Prenatal Malnutrition Research Articles

Prenatal malnutrition and lead intake produce increased brain lipid peroxidation levels in newborn rats

Objectives: Prenatal malnutrition (M) and lead intoxication (Pb) have adverse effects on neuronal development; one of the cellular mechanisms involved is a disruption of the pro- and anti-oxidant balance. In the developing brain, the vulnerability of neuronal membrane phospholipids is variable across the different brain areas. This study assesses the susceptibility of different brain regions to damage by quitar tissue oxidative stress and lead quitar concentrations to determine whether the combined effect of prenatal malnutrition (M) and lead (Pb) intoxication is worse than the effect of either of them individually.Methods: M was induced with an isocaloric and hypoproteinic (6% casein) diet 4 weeks before pregnancy. Intoxication was produced with lead acetate in drinking water, from the first gestational day. Both the M and Pb models were continued until the day of birth. Four brain regions (hippocampus, cortex, striatum, and cerebellum) were dissected out to analyze the lipid peroxidation (LP) levels in four groups: normally nourished (C); normally nourished but intoxicated with lead (CPb); malnourished (M); and M intoxicated with lead (MPb).Results: Dam body and brain weights were significantly reduced in the fourth gestational week in the MPb group. Their pups had significantly lower body weights than those in the C and CPb groups. The PbM group exhibited significant increases of lead concentration and LP in all areas evaluated. A potentiation effect of Pb and M on LP was found in the cerebellum.Discussion: This study provides information on how environmental conditions (intoxication and malnutrition) during the intrauterine period could differentially affect the development of neuronal plasticity and, in consequence, alter adult brain functions such as learning and memory.

Prenatal nutritional deficiency reprogrammed postnatal gene expression in mammal brains: implications for schizophrenia.

Background:Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia.Methods:The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure.Results:In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10–9 and 5.36×10–9, respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring.Conclusions:Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia.

DNA methylation signatures link prenatal famine exposure to growth and metabolism.

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.

β2-Adrenoceptor stimulation restores frontal cortex plasticity and improves visuospatial performance in hidden-prenatally-malnourished young-adult rats

Moderate reduction in dietary protein composition of pregnant rats from 25% to 8% casein, calorically compensated by carbohydrates, has been described as a “hidden malnutrition” because it does not alter body and brain weights of pups at birth. However, this dietary treatment leads to altered central noradrenergic systems, impaired cortical long-term potentiation (LTP) and worsened visuo-spatial memory performance. Given the increasing interest on the role played by β2-adrenoceptors (β2-ARs) on brain plasticity, the present study aimed to address the following in hidden-malnourished and eutrophic control rats: (i) the expression levels of β2-ARs in the frontal cortex determined by immunohistochemistry, and (ii) the effect of the β2 selective agonist clenbuterol on both LTP elicited in vivo in the prefrontal cortex and visuospatial performance measured in an eight-arm radial maze. Our results showed that, prenatally malnourished rats exhibited a significant reduction of neocortical β2-AR expression in adulthood. Concomitantly, they were unable to elicit and maintain prefrontal cortex LTP and exhibited lower visuospatial learning performance. Administration of clenbuterol (0.019, 0.038 and 0.075mg/kg i.p.) enhanced LTP in malnourished and control animals and restored visuospatial learning performance in malnourished but not in normal rats, in a dose-dependent manner. The results suggest that decreased density of neocortical β2-ARs during postnatal life, subsequent to hidden prenatal malnutrition might affect some synaptic networks required to elicit neocortical LTP and form visuospatial memory, since those neuroplastic deficits were counteracted by β2-AR stimulation.

Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology

Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying mechanisms of protection.This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

Prenatal Malnutrition Leads to Deficits in Attentional Set Shifting and Decreases Metabolic Activity in Prefrontal Subregions that Control Executive Function

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker ¹⁴C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

Late gestation under- and overnutrition have differential impacts when combined with a post-natal obesogenic diet on glucose-lactate-insulin adaptations during metabolic challenges in adolescent sheep.

