Effects Of Maternal Undernutrition Research Articles

Evaluation of The Renal Function in The Intrauterine Growth Restricted Rats and The Effect of Maternal Glucocorticoids

The purpose of the study was to determine the effect of maternal glucocorticoids on experimental growth retardedrats and the effect of maternal undernutrition in different gestation periods for function of the kidney. This studyhad two sections. In the first section, 5 groups were formed. 10g/d diet was given in the 1st, 2nd, and 3rd trimesterand throughout the pregnancy period. The control group was fed a normal diet. In the second section, 3 groupsformed and all the rats take 10 g/d diet throughout pregnancy period. To determine the effect of endogenousglucocorticoids first group was treated with metyrapone, second group metyrapone+dexamethasone and theplacebo injected saline until 14 days of pregnancy. The offsprings body and kidney weights were detected inthe 0, 3rd and 20th weeks of age. Renal extraction functions and blood pressures from tail detected in the 20thweek of age. Urinary excretion and glomerular filtration rate were low in rats that had dietary restriction in thelast trimester. The glomerular filtration rates were found to be low in the group that had diet restriction duringthe whole pregnancy. Blood pressure values were found to be lower in the group that had diet restriction duringtheir pregnancy compared to the control group. Kidney weights were similar in all groups in the first phase. Itwas observed that renal excretion functions were preserved in the group receiving metyrapone treatment, butthere was no statistically significant difference between the results. Low blood pressures were normalized withmetyrapone treatment. The kidney sizes at the 20th week of the rats which receiving metyrapone treatment werefound to be smaller than those receiving physiological saline solution. Food restriction destroys renal functionsbut no effects with high blood pressure in adulthood. Glucocortiod exposure in pregnancy may reduce renaldevelopment.

Long-term effects of early maternal undernutrition on the growth, physiological profiles, carcass and meat quality of male beef offspring

The effects of maternal undernutrition in early gestation on growth, metabolic and endocrine profiles, carcass and meat quality of male offspring in cattle were assessed. Twenty-one Parda de Montaña and 14 Pirenaica cows received a CONTROL (100% nutrition requirements) or a SUBNUT (65%) diet from day 0 to 82 of gestation and thereafter were fed to requirements until calf weaning at 4 months of age. The performance and physiological profiles of male offspring during an 8-month fattening period were analyzed. Bulls were slaughtered at 12 months of age, and their carcasses and meat color, tenderness and intramuscular fatty acid profile were evaluated. Maternal undernutrition increased plasma NEFAs and impaired the growth of Pirenaica bulls, resulting in lower weights at slaughter and fatter carcasses with impaired meat tenderness. Irrespective of the breed, maternal undernutrition affected meat color and increased the meat content of some healthy fatty acids. In summary, early maternal undernutrition affected the fetal programming of beef male offspring with persistent consequences at slaughter.

Effects of maternal undernutrition during late pregnancy on the regulatory factors involved in growth and development in ovine fetal perirenal brown adipose tissue.

