are investigating the epigenetic effects of intrauterine most important in the horse, given the variable re- environment; for example, in primates, a 30% requirements for companion qualities, willingness, duction in maternal nutrient intake caused alter- trainability, and desire to compete. ation of methylation status in the kidney both The majority of scientific evidence related to be- halfway through and at the end of gestation.52 havioral programming comes from research in ro- These data suggest that even a relatively mild nu- dent and primate models. In rats, maternal licking trient restriction can induce epigenetic alterations and grooming (LG) of pups at birth is a measure of and may alter organ function. mothering ability. It seems to be heritable (i.e., pups of a high LG mother will be high LG when they 7. Amino Acid Nutrition and Epigenetics give birth). However, cross-fostering of offspring to Of the domestic livestock species, the horse has the mothers exhibiting different levels of LG shows that most varied nutritional management. An encom- this trait is regulated by the pups’ experience, not by passing standard of nutritional requirements or its genetic makeup. Thus, LG is regulated at the recommendations, based on scientific research, is epigenetic rather than genomic level.57 In addi- lacking. Specifically, the importance of certain nu- tion, pups of high LG mothers also show reduced trients such as amino acids and other micronutri- fear and lower stress responses as adults. Mater- ents has not been established.53 The importance of nal stress can also alter the pattern of LG, which amino acids in supporting fetal growth and develop- will then be conveyed to the offspring. ment is an emerging field in many livestock species How can an experience in the first 7 days after and will undoubtedly shape the future of nutritional birth affect stress responses in the adult? Further management in the horse. In pigs, arginine sup- studies showed that high LG caused reduced meth- plementation to pregnant sows increases litter size ylation of the gene encoding the glucocorticoid recep- by two piglets.54 In sheep, maternal arginine ad- tor in the hippocampus.58 Thus, pups of high LG ministration during late gestation increased fetal mothers have higher numbers of glucocorticoid re- peri-renal brown adipose-tissue development,a ceptors in this area, resulting in enhanced glucocor-

AAEP PROCEEDINGS ր Vol. 56 ր 2010 211 IN-DEPTH: REPRODUCTION ticoid feedback sensitivity; thus, there is a decreased receptivity test compared with 50% of offspring from release of adrenocorticotropic hormone (ACTH) and high LG mothers. These data highlight an evolu- therefore, a damped stress response. This is not tionary strategy for propagation of the species, one the only change associated with high LG—studies in which quantity of offspring produced is empha- have shown that there are epigenetic changes in sized with a reduced postnatal investment (versus over 100 genes associated with this experience. one in which maternal energy is invested in rearing These findings on LG behavior in the rat may for and ensuring maximal survival of fewer off- have direct and important relevance to the horse. spring). It is tempting to speculate how these find- The capacity for horses to deal with stress, respond ings could have application both to humans and correctly to humans and training situations, and horses. Is increased sexual activity in female off- tolerate new environments is extremely important spring the direct effect of poor mothering? Perhaps to their function. It is well-known that orphan increased mothering could serve as a preventative foals, brought up without normal mothering from a treatment for later heat-related behavior that inter- mare, can be difficult to train as adults and even feres with a filly’s performance. dangerous to humans. It is likely that differences All of these maternal-related factors apply to an in foaling environment, birthing stress, level of hu- increasingly common procedure in the horse (i.e., man contact, and perinatal morbidity all play a role embryo transfer). By transferring an embryo into in establishing the permanent behavioral response a recipient mare, that embryo is going to have epi- of the foal in adulthood. genetic alterations in response to its environment, This lends new insight into the practice of “im- both in utero and neonatally, that are different from printing” of foals, as described by Dr. Robert Miller those it would have experienced if left to gestate in and others. It has been shown that tactile condi- the donor mare. How do these changes affect both