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Introduction Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response. Methods A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as ‘history-only’, and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured. Results Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in the social-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months. Conclusion Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.

The early-life maternal environment has a profound and persistent effect on offspring neuroendocrine function, neurotransmitter systems, and behavior. Studies using rodent models suggest that early-life maternal care can influence the 'developmental programming' of offspring in part through altered epigenetic regulation of specific genes. The exploration of epigenetic regulation of these genes as a biological mechanism has been important to our understanding of how animals adapt to their environments and how these developmental trajectories may be altered. However, other non-maternal factors have been shown to act directly, or to interact with maternal care, to influence later-life phenotype. Based on accumulating evidence, including our research, we discuss other important influences on the developmental programming of offspring. We highlight early-life variations in temperature exposure and offspring genotype x environment interactions as prominent examples. We conclude with recommendations for future investigations on how early-life maternal care and extra-maternal influences lead to persistent changes in the brain and behavior of the offspring throughout development.

Conditions experienced prenatally, by modulating developmental processes, have lifelong effects on individual phenotypes and fitness, ultimately influencing population dynamics. In addition to maternal biochemical cues, prenatal sound is emerging as a potent alternative source of information to direct embryonic development. Recent evidence suggests that prenatal acoustic signals can program individual phenotypes for predicted postnatal environmental conditions, which improves fitness. Across taxonomic groups, embryos have now been shown to have immediate adaptive responses to external sounds and vibrations, and direct developmental effects of sound and noise are increasingly found. Establishing the full developmental, ecological, and evolutionary impact of early soundscapes will reveal how embryos interact with the external world, and potentially transform our understanding of developmental plasticity and adaptation to changing environments.

Environmental exposures including toxins and nutrition may hamper the developing brain in utero, limiting the brain's reserve capacity and increasing the risk for Alzheimer's disease (AD). The purpose of this systematic review is to summarize all currently available evidence for the association between prenatal exposures and AD-related volumetric brain biomarkers. We systematically searched MEDLINE and Embase for studies in humans reporting on associations between prenatal exposure(s) and AD-related volumetric brain biomarkers, including whole brain volume (WBV), hippocampal volume (HV) and/or temporal lobe volume (TLV) measured with structural magnetic resonance imaging (PROSPERO; CRD42020169317). Risk of bias was assessed using the Newcastle Ottawa Scale. We identified 79 eligible studies (search date: August 30th, 2020; Ntotal=24,784; median age 10.7 years) reporting on WBV (N = 38), HV (N = 63) and/or TLV (N = 5) in exposure categories alcohol (N = 30), smoking (N = 7), illicit drugs (N = 14), mental health problems (N = 7), diet (N = 8), disease, treatment and physiology (N = 10), infections (N = 6) and environmental exposures (N = 3). Overall risk of bias was low. Prenatal exposure to alcohol, opioids, cocaine, nutrient shortage, placental dysfunction and maternal anemia was associated with smaller brain volumes. We conclude that the prenatal environment is important in shaping the risk for late-life neurodegenerative disease.

Prenatal auditory sensitivity occurs across taxa, and is increasingly understood as playing a significant role in broad cognitive development. Yet, until recently, the possibility that prenatal sounds may provide information for embryos to finetune their phenotypes to current environments had not been considered. Emerging evidence in birds show that parental vocalisations and sibling embryonic cues can alter individual developmental trajectories post-hatch to cope with particular threats in the environment. Here, I highlight the relevance of such ‘Acoustic Developmental Programming’ for understanding sensitive periods and adaptive plasticity. In particular, I discuss the evidence towards the existence of sensitive periods for programming by sound and the evolutionary advantages of obtaining such prenatal acoustic information.

Humans, similar to many other species, exhibit developmental plasticity — the ability to modify the structure and function of key vital organs during specific developmental windows. Adverse exposures during these critical periods may alter organ function to enhance survival; however, over many years — these alterations may predispose toward chronic disease. The hypothalamic–pituitary–adrenal axis plays an important role in maintaining metabolic homoeostasis and coordinating the neuropsychiatric response to stress. Decades of animal and human research suggests that the long-term function of this axis may be particularly sensitive to adverse exposures during critical developmental windows. The aim of this review is to summarise the existing knowledge of hypothalamic–pituitary–adrenal axis programming in humans and briefly discuss its implications for long-term health.

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.