ObjectiveThe experiment was conducted to evaluate the effects of maternal undernutrition during late pregnancy on the expressions of genes involved in growth and development in ovine fetal perirenal brown adipose tissue (BAT).MethodsEighteen ewes with singleton fetuses were allocated to three groups at day 90 of pregnancy: restricted group 1 (RG1, 0.33 MJ metabolisable energy [ME]/kg body weight [BW]0.75/d, n = 6), restricted group 2 (RG2, 0.18 MJ ME/kg BW0.75/d, n = 6), and a control group (CG, ad libitum, 0.67 MJ ME/kg BW0.75/d, n = 6). The fetuses were removed at day 140 of pregnancy. All data were analyzed by using the analysis of variance procedure.ResultsThe perirenal fat weight (p = 0.0077) and perirenal fat growth rate (p = 0.0074) were reduced in RG2 compared to CG. In fetal perirenal BAT, the protein level of uncoupling protein 1 (UCP1) (p = 0.0001) was lower in RG1 and RG2 compared with CG and UCP1 mRNA expression (p = 0.0265) was decreased in RG2. The protein level of myogenic factor 5 (Myf5) was also decreased in RG2 (p = 0.0001). In addition, mRNA expressions of CyclinA (p = 0.0109), CyclinB (p = 0.0019), CyclinD (p = 0.0015), cyclin-dependent kinase 1 (CDK1) (p = 0.0001), E2F transcription factor 1 (E2F1) (p = 0.0323), E2F4 (p = 0.0101), and E2F5 (p = 0.0018) were lower in RG1 and RG2. There were decreased protein expression of peroxisome proliferator-activated receptor-γ (PPARγ) (p = 0.0043) and mRNA expression of CCAAT/enhancer-binding protein-α (C/EBPα) (p = 0.0307) in RG2 and decreased PPARγ mRNA expression (p = 0.0008) and C/EBPα protein expression (p = 0.0015) in both RG2 and RG1. Furthermore, mRNA expression of bone morphogenetic protein 4 (BMP4) (p = 0.0083) and BMP7 (p = 0.0330) decreased in RG2 and peroxisome proliferator-activated receptor co-activator-1α (PGC-1α) reduced in RG2 and RG1.ConclusionOur observations support that repression of regulatory factors promoting differentiation and development results in the inhibition of BAT maturation in fetal perirenal fat during late pregnancy with maternal undernutrition.

MicroRNA and mRNA Sequencing Analyses Reveal Key Hepatic Metabolic Pathways Responsive to Maternal Malnutrition in Full-Term Fetal Pigs

ObjectivesMaternal and infant undernutrition is highly prevalent in developing countries, leading to serious fetus/infant mortality, intrauterine growth restriction, stunting, and severe wasting. However, the effects of maternal undernutrition have generally focused on the reduced maternal nutrient supply to the fetus. The potential impairment of fetal metabolic pathways has not been well studied. MethodsPregnant gilts (Landrace x Yorkshire x Duroc) received the NRC gestation diet with (n = 4) or without (n = 4) 50% intake restriction at insemination day and 70% for the following gestation period. Full term fetuses were obtained via C-section, two piglets were selected from each gilt in both groups and subject to hepatic tissue collection. MicroRNA and mRNA deep sequencing analysis was performed using the Illumina GAIIx system. The mRNA-miRNA correlation and associated signaling pathways were analyzed via CLC workbench, Ingenuity Pathway Analysis Software. ResultsA total of 42 differentially expressed miRNAs were identified between intake-restriction and full-nutrition group. Among of these, mir-206, mir-133b, mir-1246, mir-1843 and mir-7139 are the most downregulated and mir-10b, mir-708 and mir-222 are the most upregulated miRNAs. A total of 1215 mRNAs were identified to differentially expressed between two groups. Two metabolic pathways: retinol biosynthesis and oxidative phosphorylation were significantly modified, and the modification was associated with the miRNA changes induced by the maternal feed restriction. Briefly, the retinol biosynthesis pathway was upregulated (p < 0.01), in which those differential expressed mir-221, mir-4492, mir-1281 and mir-4492 were predicted targeting genes AADAC, CES3, PNPLA3 and RDH13 in the pathway. The oxidative phosphorylation pathway was upregulated (p < 0.05), and those differential expressed mir-1843, mir-222 and mir-184 were predicted targeting genes ATP5F1C, NDUFA1, NDUFB10, and NDUFS7 in this pathway. ConclusionsThese results provide the framework for further understanding of negative impact of maternal malnutrition on hepatic metabolic pathways via miRNA-RNA interactions in full-term fetal pigs. Funding SourcesSupported in part by the Bill and Melinda Gates Foundation (GCE OPP1061037) and by the North Carolina Agricultural Research Service.

Role of Maternal Dietary Protein and Amino Acids on Fetal Programming, Early Neonatal Development, and Lactation in Swine.