tioning of foals at birth and at 24 h reduced resis- behavior and physiology? Very little work has been tance to touching of the legs and picking up the hind done in this area. feet at 3 mo of age compared with unconditioned Given the current evidence available in other spe- controls.59 However, as shown with orphan foals, cies that experience in utero and immediately after we probably do not yet know the neonatal environ- birth can permanently alter not only behavior but ment that best promotes what humans would con- metabolism and the clear ability for experience to sider the most successful equine adult behavior. alter the human/foal relationship, we must begin to A recent study by Henry et al.60 found that early consider that these interactions may have benefits exposure to a motionless human improved the foals’ and/or consequences not only with the present indi- reaction to humans, whereas forced stroking and vidual but also its future offspring. handling did not improve later human/foal relations. Interference with development of the fetal/maternal bond by assisting with the first suckling caused foals References and Footnotes to avoid human approach and physical contact at 2 1. Firshman AM, Valberg SJ. Factors affecting clinical assess- 60 ment of insulin sensitivity in horses. Equine Vet J 2007;39: and 4 wk of age, respectively. 567–575. The role of maternal experience (stress during 2. Barker DJ, Osmond C. Infant mortality, childhood nutrition, pregnancy) in fetal programming of adult health and and ischaemic heart disease in England and Wales. Lancet disease has also been investigated. Interestingly, 1986;1:1077–1081. 3. Barker DJ. The origins of the developmental origins theory. young adults of normal birth weight but whose J Intern Med 2007;261:412–417. mothers had experienced psychosocial stress during 4. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) dia- gestation showed an increase in the incidence of betes mellitus: the thrifty phenotype hypothesis. Diabeto- primary insulin resistance and a lipid profile indic- logia 1992;35:595–601. ative of metabolic syndrome.61 In addition, these 5. Roseboom TJ, Van Der Meulen JH, Ravelli AC, et al. Per- ceived health of adults after prenatal exposure to the Dutch individuals exhibited altered immune and endocrine famine. Paediatr Perinat Epidemiol 2003;17:391–397. function as well as compromised cognitive func- 6. Norman JF, LeVeen RF. Maternal atherogenic diet in swine tion.62–64 These findings again have direct appli- is protective against early atherosclerosis development in cation to the horse. For example, does trailering a offspring consuming an atherogenic diet post-natally. Ath- erosclerosis 2001;157:41–47. pregnant mare for hours to the breeding farm or 7. Cleal JK, Poore KR, Boullin JP, et al. Mismatched pre- and foaling shed have permanent effects on the health of postnatal nutrition leads to cardiovascular dysfunction and the foal in utero? Are there effects of maternal altered renal function in adulthood. Proc Natl Acad Sci stress during pregnancy that will not be seen until USA 2007;104:9529–9533. this foal is an adult? The possibility exists, and 8. Wilsher S, Allen WR. Effects of a Streptococcus equi infec- tion-mediated nutritional insult during mid-gestation in pri- much further study in this area is needed. miparous Thoroughbred fillies. Part 1: placental and fetal An interesting aspect of LG behavior in the rat is development. Equine Vet J 2006;38:549–557. that female offspring of mothers with low levels of 9. Ousey JC, Fowden AL, Wilsher S, et al. The effects of ma- LG exhibited increased rates of sexual receptivity ternal health and body condition on the endocrine responses compared with female offspring from high LG moth- of neonatal foals. Equine Vet J 2008;40:673–679. 57 10. Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine ers. Furthermore, 80% of female offspring from programming and consequential risks in the offspring. Rev low LG mothers became pregnant under a controlled Endocr Metab Disord 2008;9:203–211.

