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The conditions animals experience during the early developmental stages of their lives can have critical ongoing effects on their future health, welfare, and proper development. In this paper we draw on evolutionary theory to improve our understanding of the processes of developmental programming, particularly Predictive Adaptive Responses (PAR) that serve to match offspring phenotype with predicted future environmental conditions. When these predictions fail, a mismatch occurs between offspring phenotype and the environment, which can have long-lasting health and welfare effects. Examples include metabolic diseases resulting from maternal nutrition and behavioral changes from maternal stress. An understanding of these processes and their evolutionary origins will help in identifying and providing appropriate developmental conditions to optimize offspring welfare. This serves as an example of the benefits of using evolutionary thinking within veterinary science and we suggest that in the same way that evolutionary medicine has helped our understanding of human health, the implementation of evolutionary veterinary science (EvoVetSci) could be a useful way forward for research in animal health and welfare. [ABSTRACT FROM AUTHOR]

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944–45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health. [ABSTRACT FROM AUTHOR]

The strength of the avian stress response declines with age. A recently published study of European starlings (Sturnus vulgaris) found that a marker of biological age predicted the strength of the stress response even in individuals of the same chronological age. Specifically, birds that had experienced greater developmental telomere attrition (DTA) showed a lower peak corticosterone (CORT) response to an acute stressor, and more rapid recovery of CORT levels towards baseline. Here, we performed a follow-up study using the same capture-handling-restraint stressor in a separate cohort of starlings that had been subjected to a developmental manipulation of food availability and begging effort. We measured the CORT response at two different age points (4 and 18 months). Our data suggest a decline in the strength of the CORT response with chronological age: peak CORT was lower at the second age point, and there was relatively more reduction in CORT between 15 and 30 min. Individual consistency between the two age points was low, but there were modest familial effects on baseline and peak CORT. The manipulation of begging effort affected the stress response (specifically, the reduction in CORT between 15 and 30 min) in an age-dependent manner. However, we did not replicate the associations with DTA observed in the earlier study. We meta-analysed the data from the present and the earlier study combined, and found some support for the conclusions of the earlier paper. [ABSTRACT FROM AUTHOR]

The social world is filled with different types of interactions, and social experience interacts with stress on several different levels. Activation of the neuroendocrine axis that regulates the response to stress can have consequences for innumerable behavioural responses, including social decision-making and aspects of sociality, such as gregariousness and aggression. This is especially true for stress experienced during early life, when physiological systems are developing and highly sensitive to perturbation. Stress at this time can have persistent effects on social behaviours into adulthood. One important question remaining is to what extent these effects are adaptive. This paper initially reviews the current literature investigating the complex relationships between the hypothalamic-pituitary-adrenal (HPA) axis and other neuroendocrine systems and several aspects of social behaviour in vertebrates. In addition, the review explores the evidence surrounding the potential for 'social programming' via differential development and activation of the HPA axis, providing an insight into the potential for positive effects on fitness following early life stress. Finally, the paper provides a framework from which novel investigations could work to fully understand the adaptive significance of early life effects on social behaviours. [ABSTRACT FROM AUTHOR]

It is now widely recognized that children exposed to adverse life events in the first years of life are at increased risk for a variety of neural, behavioral, and psychological sequelae. As we discuss in this paper, adverse events represent a violation of the expectable environment. If such violations occur during a critical period of brain development, the detrimental effects of early adversity are likely to be long lasting. Here we discuss the various ways adversity becomes neurobiologically embedded, and how the timing of such adversity plays an important role in determining outcomes. We conclude our paper by offering recommendations for how to elucidate the neural mechanisms responsible for the behavioral sequelae and how best to model the effects of early adversity. Adversity might best be thought of as a violation of the expectable environment. Adversity can take many forms, including exposure to biological and psychosocial hazards, which often coexist as complex exposures. Many forms of early adversity are not time limited, making it difficult to tease apart the cumulative effects of adversity from the effects of early life adversity. Exposure to various forms of adversity early in life is associated with alterations in brain development, which in turn is associated with psychological, behavioral, and physical health consequences. Exposure to adversity during critical periods of development is more likely to lead to permanent rather than transient effects on the brain. Parallel studies across humans and animal models of early adversity will prove essential to understanding how adversity becomes neurobiologically embedded. [ABSTRACT FROM AUTHOR]