The concept that a father’s wellbeing at the time of conception influences the development and long-term health of his offspring is now well established. However, the mechanisms underlying the paternal programming of offspring health are not fully defined. While sperm-mediated effects on offspring development have been investigated in detail, the significance of seminal plasma has been over-looked. Typically, the seminal plasma is viewed as a simple medium, with a main role to transport sperm into the female reproductive tract at the time of conception. However, a more sophisticated role for seminal plasma in the modulation of the maternal periconception cell-signalling, inflammatory and immunological physiology is emerging. Seminal plasma comprises a complex mix of nutrients, proteins, signalling molecules and cell-free genetic material which all interact with the endometrium to regulate gene expression, vascular remodelling, leukocyte recruitment and the priming of regulatory T cells (Tregs). These seminal plasma effects on the maternal periconception environment all act to facilitate uterine remodelling, embryo implantation and fetal development. Evidence is now emerging that poor paternal lifestyle factors such as diet, can modify these essential uterine responses, altering fetal development and ultimately long-term offspring health. The use of animal models has enhanced our understanding of the effects of seminal plasma on maternal uterine physiology, embryo development and offspring health. However, further studies are needed to define the interaction between seminal plasma components and female reproductive tissues in humans. Such studies will be central in providing better information and infertility treatments to intending parents.

Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. Once differentiation ensues, DNMT1 preferentially promotes neuronal and inhibits astroglial fate. We hypothesized that the programmed dysfunction of NPC proliferation and differentiation in SGA offspring is epigenetically mediated via DNMT1. Pregnant rats received either ad libitum food (Control) or were 50% food-restricted to create SGA offspring. Primary hypothalamic NPCs from 1 day old SGA and Controls newborns were cultured and transfected with nonspecific or DNMT1-specific siRNA. NPC proliferation and protein expression of specific markers of NPC (nestin), neuroproliferative transcription factor (Hes1), neurons (Tuj1) and astrocytes (GFAP) were determined. Under basal conditions, SGA NPCs exhibited decreased DNMT1 and reduced proliferation and differentiation, as compared to Controls. In both SGA and Controls, DNMT1 siRNA in complete media inhibited NPC proliferation, consistent with reduced expression of nestin and Hes1. In differentiation media, DNMT1 siRNA decreased expression of Tuj1 but increased GFAP. In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring.

Fetal stress induces developmental adaptations that result in intrauterine growth restriction (IUGR) and low birthweight. These adaptations reappropriate nutrients to the most essential tissues, which benefits fetal survival. The same adaptations are detrimental to growth efficiency and carcass value in livestock, however, because muscle is disproportionally targeted. IUGR adipocytes, liver tissues, and pancreatic β-cells also exhibit functional adaptations. Identifying mechanisms underlying adaptive changes is fundamental to improving outcomes and value in low birthweight livestock. The article outlines studies that have begun to identify stress-induced fetal adaptations affecting growth, metabolism, and differential nutrient utilization in IUGR-born animals.

Developmental programming became an area of interest to understand negative environmental impacts on progeny performance. Recently, the concept that we may be able to harness developmental programming to target animals to their niche in the production system has gained recognition. Female fertility is an area where developmental programming has been moderately successful; however, the mechanisms remain unclear. Although some studies have demonstrated differences in gonadal development and attainment of puberty in response to developmental programming, these have not translated to improved fertility. To improve response to developmental programming, it is critical to identify factors that contribute to inconsistencies across studies.

The greatest loss in ruminant production systems occurs during the neonatal period. The maternal environment (nutrition and physiologic status) influences neonatal mortality and morbidity as it reportedly affects (a) Dystocia, both via increasing birth weight and placental dysfunction; (b) Neonatal thermoregulation, both via altering the amount of brown adipose tissue and its ability to function via effects upon the hypothalamic-pituitary-thyroid axis; (c) Modification of the developing immune system and its symbiotic nutrient sources; (d) Modification of maternal and neonatal behavior.

Maternal stressors that affect fetal development result in "developmental programming," which is associated with increased risk of various chronic pathologic conditions in the offspring, including metabolic syndrome; growth abnormalities; and reproductive, immune, behavioral, or cognitive dysfunction that can persist throughout their lifetime and even across subsequent generations. Developmental programming thus can lead to poor health, reduced longevity, and reduced productivity. Current research aims to develop management and therapeutic strategies to optimize fetal growth and development and thereby overcome the negative consequences of developmental programming, leading to improved health, longevity, and productivity of offspring.