Simple SummaryDietary protein is an important nutrient source for sows, necessary for not only growth and production, but also other physiological functions. Protein limitations in maternal diets have the potential to impair fetal myogenesis, while excess maternal dietary protein appears to only have minor effects on early fetal muscle formation. Effects of maternal protein deficiency on increased fat deposition in porcine neonates is inconsistent with gene expressions in the neonates. Sufficient maternal dietary protein can enhance porcine milk protein and fat concentration. Understanding the function of protein and amino acids in sows and the effects on their offspring can provide rational approaches for the regulation of piglet growth and further improvements in meat quality in the future.Maternal nutrition plays a vital role in fetal development, early development of neonates, and lactation and regulates the lifetime productivity of offspring. During pregnancy, maternal nutrition alters expression of the fetal genome and the development of tissues and organs via fetal programming. After parturition, maternal nutrition continues to regulate growth and development of piglets through maternal milk, which contains carbohydrates, lipids, proteins and oligosaccharides. Thus, deficiencies in maternal nutrition are detrimental to development of piglets, which can lead to inefficient growth and decreased carcass merit. Protein is an important nutritional component for sows, which not only functions in muscle development, but also plays a vital role in embryonic and neonatal development and lactation. Although effects of maternal undernutrition on neonatal development have been widely studied in sows, the function of different maternal dietary protein levels on fetal development, neonatal growth and lactation performance of sows is largely unknown. Determination of the effects and underlying mechanisms of maternal dietary protein levels on development of piglets is vital to the pork industry. Therefore, we summarized recent reports regarding mechanisms of effects of maternal protein levels on regulation of conceptus growth and early postnatal development though uterine fetal programming and lactation in swine.

55 Peri-conceptional undernourishment perturbs offspring sperm methylome

Whereas an organism’s genotype is relatively static throughout life, the epigenome is highly dynamic and can adapt, or be altered, in response to the external environment such as diet. Intrauterine exposure to nutrient availability can alter the establishment of epigenetic marks, not only in the exposed individuals, but also in their offspring. Inheritance of such an environmentally acquired phenotype by the subsequent generation occurs through epigenetic modifications in the germline. Here, using a genome-wide approach, we evaluate how modification of the maternal diet pre- (14 days) and post- (28 days) conception can affect methylation status of the sperm of male offspring. Specifically, using a sheep model, we focused on the effect of maternal undernutrition on adult sperm methylation and its long-term consequences on sperm physiology and quality. Moreover, we investigated if supplementation of folic acid, to increase the availability of methyl donors, could prevent or ameliorate the adverse uterine environment caused by maternal undernutrition. Male lambs obtained from mothers subjected to different nutritional regimens (UND: undernutrition; FA: undernutrition and folic acid supplementation) appeared normal at birth, with a comparable body weight until Day 30 postpartum. Sperm DNA methylation, obtained by reduced representation bisulfite sequencing, differed in offspring that experienced in utero undernutrition (UND and FA) compared with the control group (CTR). In particular, the number of differentially methylated regions (DMR) was lower when UND and FA groups were compared, whereas a higher number of DMR was observed by comparison of CTR with both experimental groups. In addition, a high percentage of DMR were shared between UND and FA groups when compared with CTR, clearly indicating a influence of maternal nutrition on the offspring sperm DNA methylation rearrangement. Gene ontology (GO) analysis showed variation in functional categories related to sperm functionality such as chondroitin sulfate synthesis, potassium ion import, and others related to metabolism (biotin and glucagon). Furthermore, using computer-assisted semen analysis and flow cytometric measurement, we observed lower a sperm motility index and higher incidence of chromatin structure alterations in spermatozoa collected from UND and FA groups compared with CTR. Finally, to verify the effect of such reported abnormality on lamb fertility, we used the semen for in vitro embryo production. While we obtained good quality blastocysts from all 3 groups, a reduction in the percentage of embryo development, partially compensated in the FA group, was found using spermatozoa from UND rams. Taken together, our results confirm that a nutritional stress during early mammalian development can lead to epigenetic modification in the offspring. This damage can be partially ameliorated with folic acid supplementation; however, some alteration still persists in the germline and could be passed to the next generation, with as yet unknown consequences.