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases. This review summarizes the intrauterine mechanisms, gender differences, and multi-generational genetic effects of offspring's multi-organ developmental toxicity, programming alterations and susceptibility to multiple diseases induced by medication during pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

Context: A maternal high-fat diet is thought to pose a risk to spermatogenesis in the progeny. Aims: We tested whether a maternal high-fat diet would affect Sertoli cell expression of transcription factors (insulin-like growth factor I (IGF-I); glial-cell line-derived neurotrophic factor (GDNF); Ets variant 5 (ETV5)) and cell proliferation and apoptotic proteins, in the testis of adult offspring. Methods: Pregnant rats were fed ad libitum with a standard diet (Control) or a high-fat diet (HFat) throughout pregnancy and lactation. After weaning, male pups were fed the standard diet until postnatal day 160. Males were monitored daily from postnatal day 34 to determine onset of puberty. On postnatal day 160, their testes were processed for morphometry and immunohistochemistry. Key results: The HFat diet increased seminiferous-tubule diameter (P < 0.03), the numbers of Sertoli cells (P < 0.0001) and Ki-67-positive spermatogonia (P < 0.0006), and the areas immunostained for ETV5 (P < 0.0001), caspase-3 (P < 0.001) and Bcl-2 (P < 0.0001). By contrast, the HFat diet reduced the areas immunostained for IGF-I (P < 0.01) and GDNF (P < 0.0001). Conclusions: A maternal high-fat diet alters the balance between spermatogonia proliferation and spermatid apoptosis. Implications: A maternal high-fat diet seems to 'program' adult male fertility. In rats, we tested whether a high-fat diet fed to mothers during pregnancy and lactation would affect Sertoli cell function in their adult offspring. Changes in transcription factors and proteins that control proliferation and apoptosis in germ cells suggest that the high-fat diet alters the balance between cell proliferation and apoptosis, potentially reducing sperm production. Image by Graciela Pedrana, Grame Martin. [ABSTRACT FROM AUTHOR]

A number of experimental and epidemiological investigations have provided evidence that the health status and aging rate may largely depend on the conditions of early development. Several recent studies provided data suggesting that effects of stresses in early development can be inherited transgenerationally, causing changes of various characteristics in subsequent generations. It has been shown that epigenetic factors associated with regulation of genetic expression, including DNA methylation and modifications of histones and microRNAs, can play a key role in transgenerational inheritance. Until now, it has been generally accepted that the complete erasure of epigenetic marks takes place during gametogenesis and early embryogenesis. In recent years, however, several papers obtained data demonstrating that, in certain cases, epigenetic modifications induced during early ontogenesis could not be erased completely and be transmitted to descendants, affecting their phenotype over several generations. This review provides data of epidemiological and experimental studies showing the possibility of transgenerational inheritance of life expectancy and longevity-associated traits in several generations. [ABSTRACT FROM AUTHOR]

The rise in the occurrence of obesity to epidemic proportions has made it a global concern. Great difficulty has been experienced in efforts to control this growing problem with lifestyle interventions. Thus, attention has been directed to understanding the events of one of the most critical periods of development, perinatal life. Early life adversity driven by maternal obesity has been associated with an increased risk of metabolic disease and obesity in the offspring later in life. Although a mechanistic link explaining the relationship between maternal and offspring obesity is still under investigation, the gut microbiota has come forth as a new factor that may play a role modulating metabolic function of both the mother and the offspring. Emerging evidence suggests that the gut microbiota plays a much larger role in mediating the risk of developing non-communicable disease, including obesity and metabolic dysfunction in adulthood. With the observation that the early life colonization of the neonatal and postnatal gut is mediated by the perinatal environment, the number of studies investigating early life gut microbial establishment continues to grow. This paper will review early life gut colonization in experimental animal models, concentrating on the role of the early life environment in offspring gut colonization and the ability of the gut microbiota to dictate risk of disease later in life. [ABSTRACT FROM PUBLISHER]