Across the field of developmental programming, changes in epigenetic modifications are often cited as the sole explanation for disease phenotype. However, there is now evidence that many of these changes should be viewed as a consequence of transcription and not the main driver of altered gene expression. Using a range of lifestyle and environmental exposures, this review will contrast instances where induced changes in DNA methylation can be inferred to be causal in the alteration of gene transcription, as compared with those that are either symptomatic or not biologically significant. Through this review, we find that most functionally significant changes map to gene enhancers and that low-magnitude changes cannot automatically be inferred to associate with changes in gene expression, especially as it pertains to the regulation of imprinted loci. Providing functional context and distinguishing between symptom and cause is essential for researchers in the field of developmental programming to transition beyond an inferred association and obtain a deeper, mechanistic understanding of the role epigenetic mechanisms have in altering the developmental program.

Cardiovascular diseases (CVD) are a leading cause of mortality worldwide. Despite recognizing the importance of risk factors in dictating CVD susceptibility and onset, patient treatment remains a challenging endeavor. Increasingly, the benefits of prevention and mitigation of risk factors earlier in life are being acknowledged. The developmental origins of health and disease posits that insults during specific periods of development can influence long-term health outcomes; this occurs because the developing organism is highly plastic, and hence vulnerable to environmental perturbations. By extension, targeted therapeutics instituted during critical periods of development may confer long-term protection, and thus reduce the risk of CVD in later life. This review provides a brief overview of models of developmental programming, and then discusses the impact of perinatal therapeutic interventions on long-term cardiovascular function in the offspring. The discussion focuses on bioactive food components, as well as pharmacological agents currently approved for use in pregnancy; in short, those agents most likely to be used in pregnancy and early childhood.

Background: The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, diabetes, and cardiovascular disease. The incidence of metabolic disease is different between males and females. How the early life environment may underlie these sex differences is an area of active investigation. Scope of review: The purpose of this review is to summarize our current understanding of how the early life environment influences metabolic disease risk in a sex specific manner. We also discuss the possible mechanisms responsible for mediating these sexually dimorphic effects and highlight the results of recent intervention studies in animal models. Major conclusions: Exposure to states of both under- and over-nutrition during early life predisposes both sexes to develop metabolic disease. Females seem particularly susceptible to develop increased adiposity and disrupted glucose homeostasis as a result of exposure to in utero undernutrition or high sugar environments, respectively. The male placenta is particularly vulnerable to damage by adverse nutritional states and this may underlie some of the metabolic phenotypes observed in adulthood. More studies investigating both sexes are needed to understand how changes to the early life environment impact differently on the long-term health of male and female individuals. Keywords: Pregnancy, Perinatal, Under nutrition, Obesity, Diabetes, Developmental programming, Sex differences

While nursing, mammals progress through critical developmental periods for the cardiovascular, musculoskeletal, and central nervous systems. The suckling period in mammals is therefore especially vulnerable to environmental factors that may affect the "developmental programming" of many complex traits. As a result, various aspects of maternal behavior and physiology can influence offspring in ways that have lasting effects into adulthood. Several recent studies of animal models have shown that maternal effects can partially program adult activity behaviors, which has important implications for health and locomotor performance. Here, we used cross-fostering to test for possible maternal effects on adult wheel-running behavior (voluntary exercise), maximal aerobic capacity during forced exercise (VO2max), body mass and composition, and organ masses. Subjects were from a line of mice that has been selectively bred for ∼90 generations for high voluntary wheel-running behavior (High Runner; HR) and a non-selected Control (C) line. Adult HR mice run ∼3-fold the daily distances of C mice and have evolved other differences associated with exercise capacity, including elevated VO2max, reduced body mass and fat mass, and larger hearts. At birth, we fostered offspring to create 4 experimental groups: C pups to other C dams (in-foster), HR pups to other HR dams (in-foster), C pups to HR dams (cross-foster), HR pups to C dams (cross-foster). Thus, all pups were fostered to a different mother. Mice were weaned 3 weeks later, and adult testing began at ∼6 weeks of age. At weaning, pups raised by HR dams were smaller than those raised by C dams for both sexes and as expected, HR pups raised by HR dams weighed less than C pups raised by C dams. As adults, mice raised by HR dams continued to have reduced body masses. As expected, adult HR mice ran approximately 3-fold more than their C counterparts and females ran more than males. However, cross-fostering did not statistically affect any aspect of wheel-running behavior (distance, duration, speed). Similarly, with body mass as a covariate, HR mice had higher VO2max than C mice, and males had higher VO2max than females, but cross-fostering had no effect. With body mass as a covariate, cross-fostering had variable effects on adult organ masses in a sex-specific manner. Overall, our results indicate that development of the adult High Runner phenotype does not require rearing by an HR dam, suggesting that high adult activity in humans may be independent of high maternal activity.