Neonatal leptin treatment reverses the bone-suppressive effects of maternal undernutrition in adult rat offspring

Alterations in the early life environment, including maternal undernutrition (UN) during pregnancy, can lead to increased risk of metabolic and cardiovascular disorders in offspring. Leptin treatment of neonates born to UN rats reverses the programmed metabolic phenotype, but the possible benefits of this treatment on bone tissue have not been defined. We describe for the first time the effects of neonatal leptin treatment on bone in adult offspring following maternal UN. Offspring from either UN or ad libitum-fed (AD) rats were treated with either saline or leptin (2.5 µg/ g.d on postnatal days (D)3–13) and were fed either a chow or high fat (HF) diet from weaning until study completion at D170. Analysis of micro-tomographic data of the left femur showed highly significant effects of UN on cortical and trabecular bone tissue indices, contributing to inferior microstructure and bone strength, almost all of which were reversed by early leptin life treatment. The HF fat diet negatively affected trabecular bone tissue, but the effects of only trabecular separation and number were reversed by leptin treatment. The negative effects of maternal UN on skeletal health in adult offspring might be prevented or attenuated by various interventions including leptin. Establishment of a minimal efficacious leptin dose warrants further study.

The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport.

BackgroundFetal exposure to a maternal low protein diet during rat pregnancy is associated with hypertension, renal dysfunction and metabolic disturbance in adult life. These effects are present when dietary manipulations target only the first half of pregnancy. It was hypothesised that early gestation protein restriction would impact upon placental gene expression and that this may give clues to the mechanism which links maternal diet to later consequences.MethodsPregnant rats were fed control or a low protein diet from conception to day 13 gestation. Placentas were collected and RNA sequencing performed using the Illumina platform.ResultsProtein restriction down-regulated 67 genes and up-regulated 24 genes in the placenta. Ingenuity pathway analysis showed significant enrichment in pathways related to cholesterol and lipoprotein transport and metabolism, including atherosclerosis signalling, clathrin-mediated endocytosis, LXR/RXR and FXR/RXR activation. Genes at the centre of these processes included the apolipoproteins ApoB, ApoA2 and ApoC2, microsomal triglyceride transfer protein (Mttp), the clathrin-endocytosis receptor cubilin, the transcription factor retinol binding protein 4 (Rbp4) and transerythrin (Ttr; a retinol and thyroid hormone transporter). Real-time PCR measurements largely confirmed the findings of RNASeq and indicated that the impact of protein restriction was often striking (cubilin up-regulated 32-fold, apoC2 up-regulated 17.6-fold). The findings show that gene expression in specific pathways is modulated by maternal protein restriction in the day-13 rat placenta.ConclusionsChanges in cholesterol transport may contribute to altered tissue development in the fetus and hence programme risk of disease in later life.Electronic supplementary materialThe online version of this article (doi:10.1186/s12263-016-0541-3) contains supplementary material, which is available to authorized users.

The Effects of Maternal Under-Nutrition and a Post-Natal High Fat Diet on Lens Growth, Transparency and Oxidative Defense Systems in Rat Offspring

ABSTRACTPurpose: A poor early life nutrition environment is well established to result in a range of cardiometabolic disorders in offspring in later life. These effects can be exacerbated via exposure to an obesogenic dietary environment. To date, the effect of maternal diet and/or a post-natal obesogenic nutritional environment on key characteristics related to lens growth and oxidative stress has not been undertaken. The present study, therefore, examined the characteristics and oxidative status of the lens.Materials and Methods: Using a model of moderate maternal under-nutrition, rat dams were fed either a control diet (100% ad libitum, CON) or undernourished throughout pregnancy (50% of ad libitum intake, UN) and offspring fed either a control (5% fat, C) or high fat (30% fat, HF) diet post-weaning, resulting in four nutritional groups; CON-C, CON-HF, UN-C, and UN-HF. Offspring lenses were extracted at 160 days of age, weighed, imaged under dark and bright field microscopy, and then dissected into cortical and core fractions for biochemical analyses of oxidative stress markers.Results: Our findings reveal that lenses from all groups were transparent. However, gender specific changes were evident at the biochemical level with increased oxidative stress detected in the cortex and core of female but not male UN-C lenses, and in the cortex of male but not female CON-HF lenses. The greatest increase in oxidative stress was detected in the UN-HF group in the cortex and core regions of the lens and for both genders.Conclusions: These findings show that oxidative stress is exacerbated in the lens as a result of a combination of altered pre-natal and post-natal diet. This demonstrates a novel interaction between the two developmental windows and warrants further investigations toward devising appropriate nutritional strategies for minimizing oxidative stress in the lens.