The developmental program of the embryo displays a plasticity that can result in long-acting effects that extend into postnatal life. In mammals, adult phenotype can be altered by changes in the maternal environment during the preimplantation period. One characteristic of developmental programming during this time is that the change in adult phenotype is often different for female offspring than for male offspring. In this paper, we propose the hypothesis that sexual dimorphism in preimplantation programming is mediated, at least in part, by sex-specific responses of embryos to maternal regulatory molecules whose secretion is dependent on the maternal environment. The strongest evidence for this idea comes from the study of colony-stimulating factor 2 (CSF2). Expression of CSF2 from the oviduct and endometrium is modified by environmental factors of the mother, in particular seminal plasma and obesity. Additionally, CSF2 alters several properties of the preimplantation embryo and has been shown to alleviate negative consequences of culture of mouse embryos on postnatal phenotype in a sex-dependent manner. In cattle, exposure of preimplantation bovine embryos to CSF2 causes sex-specific changes in gene expression, interferon-τ secretion and DNA methylation later in pregnancy (day 15 of gestation). It is likely that several embryokines can alter postnatal phenotype through actions directed towards the preimplantation embryo. Identification of these molecules and elucidation of the mechanisms by which sexually-disparate programming is established will lead to new insights into the control and manipulation of embryonic development. [ABSTRACT FROM AUTHOR]

Despite their unique histories, environments, and lifestyles, historically subjugated populations consistently show poorer health outcomes compared to the general population. The theory of historical trauma, which argues that a collective trauma experienced by one generation can negatively impact the wellbeing of future generations, is a potential framework to understand the adverse health outcomes seen among populations with histories of subjugation. However, the biological pathways through which historical trauma actually impacts health have been unclear. In this paper, we present a cumulative, two pathway model that describes how historical trauma can impact health in contemporary generations. The first pathway suggests that personal exposure to trauma or stressors, which are more common among populations that have experienced historical trauma, can induce epigenetic modifications that can contribute to the development of poor health. The second pathway posits that poor health can occur through intergenerational epigenetic modifications in response to parental and grandparental trauma or stressor exposures. Taken together, these pathways can provide insight into the higher rates of adverse health outcomes among individuals from populations that have historically endured collective trauma. Importantly, the potential reversible nature of epigenetic modifications suggests that these trauma-induced epigenetic effects are not necessarily permanent and that improvements in environmental conditions could reduce the high prevalence of poor health among historically disadvantaged communities. • Presents a conceptual model for understanding health impacts of historical trauma. • Describes how epigenetic modifications can facilitate these effects. • Discusses life course and intergenerational impacts of trauma and stressor exposure. • Recognizes that epigenetic-mediated historical trauma health effects could be ameliorated. [ABSTRACT FROM AUTHOR]

The developmental origins of health and disease (DOHaD) framework has highlighted the importance of the early life period on disease risk in later life with impacts that can span generations. A primary focus to date has been around maternal health and the 'First Thousand Days' as a key developmental window whereby an adverse environment can have lasting impacts on both mother and offspring. More recently, the impact of paternal health has gathered increasing traction as a key window for early life developmental programming. However, to date, adolescents, the next generation of parents, have attracted less attention as a key DOHaD window although many behavioural traits become entrained during adolescence and track into adulthood. This systematic review examined literature focused on identifying adolescent understanding of DOHaD concepts. Consistent across the eligible articles was that overall understanding of DOHaD-related concepts in adolescents was low. Three key themes emerged: 1. Individual-level awareness of DOHaD concepts (cognitive engagement and action of the adolescents themselves); 2. Interpersonal communication and social awareness of DOHaD concepts (cognitive engagement and communication of the DOHaD concepts to family and wider community); and 3. Health literacy and the promotion of adolescence as a key DOHaD life stage. These findings highlight the need to develop strategic approaches to increase DOHaD awareness that are not only appealing to adolescents but can also support sustained changes in health behaviour. Investment in today's adolescents has the potential to act as a NCD 'circuit breaker' and thus will yield significant dividends for future generations. [ABSTRACT FROM AUTHOR]

