Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum. MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

Premature birth, bronchopulmonary dysplasia or restrictive nutrition in the first weeks of postnatal life may have repercussions on lung development and affect long-term lung function outcomes. This prospective observational study is based on a cohort of 313 very low birth weight (VLBW) neonates, born between 1 January 2008 and 1 December 2016. The daily intake of calories, protein, fat and carbohydrates during the first week of life and evidence of inadequate weight gain (Δwt) until week 36 of gestational age (GA) were recorded. FEV1, FEF25–75 %, forced vital capacity (FVC) and the FEV1/FVC ratio were determined. The relations between these parameters were determined by regression analysis. Spirometric parameters were obtained for 141 children with a mean age of 9 years (95 % CI 7, 11); 69 of them (48·9 %) had presented wheezing episodes on more than three occasions. In addition, 60 (42·5 %) had a history of bronchopulmonary dysplasia. Of these, n 40 (66·6 %) had a history of wheezing. Significant association between protein/energy intake in the first week of life and the lung function parameters analysed was observed. Poor Δwt to GA week 36 was significantly associated with decreased mean pulmonary flow. Inadequate protein/energy intake in the first week of life of VLBW newborns and poor Δwt to week 36 of GA is associated with a significant worsening of lung function parameters.

There is a strong relationship between low birth weight (LBW) and an increased risk of developing cardiovascular disease (CVD). In postnatal life, LBW offspring are becoming more commonly exposed to the additional independent CVD risk factors, such as an obesogenic diet. However, how an already detrimentally programmed LBW myocardium responds to a secondary insult, such as an obesogenic diet (western diet; WD), during postnatal life is ill defined. Herein, we aimed to determine in a pre-clinical guinea pig model of CVD, both the independent and interactive effects of LBW and a postnatal WD on the molecular pathways that regulate cardiac growth and metabolism. Uterine artery ablation was used to induce placental insufficiency (PI) in pregnant guinea pigs to generate LBW offspring. Normal birth weight (NBW) and LBW offspring were weaned onto either a Control diet or WD. At ˜145 days after birth (young adulthood), male and female offspring were humanely killed, the heart weighed and left ventricle tissue collected. The mRNA expression of signalling molecules involved in a pathological hypertrophic and fibrotic response was increased in the myocardium of LBW male, but not female offspring, fed a WD as was the mRNA expression of transcription factors involved in fatty acid oxidation. The mRNA expression of glucose transporters was downregulated by LBW and WD in male, but not female hearts. This study has highlighted a sexually dimorphic cardiac pathological hypertrophic and fibrotic response to the secondary insult of postnatal WD consumption in LBW offspring.

Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6–13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

Nonhuman primate (NHP) studies are crucial to biomedical research. NHPs are the species most similar to humans in lifespan, body size, and hormonal profiles. Planning research requires statistical power evaluation, which is difficult to perform when lacking directly relevant preliminary data. This is especially true for NHP developmental programming studies, which are scarce. We review the sample sizes reported, challenges, areas needing further work, and goals of NHP maternal nutritional programming studies. The literature search included 27 keywords, for example, maternal obesity, intrauterine growth restriction, maternal high-fat diet, and maternal nutrient reduction. Only fetal and postnatal offspring studies involving tissue collection or imaging were included. Twenty-eight studies investigated maternal over-nutrition and 33 under-nutrition; 23 involved macaques and 38 baboons. Analysis by sex was performed in 19; minimum group size ranged from 1 to 8 (mean 4.7 ± 0.52, median 4, mode 3) and maximum group size from 3 to 16 (8.3 ± 0.93, 8, 8). Sexes were pooled in 42 studies; minimum group size ranged from 2 to 16 (mean 5.3 ± 0.35, median 6, mode 6) and maximum group size from 4 to 26 (10.2 ± 0.92, 8, 8). A typical study with sex-based analyses had group size minimum 4 and maximum 8 per sex. Among studies with sexes pooled, minimum group size averaged 6 and maximum 8. All studies reported some significant differences between groups. Therefore, studies with group sizes 3–8 can detect significance between groups. To address deficiencies in the literature, goals include increasing age range, more frequently considering sex as a biological variable, expanding topics, replicating studies, exploring intergenerational effects, and examining interventions.

Numerous studies have investigated the risk of developing asthma due to early-life experiences and environmental exposures. However, the influence of intrauterine growth restriction and postnatal undernutrition on childhood wheezing/asthma remains unclear. Thus, we examined the effects of both small for gestational age (SGA) and postnatal stunted growth on ever asthma among children in the rural areas in Bangladesh.

Multiple follow-up studies were conducted in a cohort of randomized clinical trial of nutrition interventions during pregnancy (the MINIMat trial). Overall, 1208 and 1697 children were followed-up for asthma at 4.5 and 10 years, respectively. Anthropometric measurements were obtained at various intervals from birth to 10 years of age. Ever asthma was identified using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire.