Impact of Interventions to Improve Prenatal Nutrition in Developing Countries on Maternal Health: Obstetric Outcomes and Fetal Health

Maternal undernutrition has direct and indirect impacts on the mother’s health, that of the fetus, and may also transcend to future generations. Prenatal nutrition supplementation has been used for many years to reduce the adverse effects of maternal undernutrition. While a lot is known about the deleterious effects of poor nutrition periconception and during pregnancy, there are relatively very few effective interventions to prevent and correct nutritional deficiencies preconception and during pregnancy. The magnitude of maternal undernutrition is a cause of concern, and recently, there have been renewed efforts to find interventions that can address this problem considering its impact on human development. In this desk review, we highlight some of the proven interventions and highlight interventions that are showing promise.

Perinatal low-protein diet alters brainstem antioxidant metabolism in adult offspring

Background and objectives: Studies in humans and animal models have established a close relationship between early environment insult and subsequent risk of development of non-communicable diseases, including the cardiovascular. Whereas experimental evidences highlight the early undernutrition and the late cardiovascular disease relation, the central mechanisms linking the two remain unknown. Owing to the oxidative balance influence in several pathologies, the aim of the present study was to evaluate the effects of maternal undernutrition (i.e. a low-protein (LP) diet) on oxidative balance in the brainstem.Methods and results: Male rats from mothers fed with an LP diet (8% casein) throughout the perinatal period (i.e. gestation and lactation) showed 10× higher lipid peroxidation levels than animals treated with normoprotein (17% casein) at 100 days of age. In addition, we observed the following reductions in enzymatic activities: superoxide dismutase, 16%; catalase, 30%; glutathione peroxidase, 34%; glutathione-S-transferase, 51%; glutathione reductase, 23%; glucose-6-phosphate dehydrogenase, 31%; and in non-enzymatic glutathione system, 46%.Discussion: This study is the first to focus on the role of maternal LP nutrition in oxidative balance in a central nervous system structure responsible for cardiovascular control in adult rats. Our data observed changes in oxidative balance in the offspring, therefore, bring a new concept related to early undernutrition and can help in the development of a new clinical strategy to combat the effects of nutritional insult. Wherein the central oxidative imbalance is a feasible mechanism underlying the hypertension risk in adulthood triggered by maternal LP diet.

Maternal obesity in Africa: Is it time to pay more attention?

Many African countries are experiencing a double burden of under- and over-nutrition due to factors such as globalisation, urbanisation, changing diet, and cultural perceptions of weight. Pregnancy is a trigger point for the development of obesity, and maternal obesity is associated with short- and long-term adverse effects in the mother and child. However, while the effects of maternal under-nutrition are well known and addressed, there is scarcity of data on maternal obesity in African countries.

Effect of maternal undernutrition during late pregnancy on hormonal status and metabolic changes in neonatal lambs