Mammalian studies have shown that nutritional constraints during the perinatal period are able to program the progeny (metabolism, performance). The presented research aimed to investigate if broiler breeders and their offspring performance could be influenced by reducing the dietary crude protein (CP) level with 25% level in the feed of breeders. A total of 160 one-day old pure line A breeder females were randomly divided over 2 dietary treatments. The control group was fed commercial diets, whereas the reduced balanced protein (RP) birds received an isoenergetic diet that was decreased with 25% in dietary CP and amino acid during their entire lifespan. The RP birds required an increased feed allowance, varying between 15 and 3%, to meet the same BW goals as their control counterparts. The difference in feed allocations and reduction of the dietary CP level resulted in a net protein reduction varying between 14 and 23%. At 27 and 40 weeks, the body composition of the breeders was changed as a result of the dietary treatment. At both ages the proportional abdominal fat pad weight of the RP breeders was increased (P < 0.001), whereas the proportional breast muscle weight was only higher at 27 weeks in the control group compared to the RP group (P < 0.001). Egg weight (P < 0.001) and egg production (P < 0.001) was decreased for the RP fed birds. The lower dietary CP level reduced the proportional albumen weight of the RP eggs (P = 0.006). Male offspring from RP breeders were characterized by an increase in BW from 28 days until 35 days of age (P= 0.015). Moreover, female progeny of RP breeders showed a reduced FCR (P = 0.025), whereas male progeny showed a tendency (P = 0.052) towards a lower FCR at 5 weeks of age. In conclusion lowering dietary CP levels in rearing and laying phase of breeders had a negative effect on breeder performance but enhanced live performance of the offspring. ispartof: Poultry Science vol:96 issue:96 pages:3949-3959 ispartof: location:England status: published

There is a large consensus that the prenatal environment determines the susceptibility to pathological conditions later in life. The hypothesis most widely accepted is that exposure to insults inducing adverse conditions in-utero may have negative effects on the development of target organs, disrupting homeostasis and increasing the risk of diseases at adulthood. Several models have been proposed to investigate the fetal origins of adult diseases, but although these approaches hold true for almost all diseases, particular attention has been focused on disorders related to the central nervous system, since the brain is particularly sensitive to alterations of the microenvironment during early development. Neurobiological disorders can be broadly divided into developmental, neurodegenerative and neuropsychiatric disorders. Even though most of these diseases share genetic risk factors, the onset of the disorders cannot be explained solely by inheritance. Therefore, current understanding presumes that the interactions of environmental input, may lead to different disorders. Among the insults that can play a direct or indirect role in the development of neurobiological disorders are stress, infections, drug abuse, and environmental contaminants. Our laboratories have been involved in the study of the neurobiological impact of gestational stress on the offspring (Dr. Antonelli´s lab) and on the effect of gestational exposure to toxicants, mainly methyl mercury (MeHg) and perfluorinated compounds (PFCs) (Dr. Ceccatelli´s lab). In this focused review, we will review the specialized literature but we will concentrate mostly on our own work on the long term neurodevelopmental consequences of gestational exposure to stress and neurotoxicants. Fil: Antonelli, Marta Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Pallares, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Ceccatelli, Sandra. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Spulber, Stefan. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia

Summary We report the emergence of an endogenous circadian clock that regulates organogenesis in mouse fetal kidney. We detect circadian rhythms both in vivo with transcriptional profiling and ex vivo by bioluminescence. High-resolution structural analysis of embryonic explants reveals that global or local clock disruption results in defects that resemble human congenital abnormalities of the kidney. The onset of fetal rhythms strongly correlates with the timing of a distinct transition in branching and growth rates during a gestational window of high fetal growth demands. Defects in clock mutants typically have been attributed to accelerated aging; however, our study establishes a role for the fetal circadian clock as a developmental timer that regulates the pathways that control organogenesis, branching rate, and nephron number and thus plays a fundamental role in kidney development.