To determine whether late gestation under- and overnutrition programme metabolic plasticity in a similar way, and whether metabolic responses to an obesogenic diet in early post-natal life depend on the foetal nutrition history. In a 3 × 2 factorial design, twin-pregnant ewes were for the last 6 weeks of gestation (term = 147 days) assigned to HIGH (N = 13; 150 and 110% of energy and protein requirements, respectively), NORM (N = 9; 100% of requirements) or LOW (N = 14; 50% of requirements) diets. The twin offspring were raised on high-carbohydrate-high-fat (HCHF; N = 35) or conventional (CONV; N = 35) diets from 3 days to 6 months of age (around puberty). Then intravenous glucose (GTT; overnight fasted), insulin (ITT; fed) and propionate (gluconeogenetic precursor; PTT; both fed and fasted) tolerance tests were conducted to evaluate (hepatic) metabolic plasticity. Prenatal malnutrition differentially impacted adaptations of particularly plasma lactate followed by glucose, cholesterol and insulin. This was most clearly expressed during PTT in fasted lambs and much less during ITT and GTT. In fasted lambs, propionate induced more dramatic increases in lactate than glucose, and HIGH lambs became more hyperglycaemic, hyperlactataemic and secreted less insulin compared to the hypercholesterolaemic LOW lambs. Propionate-induced insulin secretion was virtually abolished in fasted HCHF lambs, but upregulated in fasted compared to fed CONV lambs. HCHF lambs had the greatest glucose-induced insulin secretory responses. Prenatal malnutrition differentially programmed glucose-lactate metabolic pathways and cholesterol homeostasis. Prenatal overnutrition predisposed for hyperglycaemia and hyperlactataemia, whereas undernutrition predisposed for hypercholesterolaemia upon exposure to an obesogenic diet. Prenatal overnutrition (not undernutrition) interfered with pancreatic insulin secretion by non-glucose-dependent mechanisms.

Vitamin supplementation in the treatment of schizophrenia.

This article reviews the current literature addressing the treatment of schizophrenia with vitamin supplementation. It describes the important roles that vitamins play in normal metabolism, and reviews the evidence pertaining to vitamin deficiency and supplementation in patients with schizophrenia. There is mounting evidence suggesting that vitamin supplementation, in particular with folic acid, vitamin B12 and vitamin D, may be important in treatment within certain subgroups of patients. There is a need for larger randomized controlled trials, and further studies examining the incidence of schizophrenia in countries with poor prenatal care and malnutrition, as well as in countries that have adopted mandatory folic acid fortification of grain products, are recommended.

Prenatal programming of obesity in a swine model of leptin resistance: modulatory effects of controlled postnatal nutrition and exercise.

The main role of early nutritional programming in the current rise of obesity and associated diseases is well known. However, translational studies are mostly based in postnatal food excess and, thus, there is a paucity of information on the phenotype of individuals with prenatal deficiencies but adequate postnatal conditions. Thus, we assessed the effects of prenatal programming (comparing descendants from females fed with a diet fulfilling 100 or only 50% of their nutritional requirements for pregnancy) on gene expression, patterns of growth and fattening, metabolic status and puberty attainment of a swine model of obesity/leptin resistance with controlled postnatal nutrition and opportunity of exercise. Maternal restriction was related to changes in the relationships among gene expression of positive (insulin-like growth factors 1 and 2) and negative (myostatin) regulators of muscle growth, with negative correlations in gilts from restricted pregnancies and positive relationships in the control group. In spite of these differences, the patterns of growth and fattening and the metabolic features during juvenile growth were similar in control gilts and gilts from restricted pregnancies. Concomitantly, there was a lack of differences in the timing of puberty attainment. However, after reaching puberty and adulthood, females from restricted pregnancies were heavier and more corpulent than control gilts, though such increases in weight and size were not accompanied by increases in adiposity. In conclusion, in spite of changes in gene expression induced by developmental programming, the propensity for higher weight and adiposity of individuals exposed to prenatal malnutrition may be modulated by controlled food intake and opportunity of physical exercise during infant and juvenile development.