Advanced age at conception usually refers to human mothers aged 35 years plus and fathers aged 40 years plus. Advanced parental age may be responsible for genetic and/or epigenetic alterations and may affect the health of offspring. Limited epidemiological and experimental studies have addressed the effect of advanced parental age on cardio‐metabolic functions in human and rodent offspring. This mini review aimed to present the knowledge by focusing on adverse and favourable outcomes related to sex‐specific risks and intergenerational inheritance. The outcomes identified by this review were mainly negative, but there were also some positive results. [ABSTRACT FROM AUTHOR]

'Androgenized' rodent models are widely used to explore the pathophysiology underlying human polycystic ovary syndrome (PCOS), including reproductive and metabolic dysfunction. Based on a recent study using a dihydrotestosterone (DHT)-treated murine model, it has been proposed that prenatal androgen excess alone can predispose to transgenerational transmission of PCOS. From RNA sequencing analysis of metaphase II (MII) oocytes of androgenized lineages, the authors speculated that oocyte factors, including up-regulation of cytotoxic granulosa-associated RNA binding protein-like 1 (TiaL1), are sufficient to promote disease transfer across generations. Although this is an intriguing concept, it was not considered in the context of earlier publications in which the transcriptomes of human MII oocytes from PCOS women undergoing IVF were compared with women without PCOS. In one of these papers, a number of differentially expressed genes in PCOS MII oocytes (TIAL1 was not differentially expressed) were found to have putative response elements in their promoters for androgen receptors and peroxisome proliferating receptor gamma, providing a mechanism for how excess androgens and/or metabolic defects associated with PCOS might affect female germ cells. [ABSTRACT FROM AUTHOR]

Abstract While the role of vitamin D in supporting bone homeostasis during growth and maintenance is well substantiated, emerging evidence from ecological and observational studies suggests that a deficiency of vitamin D is associated with some cancers, immune disorders, cardiovascular disease, abnormal glucose metabolism, and neurodegenerative diseases. Biological plausibility for extraskeletal functions originated with the discovery of the vitamin D receptor in many body tissues and knowledge that the conversion of 25-hydroxyvitamin D (25(OH)D) to its active metabolite 1,25(OH) 2 D occurs in many cell types in addition to the kidney. The association of vitamin D status in humans as an etiological factor in developmental programming of bone, in some chronic diseases, and in all-cause mortality, in addition to skeletal morbidity, is supported by some but not all observational studies and randomized controlled trials. These clinical observations have implications for paleopathology, both in terms of specific comorbidities and the potential role of vitamin D in individuals who display no evidence for skeletal disease. This paper outlines recent clinical research on vitamin D metabolism and its novel biological roles, and explores the possible relevance to paleopathological research designs, theoretical models, and interpretations of disease experience. [ABSTRACT FROM AUTHOR]

Context: Leptin and adiponectin play important roles in systemic metabolic homeostasis, beginning in utero. Limited data exist on the levels and trajectories of these 2 hormones at birth and in childhood and their biological and social determinants. Objective: We examined the longitudinal trajectories of leptin and adiponectin from birth to early childhood, along with influential prenatal and infancy factors, and whether the trajectories and risk factors differ by preterm birth status. Methods: We included mother-infant pairs in the Boston Birth Cohort, a predominantly Black, indigenous, and people of color (BIPOC) study population. We measured infant plasma leptin and adiponectin levels at birth and in early childhood. We examined longitudinal trajectories and the associated prenatal maternal and infancy factors. We analyzed 716 infants (158 preterm) who had leptin and adiponectin measured at birth and in early childhood (mean corrected age 2.18 years [interquartile range, 0.4-10.4]). Results: Cord leptin was higher in term infants (40 230 vs 20 481 in preterm, P<0.0001) but childhood leptin did not differ by prematurity (4123 in term vs 4181 in preterm, P=0.92). Adiponectin was higher in term infants at birth (18 416 vs 11 223, P<0.0001) and in childhood (12 108 vs 10532, P=0.04). In stepwise regression, Black race was associated with higher childhood leptin and lower childhood adiponectin. Female sex was associated with higher childhood leptin levels and lower childhood adiponectin levels in multivariable regression models. Conclusion: Our results highlight preterm status, race, and biological sex as predictors of adipokine trajectory throughout childhood. These findings raise the possibility that early life programming of adipokines may contribute to higher metabolic risk in life, especially among Black children born preterm. [ABSTRACT FROM AUTHOR]

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.