Clinically, we apply synthetic glucocorticoids to treat fetal and maternal diseases, such as premature labor and autoimmune diseases. Although its clinical efficacy is positive, the fetus will be exposed to exogenous synthetic glucocorticoids. Prenatal adverse environments (such as xenobiotics exposure, malnutrition, infection, hypoxia and stress) can cause fetuses overexposure to excessive endogenous maternal glucocorticoids. The level of glucocorticoids is the key to fetal tissue maturation and postnatal fate. A large number of studies have found that prenatal glucocorticoids exposure can lead to fetal adrenal dysplasia and dysfunction, continuing after birth and even into adulthood. As the core organ of fetal-originated adult diseases, fetal adrenal dysplasia is closely related to the susceptibility and occurrence of multiple chronic diseases, and there are also obvious gender differences. However, its intrauterine programming mechanisms have not been fully elucidated. This review summarizes recent advances in prenatal glucocorticoids exposure and fetal adrenal developmental programming alterations, which is of great significance for explaining adrenal developmental toxicity and the intrauterine origin of fetal-originated adult diseases.

This article is part of a Special Issue "SBN 2014". Obesity in women of child-bearing age is a growing problem in developed and developing countries. Evidence from human studies indicates that maternal BMI correlates with offspring adiposity from an early age and predisposes to metabolic disease in later life. Thus the early life environment is an attractive target for intervention to improve public health. Animal models have been used to investigate the specific physiological outcomes and mechanisms of developmental programming that result from exposure to maternal obesity in utero. From this research, targeted intervention strategies can be designed. In this review we summarise recent progress in this field, with a focus on cardiometabolic disease and central control of appetite and behaviour. We highlight key factors that may mediate programming by maternal obesity, including leptin, insulin, and ghrelin. Finally, we explore potential lifestyle and pharmacological interventions in humans and the current state of evidence from animal models.

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic-pituitary-adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.

Highlights • Aberrant exposures to glucocorticoids during fetal life programme the risk of psychiatric disease in offspring. • Placental 11β-HSD2 protects the fetus from maternal glucocorticoids. • This study investigates the role of 11β-HSD2 in the fetal brain. • Deletion of 11β-HSD2 in the fetal brain causes depressive-like and cognitive dysfunction in adults. • Thus fetal brain 11β-HSD2 protects against programming of adult brain function., Summary Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions.

It is now well established that the environment to which we are exposed during fetal and neonatal life can have a long-term impact on our health. This has been termed the developmental origins of health and disease. Factors known to have such programming effects include intrauterine nutrient availability, (determined by maternal nutrition and placental function), endocrine disruptors, toxins and infectious agents. Epigenetic processes have emerged as a key mechanism by which the early environment can permanently influence cell function and metabolism after multiple rounds of cell division. More recently it has been suggested that programmed effects can be observed beyond the first generation and that therefore epigenetic mechanisms could form the basis of transmission of phenotype from parent to child to grandchild and beyond. Here we review the evidence for such processes.

Information is rapidly accumulating regarding the role of miRNAs as key regulators of immune system development and function. It is also increasingly evident that miRNAs play an important role in host-pathogen interactions through regulation of both innate and acquired immune responses. Little is known, however, about the specific role of miRNAs in regulating normal development of the mucosal immune system, especially during the neonatal period. Furthermore, there is limited knowledge regarding the possible role the commensal microbiome may play in regulating mucosal miRNAs expression, although evidence is emerging that a variety of enteric pathogens influence miRNA expression. The current review focuses on recent information that miRNAs play an important role in regulating early development of the bovine mucosal immune system. A possible role for the commensal microbiome in regulating mucosal development by altering miRNA expression is also discussed. Finally, we explore the potential advantages of using the newborn calf as a model to determine how interactions between developmental programming, maternal factors in colostrum, and colonization of the gastrointestinal tract by commensal bacteria may alter mucosal miRNA expression and immune development. Identifying the key factors that regulate mucosal miRNA expression is critical for understanding how the balance between protective immunity and inflammation is maintained to ensure optimal gastrointestinal tract function and health of the whole organism.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.