A Calcium-Deficient Diet in Rat Dams during Gestation and Nursing Affects Hepatic 11β-hydroxysteroid dehydrogenase-1 Expression in the Offspring

BackgroundPrenatal malnutrition can affect the phenotype of offspring by changing epigenetic regulation of specific genes. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. We hypothesized that pregnant female rats fed a Ca-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and that lactation would modify these alterations.MethodologyWe determined the effects of Ca deficiency during pregnancy and/or lactation on hepatic 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1) expression in offspring. Female Wistar rats consumed either a Ca-deficient (D: 0.008% Ca) or control (C: 0.90% Ca) diet ad libitum from 3 weeks preconception to 21 days postparturition. On postnatal day 1, pups were cross-fostered to the same or opposite dams and divided into the following four groups: CC, DD, CD, and DC (first letter: original mother's diet; second letter: nursing mother's diet). All offspring were fed a control diet beginning at weaning (day 21) and were killed on day 200±7. Serum insulin and adipokines in offspring were measured using ELISA kits.Principal FindingsIn males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were higher in the DD and DC groups than in the CC group. We found no difference in HOMA-IR between the CC and CD groups in either males or females. Expression of Hsd11b1 was lower in male DD rats than in CC rats. Hsd11b1 expression in male offspring nursed by cross-fostered dams was higher than that in those nursed by dams fed the same diet; CC vs. CD and DD vs. DC. In females, Hsd11b1 expression in DC rats was higher than that in CC rats.ConclusionsThese findings indicated that maternal Ca restriction during pregnancy and/or lactation alters postnatal growth, Hsd11b1 expression, and insulin resistance in a sex-specific manner.

Animal models of schizophrenia: developmental preparation in rats.

Schizophrenia manifests itself primarily with positive symptoms, negative symptoms and cognitive disorders. Animal models of mental diseases seem to be an important tool in understanding key theories related with pathophysiology of the disorder and are used to assess efficacy of new drugs. References describe four basic groups of animal models of schizophrenia, such as: models created by pharmacological intervention, genetic models, lesion models and models of developmental disorders of primary brain structures. Of the models referred to above, the group of developmental disorder models is particularly noteworthy, as they are primarily easy to use, and the methods are highly sensitive. High scientific value of these models is associated with the neurodevelopmental theory which stipulates that at an early stage of body development, a number of interactions between genetic and environmental factors may affect the development of neurons which may cause disorders of brain cytoarchitecture development. We review six developmental models of schizophrenia in rats (MAM--methylooxymethanol acetate, prenatal stress, maternal deprivation, isolation rearing, prenatal immune challenge and maternal malnutrition) that are all validated by disruption in PPI.

Prenatal malnutrition and subsequent foetal loss risk: Evidence from the 1959-1961 Chinese famine

AbstractBACKGROUNDScientists disagree on whether prenatal malnutrition has long-term influences on women's reproductive function, and empirical evidence of such long -term effects remains limited and inconsistent.METHODSUsing the retrospective pregnancy history of 12,567 Chinese women collected in a nationally representative sample survey in 2001, this study conducted difference-in-differences analyses to investigate the relationship between prenatal exposure to the 1959-1961 Great Leap Forward Famine in China and the subsequent risk of involuntary foetal loss, including miscarriage and stillbirth, and how this relationship changes between the rural and urban populations.RESULTSPrenatal exposure to the Great Leap Forward Famine had no long-term effect on women's risk of miscarriage. Such an exposure increased the risk of stillbirth among urban women but not among rural women.CONCLUSIONSThe results support the foetal origins hypothesis. The significant urban-rural difference in the effect of prenatal famine exposure on stillbirth suggests the presence of a long- term negative foetal origins effect and a strong selection effect caused by famine-induced population attrition.(ProQuest: ... denotes formulae omitted.)1. IntroductionScientists disagree on whether prenatal malnutrition has long-term influences on subsequent reproductive outcomes. On the one hand, the 'foetal origins' hypothesis and its straightforward extensions predict that prenatal malnutrition has a long-term negative influence on the female reproductive system by affecting the in utero development of the female foetus' organs that are responsible for the production and regulation of reproductive hormones (Drake and Walker 2004; Gardner, Ozanne, and Sinclair 2009; Lumey and Stein 1997; Lummaa 2003). On the other hand, based on the evolutionary life-history regulation theory, if prenatal malnutrition is associated with impaired health later in life, as predicted by the foetal origins hypothesis, an enhanced reproductive function is likely to present as a life-history compensation (Bateson et al. 2004; Painter et al. 2008). Both arguments are based on sound scientific theories; therefore the final adjudication depends on which argument is better supported by empirical evidence. Given the rampant poverty and malnutrition and high prevalence of involuntary foetal loss in many developing countries, testing the relationship between prenatal malnutrition and subsequent involuntary foetal loss risk is not only of important scientific value but also of significant policy relevance.Due to the legal and ethical restrictions on the use of human subjects in scientific research, empirical evidence on the relationship between prenatal malnutrition and subsequent reproductive function has mainly been derived from observational studies. A number of such studies showed that women's prenatal conditions, as measured by their birth weight, are negatively associated with their subsequent risk of foetal loss and preterm birth, and positively associated with babies' birth weight and chance of survival (Emanuel et al. 1992; Hackman et al. 1983; Klebanoff, Meirik, and Berendes 1989; Little 1987; Sanderson, Emanuel, and Holt 1995; Skjaerven, Wilcox, and Magnus 1997). However, due to the weaknesses of observational design, the causal nature of these findings remains unclear. More specifically, the observed association between women's birth weight and their subsequent reproductive outcomes may be the result of the causal mechanism articulated by the foetal origins hypothesis or the result of inadequate control of the common determinants of both women's birth weight and their reproductive outcomes that cannot be directly observed (Clarke 2005; Murnane and Willett 2010).Famine provides an 'experiment-like' opportunity to address this important question. Similar to a randomised experiment, the assignment of the famine 'treatment' condition (i. …