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11. Sathishkumar K, Elkins R, Yallampalli U, et al. Protein 32. Samuelsson AM, Matthews PA, Argenton M, et al. Diet- restriction during pregnancy induces hypertension and im- induced obesity in female mice leads to offspring hyperpha- pairs endothelium-dependent vascular function in adult fe- gia, adiposity, hypertension, and insulin resistance: a novel male offspring. J Vasc Res 2009;46:229–239. murine model of developmental programming. Hyperten- 12. Harrison M, Langley-Evans SC. Intergenerational pro- sion 2008;51:383–392. gramming of impaired nephrogenesis and hypertension in 33. Dunn GA, Bale TL. Maternal high-fat diet promotes rats following maternal protein restriction during pregnancy. body length increases and insulin insensitivity in second- Br J Nutr 2009;101:1020–1030. generation mice. Endocrinology 2009;150:4999–5009. 13. Vonnahme KA, Hess BW, Hansen TR, et al. Maternal un- 34. Ford SP, Zhang L, Zhu M, et al. Maternal obesity ac- dernutrition from early- to mid-gestation leads to growth celerates fetal pancreatic beta-cell but not alpha-cell devel- retardation, cardiac ventricular hypertrophy, and increased opment in sheep: prenatal consequences. Am J Physiol liver weight in the fetal sheep. Biol Reprod 2003;69:133– Regul Integr Comp Physiol 2009;297:R835–R843. 140. 35. Zhu MJ, Du M, Nijland MJ, et al. Down-regulation of 14. Han HC, Austin KJ, Nathanielsz PW, et al. Maternal nu- growth signaling pathways linked to a reduced cotyledonary trient restriction alters gene expression in the ovine fetal vascularity in placentomes of over-nourished, obese pregnant heart. J Physiol 2004;558:111–121. ewes. Placenta 2009;30:405–410. 15. Chan LL, Sebert SP, Hyatt MA, et al. Effect of maternal 36. Wallace JM, Milne JS, Aitken RP. The effect of overnour- nutrient restriction from early to midgestation on cardiac ishing singleton-bearing adult ewes on nutrient partitioning function and metabolism after adolescent-onset obesity. Am J to the gravid uterus. Br J Nutr 2005;94:533–539. Physiol Regul Integr Comp Physiol 2009;296:R1455–R1463. 37. Tong JF, Yan X, Zhu MJ, et al. Maternal obesity downregu- 16. Williams PJ, Kurlak LO, Perkins AC, et al. Hypertension lates myogenesis and beta-catenin signaling in fetal skeletal and impaired renal function accompany juvenile obesity: muscle. Am J Physiol Endocrinol Metab 2009;296:E917– the effect of prenatal diet. Kidney Int 2007;72:279–289. E924. 17. Sharkey D, Gardner DS, Symonds ME, et al. Maternal nu- 38. Philp LK, Muhlhausler BS, Janovska A, et al. Maternal trient restriction during early fetal kidney development at- overnutrition suppresses the phosphorylation of 5Ј-AMP- tenuates the renal innate inflammatory response in obese activated protein kinase in liver, but not skeletal muscle, young adult offspring. Am J Physiol Renal Physiol 2009; in the fetal and neonatal sheep. Am J Physiol Regul Integr 297:F1199–F1207. Comp Physiol 2008;295:R1982–R1990. 18. Wu G, Bazer FW, Wallace JM, et al. Board-invited review. 39. Muhlhausler BS, Duffield JA, McMillen IC. Increased ma- Intrauterine growth retardation: implications for the ani- ternal nutrition increases leptin expression in perirenal and mal sciences. J Anim Sci 2006;84:2316–2337. subcutaneous adipose tissue in the postnatal lamb. Endo- 19. Greenwood PL, Hunt AS, Hermanson JW, et al. Effects of crinology 2007;148:6157–6163. birth weight and postnatal nutrition on neonatal sheep. I. 40. George LA, Staniar WB, Treiber KH, et al. Insulin sensitiv- Body growth and composition, and some aspects of energetic ity and glucose dynamics during pre-weaning foal develop- efficiency. J Anim Sci 1998;76:2354–2367. ment and in response to maternal diet composition. Domest 20. Greenwood PL, Hunt AS, Hermanson JW, et al. Effects of Anim Endocrinol 2009;37:23–29. birth weight and postnatal nutrition on neonatal sheep. II. 41. Thorson JF, Karren BJ, Bauer ML, et al. Effect of selenium Skeletal muscle growth and development. J Anim Sci 2000; supplementation and plane of nutrition on mares and their 78:50–61. foals: foaling data. J Anim Sci 2010;88:982–990. 21. Powell SE, Aberle ED. Effects of birth weight on growth and 42. Brooks AA, Johnson MR, Steer PJ, et al. Birth weight: carcass composition of swine. J Anim Sci 1980;50:860–868. nature or nurture? Early Hum Dev 1995;42:29–35. 22. Bee G. Effect of early gestation feeding, birth weight, and 43. Walton A, Hammond J. The maternal effects on growth and gender of progeny on muscle fiber characteristics of pigs at conformation in Shire horse-Shetland pony crosses. Proc R slaughter. J Anim Sci 2004;82:826–836. Soc Lond B Biol Sci 1938;125:311–335. 23. Rossdale PD, Ousey JC. Fetal programming for athletic 44. Allen WR, Wilsher S, Turnbull C, et al. Influence of mater- performance in the horse: potential effects of IUGR. Equine nal size on placental, fetal and postnatal growth in the horse. Vet Edu 2002;14:98–112. I. Development in utero. Reproduction 2002;123:445–453. 24. Sillence M, Noble G, McGowan C. Fast food and fat fillies: 45. Allen WR, Wilsher S, Tiplady C, et al. The influence of the ills of western civilization. Vet J 2006;172:396–397. maternal size on pre- and postnatal growth in the horse. III. 25. Johnson PJ, Wiedmeyer CE, Messer NT, et al. Medical Postnatal growth. Reproduction 2004;127:67–77. implications of obesity in horses-lessons for human obesity. 