The study investigated the consequences of maternal undernutrition during late pregnancy on hormonal status and metabolic changes in neonatal lambs. Four ewes out of twenty-eight multiparous ewes mated at a synchronized oestrus were slaughtered at day 90 of pregnancy to collect fetal blood to serve as an initial comparison group. Twenty-four animals were divided into three groups and offered 0.18 MJ ME&amp;middot;kg&lt;sup&gt;&amp;ndash;0.75&lt;/sup&gt;per day (restricted group 1, RG1), 0.33 MJ ME&amp;middot;kg&lt;sup&gt;&amp;ndash;0.75&lt;/sup&gt;per day (restricted group 2, RG2), and control group (ad libitum CG) during late pregnancy, respectively. Immediately after parturition, blood was collected from the neonatal lambs in each group and analyzed for growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-II, insulin (INS), thyroxine (T&lt;sub&gt;4&lt;/sub&gt;), triiodothyronine (T&lt;sub&gt;3&lt;/sub&gt;), glucose (GLU), nonesterified fatty acids (NEFA), and total amino acid (TAA), respectively. The results indicated that the maternal undernutrition during late gestation decreased the average lamb birth weight in both RG1 (P &amp;lt; 0.01) and RG2 (P &amp;lt; 0.05) compared to CG. During the late fetal development period, the concentrations of T4, INS, and IGF-I of neonatal lambs in CG were increased (P &amp;lt; 0.05) compared to those at day 90 of pregnancy; the secretions of T&lt;sub&gt;4&lt;/sub&gt;, INS, and IGF-I in RG1 and RG2 during restriction were suppressed. The neonatal INS concentrations in RG1 and RG2 were decreased (P &amp;lt; 0.05), but the neonatal GH concentration in RG1 was greater than that of CG (P &amp;lt; 0.05). The GLU concentrations of neonatal lambs in RG1 were lower than those of CG (P &amp;lt; 0.05). However, the neonatal NEFA (P &amp;lt; 0.05) and TAA (P &amp;lt; 0.01) concentrations in RG1 were greater than those of CG. Thus, maternal undernutrition can change the hormonal and metabolic status of neonatal lambs, which may have significant implications on postnatal growth and adult health.

Effect of maternal under-nutrition in late gestation on muscle and bone development in fetal sheep.

Effect of maternal under-nutrition in late gestation on muscle and bone development in fetal sheep.

Poor maternal nutrition programmes a pro-atherosclerotic phenotype in ApoE-/- mice.

Numerous animal studies have consistently shown that early life exposure to LP (low-protein) diet programmes risk factors for CVD (cardiovascular disease) such as dyslipidaemia, high BP (blood pressure) and cardiac dysfunction in the offspring. However, studies on the effect of maternal under-nutrition on offspring development of atherosclerosis are scarce. Applying our LP model to the ApoE−/− atherosclerosis-prone mouse model, we investigated the development of atherosclerotic lesions in the aortic root of 6-month-old offspring. In addition, markers of plaque progression including SMA (smooth muscle actin) and Mac3 (macrophage marker 3) were studied. Pregnant dams were fed on a control (20% protein) or on an isocaloric LP diet (8% protein) throughout pregnancy and lactation. After weaning, male offspring were maintained on 20% normal laboratory chow. At 6 months of age, LP offspring showed a significantly greater plaque area (P<0.05) with increased cholesterol clefts and significantly higher indices of DNA damage compared with controls (P<0.05). The expression of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) (P<0.05) and LDL (low-density lipoprotein) receptor in the liver of LP offspring were increased. Furthermore, LP offspring had higher LDL-cholesterol levels (P<0.05) and a trend towards elevated insulin. There were no differences in other lipid measurements and fasting glucose between groups. These observations suggest that early exposure to an LP diet accelerates the development and increases the progression of atherosclerotic lesions in young adult offspring. Future studies are needed to elucidate the specific mechanisms linking in utero exposure to a diet low in protein to the development of atherosclerosis.

The effect of maternal undernutrition on muscle development in the ovine fetus*

The effect of maternal undernutrition on muscle development of near-term ovine fetuses was studied in 2 experiments. In each experiment, Welsh mountain ewes were randomly assigned to either control (C) or nutrient-restricted (R) groups. In the first experiment, mild maternal undernutrition (85% of daily nutritional requirement (DNR)), and in the second experiment, severe maternal undernutrition (50% of DNR), were imposed between 0 and 70 days of gestation (dg). Controls for both groups were maintained on 100% of their DNR throughout the experiment. In each experiment, ewes were killed at 126 ± 1 dg by an intravenous injection of pentobarbitone. The semitendinosus muscle was dissected, and sections were stained for alkali-stable ATPase. The total number of primary and secondary fibers and the total number of fibers were estimated. In both experiments, there was a significant decrease in primary, secondary, and total fiber numbers (P < 0.05 for each). We speculate that the decrease in primary fiber number in both experiments is due to some of the large, central, and alkali-ATPase-negative (slow) fibers at near-term being secondary fibers. Therefore, the real primary fibers may not be affected.