Maternal protein restriction is often associated with structural and functional sequelae in offspring, particularly affecting growth and renal-cardiovascular function. However, there is little understanding as to whether hypertension and kidney disease occur because of a primary nephron deficit or whether controlling postnatal growth can result in normal renal-cardiovascular phenotypes. To investigate this, female Sprague-Dawley rats were fed either a low-protein (LP, 8.4% protein) or normal-protein (NP, 19.4% protein) diet prior to mating and until offspring were weaned at postnatal day (PN) 21. Offspring were then fed a non 'growth' (4.6% fat) which ensured that catch-up growth did not occur. Offspring growth was determined by weight and dual energy X-ray absorptiometry. Nephron number was determined at PN21 using the disector-fractionator method. Kidney function was measured at PN180 and PN360 using clearance methods. Blood pressure was measured at PN360 using radio-telemetry. Body weight was similar at PN1, but by PN21 LP offspring were 39% smaller than controls (Pdiet < 0.001). This difference was due to proportional changes in lean muscle, fat, and bone content. LP offspring remained smaller than NP offspring until PN360. In LP offspring, nephron number was 26% less in males and 17% less in females, than NP controls (Pdiet < 0.0004). Kidney function was similar across dietary groups and sexes at PN180 and PN360. Blood pressure was similar in LP and NP offspring at PN360. These findings suggest that remaining on a slow growth trajectory after exposure to a suboptimal intrauterine environment does not lead to the development of kidney dysfunction and hypertension. [ABSTRACT FROM AUTHOR]

Mothers influence the health and disease trajectories of their children, particularly during the critical developmental windows of fetal and neonatal life reflecting the gestational–fetal and lactational–neonatal phases. As children grow and develop, they are exposed to various stimuli and insults, such as metabolites, that shape their physiology and metabolism to impact their health. Non-communicable diseases, such as diabetes, cardiovascular disease, cancer and mental illness, have high global prevalence and are increasing in incidence. Non-communicable diseases often overlap with maternal and child health. The maternal milieu shapes progeny outcomes, and some diseases, such as gestational diabetes and preeclampsia, have gestational origins. Metabolite aberrations occur from diets and physiological changes. Differential metabolite profiles can predict the onset of non-communicable diseases and therefore inform prevention and/or better treatment. In mothers and children, understanding the metabolite influence on health and disease can provide insights for maintaining maternal physiology and sustaining optimal progeny health over the life course. The role and interplay of metabolites on physiological systems and signaling pathways in shaping health and disease present opportunities for biomarker discovery and identifying novel therapeutic agents, particularly in the context of maternal and child health, and non-communicable diseases. [ABSTRACT FROM AUTHOR]

This study investigated the effect of different prenatal nutrition approaches in 126 pregnant Nellore cows on reproductive and nutrigenetic traits of the male offspring during the finishing phase. For that purpose, three nutritional treatments were used in these cows during pregnancy: PP – protein-energy supplementation in the final third, FP – protein-energy supplementation during the entire pregnancy, and NP – (control) only mineral supplementation. The male progeny (63 bulls; 665 ± 28 days of age) were evaluated for scrotal circumference, seminal traits, number of Sertoli cells and testicular area. We performed a genomic association (700 K SNPs) for scrotal circumference at this age. In addition, a functional enrichment was performed in search of significant metabolic pathways (P < 0.05) with inclusion of genes that are expressed in these genomic windows by the MetaCore software. With the exception of major sperm defects (P < 0.1), the other phenotypes showed no difference between prenatal treatments. We found genes and metabolic pathways (P < 0.05) that are associated with genomic windows (genetic variance explained >1%) in different treatments. These molecular findings indicate that there is genotype-environment interaction among the different prenatal treatments and that the FP treatment showed greater major sperm defects compared to the NP treatment. [ABSTRACT FROM AUTHOR]