46. Giussani DA, Forhead AJ, Gardner DS, et al. Postnatal J Diabetes Sci Technol 2009;3:163–174. cardiovascular function after manipulation of fetal growth by 26. McCurdy CE, Bishop JM, Williams SM, et al. Maternal embryo transfer in the horse. J Physiol 2003;547:67–76. high-fat diet triggers lipotoxicity in the fetal livers of nonhu- 47. Forhead AJ, Ousey JC, Allen WR, et al. Postnatal insulin man primates. J Clin Invest 2009;119:323–335. secretion and sensitivity after manipulation of fetal growth 27. Cox J, Williams S, Grove K, et al. A maternal high-fat diet by embryo transfer in the horse. J Endocrinol 2004;181: is accompanied by alterations in the fetal primate metabo- 459–467. lome. Am J Obstet Gynecol 2009;201:281–289. 48. Wu C, Morris JR. Genes, genetics, and epigenetics: a cor- 28. Aagaard-Tillery KM, Grove K, Bishop J, et al. Developmen- respondence. Science 2001;293:1103–1105. tal origins of disease and determinants of chromatin struc- 49. Matouk CC, Marsden PA. Epigenetic regulation of vascular ture: maternal diet modifies the primate fetal epigenome. endothelial gene expression. Circ Res 2008;102:873–887. J Mol Endocrinol 2008;41:91–102. 50. Thambirajah AA, Li A, Ishibashi T, et al. New develop- 29. Khan IY, Dekou V, Douglas G, et al. A high-fat diet during ments in post-translational modifications and functions of rat pregnancy or suckling induces cardiovascular dysfunction histone H2A variants. Biochem Cell Biol 2009;87:7–17. in adult offspring. Am J Physiol Regul Integr Comp Physiol 51. Godfrey KM, Lillycrop KA, Burdge GC, et al. Epigenetic 2005;288:R127–R133. mechanisms and the mismatch concept of the developmental 30. Armitage JA, Lakasing L, Taylor PD, et al. Developmental origins of health and disease. Pediatr Res 2007;61:5R–10R. programming of aortic and renal structure in offspring of rats 52. Unterberger A, Szyf M, Nathanielsz PW, et al. Organ and fed fat-rich diets in pregnancy. J Physiol 2005;565:171–184. gestational age effects of maternal nutrient restriction on 31. Taylor PD, McConnell J, Khan IY, et al. Impaired glucose global methylation in fetal baboons. J Med Primatol 2009; homeostasis and mitochondrial abnormalities in offspring of 38:219–227. rats fed a fat-rich diet in pregnancy. Am J Physiol Regul 53. Council NR. Nutrient requirements of horses. National Integr Comp Physiol 2005;288:R134–R139. Academy Press, 2007.

AAEP PROCEEDINGS ր Vol. 56 ր 2010 213 IN-DEPTH: REPRODUCTION

54. Mateo RD, Wu G, Bazer FW, et al. Dietary L-arginine sup- 60. Henry S, Richard-Yris MA, Hausberger M. Influence of var- plementation enhances the reproductive performance of gilts. ious early human-foal interferences on subsequent human- J Nutr 2007;137:652–656. foal relationship. Dev Psychobiol 2006;48:712–718. 55. Sinclair KD, Allegrucci C, Singh R, et al. DNA methyl- 61. Entringer S, Wust S, Kumsta R, et al. Prenatal psychosocial ation, insulin resistance, and blood pressure in offspring stress exposure is associated with insulin resistance in young determined by maternal periconceptional B vitamin and adults. Am J Obstet Gynecol 2008;199:491–497. methionine status. Proc Natl Acad Sci USA 2007;104: 62. Entringer S, Kumsta R, Nelson EL, et al. Influence of pre- 19351–19356. natal psychosocial stress on cytokine production in adult 56. Oommen AM, Griffin JB, Sarath G, et al. Roles for nutri- women. Dev Psychobiol 2008;50:579–587. ents in epigenetic events. J Nutr Biochem 2005;16:74–77. 63. Entringer S, Kumsta R, Hellhammer DH, et al. Prenatal 57. Cameron NM, Shahrokh D, Del Corpo A, et al. Epigenetic exposure to maternal psychosocial stress and HPA axis reg- programming of phenotypic variations in reproductive strat- ulation in young adults. Horm Behav 2009;55:292–298. egies in the rat through maternal care. J Neuroendocrinol 64. Entringer S, Buss C, Kumsta R, et al. Prenatal psychosocial 2008;20:795–801. stress exposure is associated with subsequent working mem- 58. McGowan PO, Meaney MJ, Szyf M. Diet and the epigenetic ory performance in young women. Behav Neurosci 2009; (re)programming of phenotypic differences in behavior. Brain 123:886–893. Res 2008;1237:12–24. 59. Spier SJ, Berger Pusterla J, Villarroel A, et al. Outcome of tactile conditioning of neonates, or “imprint training” on se- aSatterfield MC and Wu G. Personal observation, 2009. lected handling measures in foals. Vet J 2004;168:252–258. bSatterfield MC and Wu G. Personal observations, 2010.

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