Maternal undernutrition during critical windows of development results in differential and sex-specific effects on postnatal adiposity and related metabolic profiles in adult rat offspring

It is well established that altered maternal nutrition may induce long-term metabolic consequences in offspring. However, the effects of maternal undernutrition during different developmental windows on sex-specific growth and metabolism in offspring are not well defined. We investigated the effect of moderate maternal undernutrition during pregnancy and/or lactation on postnatal growth and metabolic outcomes in offspring. Wistar rats were randomly assigned to one of four groups: (1) control (CONT) dams fed a standard diet throughout pregnancy and lactation; (2) dams undernourished to 50 % of CONT during pregnancy (UNP); (3) dams fed at 50 % of CONT throughout lactation (UNL); (4) dams fed at 50 % of CONT throughout pregnancy and lactation (UNPL). UNP and UNPL offspring were lighter at birth compared to CONT and UNL. UNL and UNPL offspring were growth restricted at weaning and remained smaller into adulthood. UNP males and females developed increased adiposity and hyperleptinaemia in adulthood compared to all other groups. Adiposity in UNL and UNPL males was similar to CONT offspring. In UNL and UNPL females, adiposity was lower than for CONT females. Markers of bone mass, lipid metabolism and hepatic function were altered in UNP offspring but were similar in UNL and UNPL offspring compared to CONT. Lack of catch-up growth during lactation in offspring of undernourished mothers prevented development of adiposity and related metabolic disorders in later life. These data highlight that the timing and duration of undernutrition during critical windows of development exert differential effects on postnatal outcomes in a sex-specific manner.

Metabolic Programming during Lactation Stimulates Renal Na+ Transport in the Adult Offspring Due to an Early Impact on Local Angiotensin II Pathways

BackgroundSeveral studies have correlated perinatal malnutrition with diseases in adulthood, giving support to the programming hypothesis. In this study, the effects of maternal undernutrition during lactation on renal Na+-transporters and on the local angiotensin II (Ang II) signaling cascade in rats were investigated.Methodology/Principal FindingsFemale rats received a hypoproteic diet (8% protein) throughout lactation. Control and programmed offspring consumed a diet containing 20% protein after weaning. Programming caused a decrease in the number of nephrons (35%), in the area of the Bowman's capsule (30%) and the capillary tuft (30%), and increased collagen deposition in the cortex and medulla (by 175% and 700%, respectively). In programmed rats the expression of (Na++K+)ATPase in proximal tubules increased by 40%, but its activity was doubled owing to a threefold increase in affinity for K+. Programming doubled the ouabain-insensitive Na+-ATPase activity with loss of its physiological response to Ang II, increased the expression of AT1 and decreased the expression of AT2 receptors), and caused a pronounced inhibition (90%) of protein kinase C activity with decrease in the expression of the α (24%) and ε (13%) isoforms. Activity and expression of cyclic AMP-dependent protein kinase decreased in the same proportion as the AT2 receptors (30%). In vivo studies at 60 days revealed an increased glomerular filtration rate (GFR) (70%), increased Na+ excretion (80%) and intense proteinuria (increase of 400% in protein excretion). Programmed rats, which had normal arterial pressure at 60 days, became hypertensive by 150 days.Conclusions/SignificanceMaternal protein restriction during lactation results in alterations in GFR, renal Na+ handling and in components of the Ang II-linked regulatory pathway of renal Na+ reabsorption. At the molecular level, they provide a framework for understanding how metabolic programming of renal mechanisms contributes to the onset of hypertension in adulthood.