Individuals born after intrauterine growth restriction (IUGR) are at risk of developing cardiovascular diseases (CVDs). Endothelial dysfunction plays a role in the pathogenesis of CVDs; and endothelial colony-forming cells (ECFCs) have been identified as key factors in endothelial repair. In a rat model of IUGR induced by a maternal low-protein diet, we observed an altered functionality of ECFCs in 6-month-old males, which was associated with arterial hypertension related to oxidative stress and stress-induced premature senescence (SIPS). Resveratrol (R), a polyphenol compound, was found to improve cardiovascular function. In this study, we investigated whether resveratrol could reverse ECFC dysfunctions in the IUGR group. ECFCs were isolated from IUGR and control (CTRL) males and were treated with R (1 μM) or dimethylsulfoxide (DMSO) for 48 h. In the IUGR-ECFCs, R increased proliferation (5′-bromo-2′-deoxyuridine (BrdU) incorporation, p < 0.001) and improved capillary-like outgrowth sprout formation (in Matrigel), nitric oxide (NO) production (fluorescent dye, p < 0.01), and endothelial nitric oxide synthase (eNOS) expression (immunofluorescence, p < 0.001). In addition, R decreased oxidative stress with reduced superoxide anion production (fluorescent dye, p < 0.001); increased Cu/Zn superoxide dismutase expression (Western blot, p < 0.05); and reversed SIPS with decreased beta-galactosidase activity (p < 0.001), and decreased p16ink4a (p < 0.05) and increased Sirtuin-1 (p < 0.05) expressions (Western blot). No effects of R were observed in the CTRL-ECFCs. These results suggest that R reverses long-term ECFC dysfunctions related to IUGR. [ABSTRACT FROM AUTHOR]

Developmental programming is the concept that 'stressors' during development (i.e. pregnancy, the perinatal period and infancy) can cause long-term changes in gene expression, leading to altered organ structure and function. Such long-term changes are associated with an increased risk of a host of chronic pathologies, or non-communicable diseases including abnormal growth and body composition, behavioural or cognitive dysfunction, metabolic abnormalities, and cardiovascular, gastro-intestinal, immune, musculoskeletal and reproductive dysfunction. Maternal nutrition during the periconceptual period, pregnancy and postnatally can have profound influences on the developmental program. Animal models, including domestic livestock species, have been important for defining the mechanisms and consequences of developmental programming. One of the important observations is that maternal nutritional status and other maternal stressors (e.g. environmental temperature, high altitude, maternal age and breed, multiple fetuses, etc.) early in pregnancy and even periconceptually can affect not only embryonic/fetal development but also placental development. Indeed, altered placental function may underlie the effects of many maternal stressors on fetal growth and development. We suggest that future directions should focus on the consequences of developmental programming during the offspring's life course and for subsequent generations. Other important future directions include evaluating interventions, such as strategic dietary supplementation, and also determining how we can take advantage of the positive, adaptive aspects of developmental programming. Developmental programming, sometimes called fetal programming, is the concept that insults to the embryo/fetus during development can have long-term consequences throughout the lifetime of the offspring, including a host of chronic health problems. One of the most obvious and well-studied insults is poor maternal nutrition. This review discusses our current understanding of how developmental programming occurs, strategies to minimise its negative consequences (and, perhaps, take advantage of its positive consequences), as well as future directions for research. [ABSTRACT FROM AUTHOR]