Impact of prenatal protein-calorie malnutrition on the odontogenesis of wistar rats

Objective: This study aimed to determine changes in odontogenesis arising from prenatal and postnatal protein-calorie malnutrition. Materials and methods: Twelve adult Wistar rats were selected; 8 females and 4 males. The females were divided into two groups, one of which received a normoproteic diet (NG) and the other received a hypoproteic diet (HG). After the birth of the litters, 24 pups were randomly separated from each group. The animals were sacrificed, 12 at five-days old and 12 at eight-days old, and their jaws were subjected to histological preparation to obtain cuts of tooth germs. Forty-eight slides were selected that presented the germs properly cut (24 from each group), which were analyzed by microscopy and measured by a calibrated examiner. The differences between means were verified by the nonparametric Mann-Whitney test. Results: The results showed that at 5 days the differences in thickness of enamel and dentin were statistically significant between NG (84.08 ± 28.9 and 141.51 ± 33.2; p = 0.026) and HG (47.26 ± 43.8 and 91.19 ± 54.7; p = 0.006). At 8 days of life there were no significant differences between the groups. Conclusion: The results showed evidence of the impact of malnutrition on the thickness of dental tissues. It is suggested that further work is carried out in this line of research with more complex designs.

Identifying the intergenerational effects of the 1959–1961 Chinese Great Leap Forward Famine on infant mortality

Using the 1959–1961 Chinese Great Leap Forward Famine as a natural experiment, this study examines the relationship between mothers’ prenatal exposure to acute malnutrition and their children's infant mortality risk. According to the results, the effect of mothers’ prenatal famine exposure status on children's infant mortality risk depends on the level of famine severity. In regions of low famine severity, mothers’ prenatal famine exposure significantly reduces children's infant mortality, whereas in regions of high famine severity, such prenatal exposure increases children's infant mortality although the effect is not statistically significant. Such a curvilinear relationship between mothers’ prenatal malnutrition status and their children's infant mortality risk is more complicated than the linear relationship predicted by the original fetal origins hypothesis but is consistent with the more recent developmental origins of health and disease theory.

Perinatal programming of obesity: an introduction to the topic

Perinatal programming of obesity: an introduction to the topic

Effects of Perinatal Undernutrition and Massage Stimulation upon the Ambiguus Nucleus in the Rat Prior to Weaning