241 EFFECT OF MATERNAL PERICONCEPTIONAL UNDERNUTRITION ON MALE OFFSPRING PHYSIOLOGY AND TESTICULAR DEVELOPMENT

Epidemiological studies in humans, as well as animal models, have shown that maternal environment at critical periods of fetal development can condition offspring adult health. Previous studies have shown effects of maternal undernutrition during early to mid gestation on Sertoli cell proliferation and seminiferous tubule diameter in male lambs of 10 months of age. Delayed follicular maturation and meiosis in female fetuses have been reported after maternal undernutrition from mating. The aim of this project was to evaluate the long-term effects of maternal periconceptional undernutrition on offspring physiology and reproductive function. Postnatal development of male offspring is presented here. Fifty-two control females of Merinos d’Arles breed (R100) were fed a normal diet adapted to their needs, and 64 restricted females (R50) received 50% of their dietary needs from 15 days before until 30 days after synchronized breeding. Thereafter, both groups were fed to meet their nutritional requirements. Males were weighed at birth and every week. Blood samples were collected monthly to monitor plasma leptin and cortisol concentrations. Organ weights were recorded at commercial slaughter (35 kg) and histological analysis was performed on testicles and adrenals. Data were analysed by ANOVA or Student’s test. Twenty-two live R100 and 34 live R50 male lambs were obtained. Gestation was significantly longer in the restricted group (P &lt; 0.01). Growth rate, live weight, and age at slaughter were not significantly different between groups. Plasma leptin concentrations were significantly lower at birth (P &lt; 0.001) and tended to be higher at 4 months of age (P = 0.09) in R50. There was a significant interaction between group, age, and litter size for basal cortisol concentrations: in singletons (n = 15 R50 and n = 8 R100), cortisol was significantly lower in R50 at 3 months of age (P &lt; 0.05) and tended to be higher at 4 months whereas in twins (n = 17 R50 and n = 10 R100), cortisol was significantly lower at birth (P &lt; 0.05) but not thereafter (triplets were not considered here because of low numbers). There was no statistical difference for carcass, testicle, or kidney weight. In contrast, carcass to live weight ratio and perirenal fat to live weight ratio were increased in all R50 (P &lt; 0.05). Adrenal to live weight ratio tended to be increased in R50 lambs (P = 0.06). Histological examination revealed no statistical difference between groups for adrenal corticomedullary ratio, zona glomerulosa to medulla ratio, and zona fasciculata to medulla ratio. There was no significant difference for the analysis of testicular tissue (diameter and surface of seminiferous tubules). The expression of genes involved in testicular differentiation (SRY, 3β-HSD, OCT3/4, VASA, stra8, SOX9) is currently being studied by quantitative PCR and will be presented. These results confirm the effects of periconceptional undernutrition on metabolic function but so far, no effect has been demonstrated on testicular histology. Litter size seems to play an important role, because effects were different between singletons and twins.

Dietary regulation of developmental programming in ruminants: epigenetic modifications in the germline

Ruminants have been utilised extensively to investigate the developmental origins of health and disease, with the sheep serving as the model species of choice to complement dietary studies in the rat and mouse. Surprisingly few studies, however, have investigated delayed effects of maternal undernutrition during pregnancy on adult offspring health and a consistent phenotype, together with underlying mechanistic pathways, has not emerged. Nevertheless, when broad consideration is given to all studies with ruminants it is apparent that interventions that are initiated very early in gestation, and/or prior to conception, lead to greater effects on adult physiology than those that are specifically targeted to late gestation. Effects induced following dietary interventions at the earliest stages of mammalian development have been shown to arise as a consequence of alterations to key epigenetic processes that occur in germ cells and pluripotent embryonic cells. Currently, our understanding of epigenetic programming in the germline is greatest for the mouse, and is considered in detail in this article together with what is known in ruminants. This species imbalance, however, looks set to change as fully annotated genomic maps are developed for domesticated large animal species, and with the advent of 'next-generation' DNA sequencing technologies that have the power to globally map the epigenome at single-base-pair resolution. These developments would help to address such issues as sexually dimorphic epigenetic alterations to DNA methylation that have been found to arise following dietary restrictions during the peri-conceptional period, the effects of paternal nutritional status on epigenetic programming through the germline, and transgenerational studies where, in future, greater emphasis in domesticated ruminants should be placed on traits of agricultural importance.