The prevalence of age-associated disease is increasing at a striking rate globally. It is known that a strong association exists between a suboptimal maternal and/or early-life environment and increased propensity of developing age-associated disease, including cardiovascular disease (CVD), type-2 diabetes (T2D) and obesity. The dissection of underlying molecular mechanisms to explain this phenomenon, which is known as 'developmental programming' is still emerging; however three common mechanisms have emerged in many models of developmental programming. These mechanisms are (a) changes in tissue structure, (b) epigenetic regulation and (c) accelerated cellular ageing. This review will examine the epidemiological evidence and the animal models of suboptimal maternal environments, focusing upon these molecular mechanisms and will discuss the progress being made in the development of safe and effective intervention strategies which ultimately could target those 'programmed' individuals who are known to be at-risk of age-associated disease.

Accumulated findings have demonstrated that the epigenetic code provides a potential link between prenatal stress and changes in gene expression that could be involved in the developmental programming of various chronic diseases in later life. Meanwhile, based on the fact that epigenetic modifications are reversible and can be manipulated, this provides a unique chance to develop multiple novel epigenetic-based therapeutic strategies against many chronic diseases in early developmental periods. This article will give a short review of recent findings of prenatal insult-induced epigenetic changes in developmental origins of several chronic diseases, and will attempt to provide an overview of the current epigenetic-based strategies applied in the early prevention, diagnosis and possible therapies for human chronic diseases.

The global rise in prevalence of obesity is not fully explained by genetics or life style factors. The developmental origins of health and disease paradigm suggests that environmental factors during early life could play a role. In this perspective, perinatal exposure to bisphenol A (BPA) has been indicated as a programming factor for obesity and related metabolic disorders later in life. Here we study early life programming by BPA using an experimental design that is relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to 8 non-toxic doses (0-3000. μg/kg body weight/day (μg/kg bw/d)) of BPA. After weaning, offspring were followed for 20 weeks without further exposure. Adult male offspring showed dose-dependent increases of body and liver weights, no effects on fat pad weights and a dose-dependent decrease in circulating glucagon. Female offspring showed a dose-dependent decrease in body weight, liver, muscle and fat pad weights, adipocyte size, serum lipids, serum leptin and adiponectin. Physical activity was decreased in exposed males and suggested to be increased in exposed females. Brown adipose tissue showed slightly increased lipid accumulation in males and lipid depletion in females, and ucp1 expression was dose-dependently increased in females. The effects in females were more reliable and robust than in males due to wide confidence intervals and potential confounding by litter size for male data. The lowest derived BMDL (lower bound of the (two-sided) 90%-confidence interval for the benchmark dose) of 233. μg/kg bw/d (for interscapular weight in females) was below the proposed BMDL of 3633. μg/kg bw/d as a basis for tolerable daily intake. Although these results suggest that BPA can program for an altered metabolic phenotype, the sexual dimorphism of effects and diversity of outcomes among studies similar in design as the present study do not mark BPA as a specific obesogen. The consistency within the complex of observed metabolic effects suggests that upstream key element(s) in energy homeostasis are modified. Sex-dependent factors contribute to the final phenotypic outcome. © 2014 Elsevier Ireland Ltd.

The evolution of nonreproductive castes is a fundamental question in evolution biology. The honeybee Apis mellifera L. has a reproductive division of labour: the queen is the primary egg-layer in a colony and has more than 200 ovarian filaments (ovarioles), whereas a worker normally does not reproduce and has fewer than 20 ovarioles. The number of ovarioles influences worker foraging behaviour and the propensity to become an egg-layer in the absence of the queen, suggesting that reproductive regulatory networks evolved with foraging division of labour in honeybee workers. Cooperation between nurse bee feeding behaviour and larval developmental programming results in the differentiation of queens and workers along with variation in ovariole number, body mass and foraging behaviour. Here, we tested how nurse bees affect ovariole number and body mass in workers, and how larvae respond to food delivery during different larval life stages. Our findings demonstrate that nurses control larvae growth and ovariole number by temporally manipulating food delivery and that the response of larvae to food differs with larval life stage and genotype. Body mass of larvae was more sensitive to nutrition during the first to the fourth instar (L1–L4), whereas ovariole number was more sensitive during the fifth instar (L5). Overall, we were able to decouple the nurse feeding program and the larval development program in honeybees. We conclude that nurse feeding behaviour during L5 is critical for modulating ovariole number in workers.