Undernutrition produces morphological brain alterations and cognitive deficiencies in children of underdeveloped countries. The central nervous system (CNS) alterations mainly interfere with the anatomical organization of areas undergoing a phase of intense postnatal cell proliferation, disrupting plastic processes like learning, memory, and phonation. In the rat pup, prenatal malnutrition interferes with the elaboration of ultrasonic vocalizations (USVs) by poorly understood mechanisms. The neuronal caudal portion of the nucleus ambiguus (Ambc) innervates the laryngeal intrinsic muscles to produce phonation, a basic USV communication system. During postnatal development, enhanced plasticity phenomena play a fundamental role in improving brain function. Thus, the massage stimulation (MS) may accelerate growth and induce neurogenesis in different areas of the brain. The current study analyzed the effects of a daily 10-min MS on the dendritic tree and perikarya measurements of Ambc multipolar motoneurons (Golgi-Cox) of perinatally underfed (U), control (C), control massage-stimulated (CMS), and underfed massage-stimulated (UMS) groups at postnatal days (PDs) 8, 12, and 15. The data indicated that the dendritic scores were reduced (p

Asking the Right Questions: How Early-Life Exposures Influence Later Development of Disease

Vol. 120, No. 10 News | Science SelectionsOpen AccessAsking the Right Questions: How Early-Life Exposures Influence Later Development of Diseaseis accompanied byPredicting Later-Life Outcomes of Early-Life Exposures Julia R. Barrett Julia R. Barrett Search for more papers by this author Published:1 October 2012https://doi.org/10.1289/ehp.120-a403aCited by:1View Article in:中文版AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail View articlePrenatal and early-life environmental insults ranging from malnutrition to toxic exposures can tilt the odds toward development of adverse health effects decades later. These effects likely occur, at least in part, through alterations in an individual’s genetic potential to thrive in the environment in which he or she will live—in other words, these early challenges set the bar for what’s “normal,” and the fetus and infant adapt for a less-than-optimal environment in ways that may contribute to adult-onset disease. A new review examines the evidence for an association between early-life exposures and later disease, and proposes an agenda for future research and risk assessment [EHP 120(10):1353–1361; Boekelheide et al.].One of the most intensively studied instances of adult disease attributable to prenatal circumstances involves children of women who were pregnant during the Dutch famine of 1944–1945. At birth these individuals were small for gestational age, and as adults they had increased incidence of obesity, diabetes, and cardiovascular disease. Furthermore, their children also were small for gestational age, suggesting that such effects can be transmitted across generations, a finding replicated in animal studies of prenatal malnutrition and toxic exposure.Human and animal studies now link a multitude of early-life hardships, including prematurity, low birth weight, maternal infection during pregnancy, toxic exposures, and malnutrition, to a wide array of adult-onset diseases. Timing of the insult appears to be an important factor in the consequences. In the Dutch cohort, for example, deprivation in early gestation was associated with coronary heart disease, hypertension, dyslipidemia, and obesity later in life, whereas mid-gestation deprivation was linked with obstructive airway disease and impaired glucose tolerance.Many adverse outcomes associated with early-life events could be explained by epigenetic changes, in which the genes themselves are unaltered but their expression is persistently blocked, increased, or decreased by environmentally induced molecular tweaks to the components controlling transcription and translation. Such changes could occur directly to a developing fetus or indirectly by, for example, undermining placental function or triggering disease-susceptibility genes. Nonepigenetic changes are also possible, as illustrated by so-called obesogenic chemicals that can activate the key regulator of fat cell growth and development.Many potential research avenues arise from the accumulating evidence for delayed effects of early-life exposures. Central themes include characterizing epigenetic and nonepigenetic changes that predict disorders, prioritizing investigations, and identifying critical time points with regard to susceptibility. Methods for collecting and analyzing the data alone constitute a research priority, while the ultimate goal is to enable accurate risk assessment. Both experimental evidence in animals and observational human data will be needed to assess causal relationships.FiguresReferencesRelatedDetailsCited By Seemann F, Peterson D, Chiang M and Au D (2017) The development of cellular immune defence in marine medaka Oryzias melastigma, Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 10.1016/j.cbpc.2017.03.010, 199, (81-89), Online publication date: 1-Sep-2017. Related articlesPredicting Later-Life Outcomes of Early-Life ExposuresJun 6, 2012, 12:00:00 AMEnvironmental Health Perspectives Vol. 120, No. 10 October 2012Metrics About Article Metrics Publication History Originally published1 October 2012Published in print1 October 2012 Financial disclosures License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Knockdown of α2C-adrenoceptors in the occipital cortex rescued long-term potentiation in hidden prenatally malnourished rats