The final weeks of gestation represent a critical period for dairy cows that can determine the success of the subsequent lactation. Many physiological changes take place and additional exogenous stressors can alter the success of the transition into lactation. Moreover, this phase is pivotal for the final stage of intrauterine development of the fetus, which can have negative long-lasting postnatal effects. Heat stress is widely recognised as a threat to dairy cattle welfare, health, and productivity. Specifically, late gestation heat stress impairs the dam's productivity by undermining mammary gland remodelling during the dry period and altering metabolic and immune responses in early lactation. Heat stress also affects placental development and function, with relevant consequences on fetal development and programming. In utero heat stressed newborns have reduced birth weight, growth, and compromised passive immune transfer. Moreover, the liver and mammary DNA of in utero heat stressed calves show a clear divergence in the pattern of methylation relative to that of in utero cooled calves. These alterations in gene regulation might result in depressed immune function, as well as altered thermoregulation, hepatic metabolism, and mammary development jeopardising their survival in the herd and productivity. Furthermore, late gestation heat stress appears to exert multigenerational effects, influencing milk yield and survival up to the third generation. As climate change continues at a rapid pace, more livestock will be subjected to heat stress for longer periods and absolute levels. In dairy cattle, heat stress profoundly impacts the subsequent productivity of late gestation cows and programs lower productivity and health in the offspring. This review considers the biological basis for the impact of heat stress on the dam and the daughter, and the epigenetic signals that result in the observed phenotypes. [ABSTRACT FROM AUTHOR]

Fall-calving primiparous crossbred beef females [body weight (BW): 451 ± 28 (SD) kg; body condition score (BCS): 5.4 ± 0.7] were allocated by fetal sex and expected calving date to receive either 100% (control; CON; n = 13) or 70% (nutrient restricted; NR; n = 13) of metabolizable energy and metabolizable protein requirements for maintenance, pregnancy, and growth from day 160 of gestation to calving. Heifers were individually-fed chopped poor quality hay and supplemented to meet targeted nutritional planes based on estimated hay intakes. Dam BW, BCS, backfat, and metabolic status were determined pre-treatment, every 21 d (BW and metabolic status) or 42 d (BCS and backfat) during gestation, and post-calving. At birth, calf BW and size were measured, and total colostrum from the most full rear quarter was collected pre-suckling. Data were analyzed with nutritional plane, treatment initiation date, and calf sex (when P < 0.25) as fixed effects. Gestational metabolites included day and nutritional plane × day as repeated measures. During late gestation, CON dams gained (P < 0.01) maternal (non-gravid) BW and maintained (P ≥ 0.17) BCS and backfat, while NR dams lost (P < 0.01) maternal BW, BCS, and backfat. Circulating glucose, urea N, and triglycerides were less (P ≤ 0.05) in NR dams than CON at most late gestational timepoints after treatment initiation. Circulating non-esterified fatty acids were greater (P < 0.01) in NR dams than CON. Post-calving, NR dams weighed 63.6 kg less (P < 0.01) and were 2.0 BCS less (P < 0.01) than CON. At 1 h post-calving, NR dams had less (P = 0.01) plasma glucose and tended to have less (P = 0.08) plasma triglycerides than CON. Nutrient restriction did not affect (P ≥ 0.27) gestation length, calf birth weight, or calf size at birth. Colostrum yield was 40% less (P = 0.04) in NR dams than CON. Protein and immunoglobulin concentrations were greater (P ≤ 0.04), but free glucose and urea N concentrations were less (P ≤ 0.03), in colostrum of NR dams than CON. Colostrum total lactose, free glucose, and urea N were less (P ≤ 0.03) in NR dams than CON, but total protein, triglycerides, and immunoglobulins were not affected (P ≥ 0.55). In summary, beef heifers experiencing late gestational nutrient restriction prioritized partitioning nutrients to fetal growth and colostrum production over maternal growth. During undernutrition, fetal and colostral nutrient demands were largely compensated for by catabolism of maternal tissue stores. [ABSTRACT FROM AUTHOR]