The Barker hypothesis of ‘foetal origin of adult diseases’ has led to emphasize the concept of ‘developmental programming’, based on the crucial role of epigenetic factors. Accordingly, it has been demonstrated that parental adversity (before conception and during pregnancy) and foetal factors (i.e., hypoxia, malnutrition and placental insufficiency) permanently modify the physiological systems of the progeny, predisposing them to premature ageing and chronic disease during adulthood. Thus, an altered functionality of the endocrine, immune, nervous and cardiovascular systems is observed in the progeny. However, it remains to be understood whether the haematopoietic system itself also represents a portrait of foetal programming. Here, we provide evidence, reporting and discussing related theories, and results of studies described in the literature. In addition, we have outlined our opinions and suggest how it is possible to intervene to correct foetal mal-programming. Some pro-health interventions and recommendations are proposed, with the hope of guarantee the health of future generations and trying to combat the continuous increase in age-related diseases in human populations.

Prolonged exposure to stress during development can have long-term detrimental effects on health and wellbeing. However, the environmental matching hypothesis proposes that developmental stress programs physiology and behaviour in an adaptive way that can enhance fitness if early environments match those experienced later in life. Most research has focused on the harmful effects that stress during a single period in early life may exert in adulthood. In this study, we tested the potential additive and beneficial effects that stress experienced during both pre- and post-hatching development may have on adult physiology and behaviour. Japanese quail experienced different stress-related treatments across two developmental life stages: pre-hatching corticosterone (CORT) injection, post-hatching unpredictable food availability, both pre- and post-hatching treatments, or control. In adulthood, we determined quails' acute stress response, neophobia and novel environment exploration. The pre-hatching CORT treatment resulted in attenuated physiological responses to an acute stressor, increased activity levels and exploration in a novel environment. Post-hatching unpredictable food availability decreased adults' latency to feed. Furthermore, there were cumulative effects of these treatments across the two developmental stages: quail subjected to both pre- and post-hatching treatments were the most explorative and risk-taking of all treatment groups. Such responses to novel environments could enhance survival in unpredictable environments in later life. Our data also suggest that these behavioural responses may have been mediated by long-term physiological programming of the adrenocortical stress response, creating phenotypes that could exhibit fitness-enhancing behaviours in a changing environment., Highlights • Pre-hatching CORT treatment attenuates stress responses and increases exploration. • Post-hatching stress decreases the latency to feed in a stressful environment. • Pre- and post-hatching treatments have cumulative effects on behaviour. • Early life may programme individuals to behave adaptively in a changing environment.

Mammals are born with an immature circadian system, which completes its development postnatally. Evidence suggests that the environment experienced by a newborn will impact and shape its development, which will have future consequences at the levels of circadian system function, circadian behaviour and physiology, and potentially, the animal's long-term health and welfare. Here we review the various stages in postnatal development of the circadian system, and discuss the data available on the long-term effects of early environment, in particular light environment, on the animal's brain, physiology and behaviour.

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain.

BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.

According to the Developmental Origins of Health and Disease hypothesis intrauterine or postnatal adaptations to the environment causes morphologic, physiologic or metabolic changes that influence health later in life. These adaptations seem to be carried out through structural, functional and epigenetic modifications. Multiple animal models of cardiovascular programming have been developed, and a brief overview of well-known models and mechanisms is presented. However, developmental programming also offers a novel approach to prevent cardiovascular and related diseases through so-called Reprogramming: administration of appropriate or inhibition of deleterious perinatal factors in induced or genetic models ameliorated undesirable development that otherwise would inevitably have lead to more severe hypertension, cardiovascular and renal disease. A comprehensive overview of these studies suggests that, in analogy to what has been previously recognised in programming, many quite different reprogramming interventions all have similar protective effects. Whether this is due to common final epigenetic pathways remains to be shown.

Adverse insults during intrauterine life can result in permanent changes in the physiology and metabolism of the offspring, which in turn leads to an increased risk of disease in adulthood. This is an adaptational response by the fetus to changes in the environmental signals that it receives during early life to ensure its survival and prepare itself for postnatal life. Increasing evidence suggests that the epigenetic regulation of gene expression patterns has a crucial role in the developmental programming of adult disease. This review summarizes recent studies of epigenetic mechanisms and focuses particularly on studies that explore identifiable epigenetic biomarkers in the promoters of specific disease-associated genes. Such biomarkers would enable early recognition of children who might be at risk of developing adult disease with fetal origins.