Moderate reduction in the protein content of the mother’s diet calorically compensated by carbohydrates (the so-called “hidden” prenatal malnutrition) leads to increased neocortical expression of the α2C-adrenoceptor subtype, together with decreased cortical release of noradrenaline and impaired long-term potentiation (LTP) and visuospatial memory performance during the rat postnatal life. Ín order to study whether overexpression of the α2C-adrenoceptor subtype is causally related to the decreased indices of neocortical plasticity found in prenatally malnourished rats, we evaluated the effect of intracortical (occipital cortex) administration of an antisense oligodeoxynucleotide (ODN) raised against the α2C-adrenoceptor mRNA on the LTP elicited in vivo in the occipital cortex of hidden prenatally malnourished rats. In addition, we compare the effect of the antisense ODN to that produced by systemical administration of the subtype-nonselective α2-adrenoceptor antagonist atipamezole. Prenatal protein malnutrition led to impaired occipital cortex LTP together with increased expression of α2C-adrenoceptors (about twice Bmax) in the same cortical region. [3H]-rauwolscine binding assay showed that a 7-day intracortical antisense ODN treatment in the malnourished rats resulted in 50% knockdown of α2C-adrenoceptor expression and, in addition, completely rescued the ability of the occipital cortex to develop and maintain long-term potentiation. Atipamezole (0.3mg/kg i.p.) also led to full recovery of neocortical LTP in malnourished rats. The present results argue in favor of our original hypothesis that the deleterious effect of prenatal malnutrition on neocortical plasticity in the adult progeny is in part consequence of increased neocortical α2C-adrenoceptor expression. This receptor subtype is known to be involved in the presynaptic control of noradrenaline release from central neurons, a neurotransmitter that critically influences LTP and memory formation.

Anatomy of corpus callosum in prenatally malnourished rats

The effect of prenatal malnutrition on the anatomy of the corpus callosum was assessed in adult rats (45-52 days old). In the prenatally malnourished animals we observed a significant reduction of the corpus callosum total area, partial areas, and perimeter, as compared with normal animals. In addition, the splenium of corpus callosum (posterior fifth) showed a significant decrease of fiber diameters in the myelinated fibers without changing density. There was also a significant decrease in diameter and a significant increase in density of unmyelinated fibers. Measurements of perimeter's fractal dimensions from sagittal sections of the brain and corpus callosum did not show significant differences between malnourished and control animals. These findings indicate that cortico-cortical connections are vulnerable to the prenatal malnutrition, and suggest this may affect interhemispheric conduction velocity, particularly in visual connections (splenium).

Hidden prenatal malnutrition in the rat: role of β1‐adrenoceptors on synaptic plasticity in the frontal cortex

Moderate reduction in the protein content of the mother's diet (hidden malnutrition) does not alter body and brain weights of rat pups at birth, but leads to dysfunction of neocortical noradrenaline systems together with impaired long-term potentiation and visuo-spatial memory performance. As β₁-adrenoceptors and downstream protein kinase signaling are critically involved in synaptic long-term potentiation and memory formation, we evaluated the β₁-adrenoceptor density and the expression of cyclic-AMP dependent protein kinase, calcium/calmodulin-dependent protein kinase and protein kinase Fyn, in the frontal cortex of prenatally malnourished adult rats. In addition, we also studied if β₁-adrenoceptor activation with the selective β₁ agonist dobutamine could improve deficits of prefrontal cortex long-term potentiation presenting these animals. Prenatally malnourished rats exhibited half of β₁-adrenoceptor binding, together with a 51% and 65% reduction of cyclic AMP-dependent protein kinase α and calcium/calmodulin-dependent protein kinase α expression, respectively, as compared with eutrophic animals. Administration of the selective β₁ agonist dobutamine prior to tetanization completely rescued the ability of the prefrontal cortex to develop and maintain long-term potentiation in the malnourished rats. Results suggest that under-expression of neocortical β₁-adrenoceptors and protein kinase signaling in hidden malnourished rats functionally affects the synaptic networks subserving prefrontal cortex long-term potentiation. β₁-adrenoceptor activation was sufficient to fully recover neocortical plasticity in the PKA- and calcium/calmodulin-dependent protein kinase II-deficient undernourished rats, possibly by producing extra amounts of cAMP and/or by recruiting alternative signaling cascades.