Feeding rumen-protected choline (RPC) to late gestation dairy cows has potential to affect growth in offspring. The objective of this study was to evaluate the effects of in utero choline exposure on the growth, feed efficiency (FE), metabolism, and carcass quality of Angus × Holstein cattle. Multiparous Holstein cows pregnant with male (N = 17) or female (N = 30) Angus-sired calves were enrolled 21 d prepartum and randomly assigned to one of four dietary treatments varying in quantity and formulation of RPC. The treatments included a control with 0 g/d supplemental RPC (CTL), supplemental RPC fed at the recommended dose (RD) of 15 g/d from either an established RPC product (RPC1RD; ReaShure; Balchem Corp.) or choline ion from a concentrated RPC prototype (RPC2RD; Balchem Corp.), or a high dose (HD) of RPC2 fed at 22 g/d (RPC2HD). From 2 to 6 mo of age, calves were group housed and offered 2.3 kg grain/hd/d (42% CP) with ad libitum grass hay, and stepped up to a complete finishing diet by 7 mo (12.0% CP; 1.34 Mcal/kg NEg). Weight and height were measured monthly. Animal FE was measured in individual pens for 35 d at 8 mo. Feed intake was measured daily, and blood was obtained on day 18 during the FE period. Afterwards, cattle were group housed and offered a free-choice finishing diet until slaughter, where carcass yield and quality characteristics were measured. Mixed models were used in PROC MIXED (SAS, 9.4) with the fixed effects of treatment, sex, time, their interactions, and the random effect of calf. Month was the repeated measure, and preplanned contrasts were used. Blood and FE data were analyzed with the fixed effect of dam choline treatment, calf sex, and the interaction. Increasing dose of RPC tended to increase weight over the entire study period. Feeding any RPC increased hip and wither height compared with CTL, and increasing RPC dose linearly increased hip and wither height. Treatment and sex interacted on DMI whereby increasing RPC intake linearly increased DMI for males but not females. Compared with control, feeding any RPC decreased plasma insulin, glucose, and an insulin sensitivity index (RQUICKI). In utero choline exposure increased kidney–pelvic–heart fat and marbling score. Mechanisms of action for intrauterine choline exposure on offspring growth, metabolism, and carcass characteristics should be explored as they have direct implications for profitability for cattle growers and feeders. [ABSTRACT FROM AUTHOR]

As obesity rates have risen around the world, so to have pregnancies complicated by maternal obesity. Obesity during pregnancy is not only associated with negative health outcomes for the mother and the baby during pregnancy and birth, there is also strong evidence that exposure to maternal obesity causes an increased risk to develop obesity, diabetes and cardiovascular disease later in life. Animal models have demonstrated that increased weight gain in offspring exposed to maternal obesity is usually preceded by increased food intake, implicating altered neuronal control of food intake as a likely area of change. The hypothalamus is the primary site in the brain for maintaining energy homeostasis, which it coordinates by sensing whole body nutrient status and appropriately adjusting parameters including food intake. The development of the hypothalamus is plastic and regulated by metabolic hormones such as leptin, ghrelin and insulin, making it vulnerable to disruption in an obese in utero environment. This review will summarise how the hypothalamus develops, how maternal obesity impacts on structure and function of the hypothalamus in the offspring, and the factors that are altered in an obese in utero environment that may mediate the permanent changes to hypothalamic function in exposed individuals. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a maternal metabolic disorder that perturbs placental development and increases the risk of offspring short- and long-term metabolic disorders. The mechanisms by which GDM impairs placental development remain poorly understood. Here, we defined the DNA methylome of GDM placentas and determined whether GDM perturbs methylation at genes important for placental development. We conducted an epigenome-wide association study of 42 placentas from pregnancies in the South African Soweto First 1000 days cohort (S1000). Using genome-wide bisulfite sequencing, we compared non-GDM placentas to GDM placentas with similar proportions from obese and non-obese mothers. Compared to non-GDM, GDM placentas exhibited a distinct methylation profile consisting of 12,210 differentially methylated CpGs (DMCs) that mapped to 3,875 genes. Epigenetically altered genes were enriched in Wnt and cadherin signalling pathways, both critical in placentation and embryogenesis. We also defined regional DNA methylation perturbation in GDM placentas at 11 placental development genes. These findings reveal extensive changes to the placental epigenome of GDM pregnancies and highlight perturbation enriched at important placental development genes. These molecular changes represent potential mechanisms for GDM-induced placental effects that may serve as candidate biomarkers for placental, maternal, and foetal health. Using a study design that used similar proportions of obese and non-obese mothers in our case and control pregnancies, we minimized the detection of changes due to obesity alone. Further work will be necessary to investigate the extent of the influence of obesity on these GDM-related placental epigenetic changes. [ABSTRACT FROM AUTHOR]