Background and aims The prevalence of pancreatic adenocarcinoma (PAC) parallels rising rates of obesity and dysmetabolism, a possible link being non-alcoholic fatty pancreas disease (NAFPD). We have recently shown that maternal obesity programmes the development of a dysmetabolic and fatty liver (non-alcoholic fatty liver disease, NAFLD) phenotype in adult offspring. Since the pancreas and liver originate from the same embryonic bud, it is plausible that maternal obesity may similarly programme the development of NAFPD. Our objective was to determine the effect of maternal obesity on development of NAFPD in offspring and ascertain contributions of the intra/extra-uterine periods. Methods Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a hypercalorific diet (16% fat, 33% sugar) for six weeks prior to mating and throughout pregnancy and lactation. Female offspring were cross-fostered for suckling to dams on the same or opposite diet to yield four groups: offspring of lean suckled by lean dams (n = 6), offspring of obese suckled by obese dams (n = 6), offspring of lean suckled by obese dams (n = 5) and offspring of obese suckled by lean dams (n = 6). All offspring were weaned onto a standard chow diet at 21 days and sacrificed at 3 months post-partum for tissue collection. Results Offspring subjected to an adverse suckling environment showed significant increases in body weight, pancreatic triglyceride content, TGF-β, collagen gene expression and SBP at rest along with an enhanced restraint stress response, indicating a dysmetabolic and NAFPD phenotype. Conclusions Developmental programming is involved in the pathogenesis of NAFPD and appears to be largely dependent on an adverse extra-uterine environment.

B-1 B cells differ from conventional B-2 B cells functionally, but how these differences relate to the ontogeny of these lineages has been unclear. Two recent Immunity articles, Kristiansen et al. (2016) and Montecino-Rodriguez et al. (2016), now provide insight into the origins of B-1 and B-2 B cells, revealing a multi-layered developmental program and successive waves of B cell precursors.

Ultrasound scanning has been used as a diagnostic and screening tool in obstetric practice for over 50 years. There is no evidence of immediate or long-term harm to the developing fetus from exposure to B mode ultrasound. However, exposure to high levels of Doppler ultrasound during early development is increasingly common, and the full safety implications of this exposure are not clear. Doppler ultrasound exposure in utero gives rise to increased apoptosis in animal models, and there is evidence of the effects of exposure to Doppler ultrasound persisting throughout life, with increased non-right-handedness observed in human epidemiological studies. We consider the idea that there may be long-term developmental implications for fetuses exposed to Doppler ultrasound early in gestation. These effects may be mediated via thermal or mechanical disruption to the developing conceptus, giving rise to free radical damage. Excess free radical exposure early in gestation is a strong candidate for the final common pathway underlying developmental programming effects, and gives rise to concern that fetuses exposed to high levels of ultrasound are at risk of a developmental programming effect. It is suggested that there is a need for animal studies of developmental programming using exposure to Doppler ultrasound scanning as the exposure of interest, and for more observational data to be collected in the clinical setting. While these data are collected, it seems prudent to continue to adhere to the principle of 'as low as reasonably achievable' (ALARA) when exposing first-trimester fetuses to Doppler ultrasound.

In young growing sheep ( ca 6 months of age), adrenaline (0.25 nmol·min −1 ·kg −1 intravenously for one hr, then 2.5 nmol·min −1 ·kg −1 for a second hr) decreased plasma K + concentration by 0.89 ± 0.109 mmol/l ( n = 4). In chronically cannulated late-gestation foetuses, however, adrenaline ( ca 2.5 then 5.0 nmol·min −1 ·kg −1 each for one hr) decreased plasma K + by only 0.26 ± 0.056 mmol/l ( n = 12), despite metabolic and cardiovascular changes of comparable magnitude to those in postnatal sheep. In vewborn lambs ( ca 1.25, then 6.0 nmol·min −1 ·kg −1 each for an hr) failed to decrease plasma K + significantly. In contrast, at 6 days of age, the decrease in plasma K + (0.71 ± 0.095 mmol/l, n = 5) during adrenaline infusion was similar to that in older sheep. The changes in plasma K + observed during adrenaline infusion into foetuses and growing sheep were totally abolished and those in lactate greatly attenuated after prolonged (6–8 days) infusion of a β 2 -selective adrenergic-receptor agonist, ritodrine. Because insulin decreases plasma K + in the foetus, these results imply a difference in developmental programming of the hypokalaemic action of catecholamines and insulin.