Results showed that SGA was significantly associated with increased risk of ever asthma at 4.5 and 10 years after adjusting for sex, body mass index, socioeconomic status, family history of asthma, gestational age at birth, mother’s parity, mother’s age at birth and intervention trial arm [odds ratio (OR)=1.97 (95% confidence interval (CI): 1.34–2.90) and 1.86 (95% CI: 1.18–2.72)]. For the postnatal effect of undernutrition, stunting at 1 and 2 years was significantly associated with ever asthma at 4.5 and 10 years [1 year: OR=1.77 (95% CI: 1.22–2.57) and OR=1.72 (95% CI: 1.16–2.56), 2 years: OR=1.49 (95% CI: 1.06–2.10) and OR=1.41 (95% CI: 1.02–1.96)].

In conclusion, SGA and undernutrition during infancy has an influence on childhood asthma among children in Bangladesh, indicating the need for nutritional interventions early in life.

Intrauterine growth restriction (IUGR) and fetal exposure to a maternal high-fat diet (HFD) independently increase the risk of developing obesity in adulthood. Excess glucocorticoids increase obesity. We hypothesized that surgically induced IUGR combined with an HFD would increase adiposity and glucocorticoids more than in non-IUGR offspring combined with the same HFD, findings that would persist despite weaning to a regular diet. Non-IUGR (N) and IUGR (I) rat offspring from dams fed either regular rat chow (R) or an HFD (H) were weaned to either a regular rat chow or an HFD. For non-IUGR and IUGR rats, this study design resulted in three diet groups: offspring from dams fed a regular diet and weaned to a regular diet (NRR and IRR), offspring rats from dams fed an HFD and weaned to a regular diet (NHR and IHR) and offspring from dams fed an HFD and weaned to an HFD (NHH and IHH). Magnetic resonance imaging or fasting visceral and subcutaneous adipose tissue collection occurred at postnatal day 60. IHH male rats had greater adiposity than NHH males, findings that were only partly normalized by weaning to a regular chow. IHH male rats had a 10-fold increase in serum corticosterone levels. IHH female rats had increased adiposity and serum triglycerides. We conclude that IUGR combined with an HFD throughout life increased adiposity, glucocorticoids and triglycerides in a sex-specific manner. Our data suggest that one mechanism through which the perinatal environment programs increased adiposity in IHH male rats may be via increased systemic glucocorticoids.

The present study used a sheep model of intrauterine growth restriction, combining maternal undernutrition and twinning, to determine possible markers of early damage to the fetal kidney. The occurrence of early deviations in fetal hemodynamics which may be indicative of changes in blood perfusion was assessed by Doppler ultrasonography. A total of 24 sheep divided in two groups were fed with the same standard grain-based diet but fulfilling either their daily maintenance requirements for pregnancy (control group; n=12, six singleton and six twin pregnancies) or only the 50% of such quantity (food-restricted group; n=12; four singleton and eight twin pregnancies). All the fetuses were assessed by both B-mode and Doppler ultrasonography at Day 115 of pregnancy. Fetal blood supply was affected by maternal undernutrition, although there were still no evidences of brain-sparing excepting in fetuses at greatest challenge (twins in underfed pregnancies). However, there were early changes in the blood supply to the kidneys of underfed fetuses and underfed twins evidenced decreases in kidney size.

The ability of the aorta to buffer blood flow and provide diastolic perfusion (Windkessel function) is a determinant of cardiovascular health. We have reported cardiac dysfunction indicating downstream vascular abnormalities in young adult baboons who were intrauterine growth restricted (IUGR) at birth as a result of moderate maternal nutrient reduction. Using 3 T MRI, we examined IUGR offspring (eight male, eight female; 5.7 years; human equivalent 25 years) and age-matched controls (eight male, eight female; 5.6 years) to quantify distal descending aortic cross-section (AC) and distensibility (AD). ANOVA showed decreased IUGR AC/body surface area (0.9±0.05 cm2/m2v. 1.2±0.06 cm2/m2, M±s.e.m., P<0.005) and AD (1.7±0.2 v. 4.0±0.5×10−3/mmHg, P<0.005) without sex difference or group-sex interaction, suggesting intrinsic vascular pathology and impaired development persisting in adulthood. Future studies should evaluate potential consequences of these changes on coronary perfusion, afterload and blood pressure.

Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM) in vitro. Pregnant Wistar rats were fed an ad libitum diet (control group) or 50% of the ad libitum diet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19–20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessed in vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescence in vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.

Intrauterine growth restriction (IUGR) and maternal stress during pregnancy are two compromises that negatively impact neurodevelopment and increase the risk of developing later life neuropsychiatric disorders such as schizophrenia, depression and behavioural disorders. Neurosteroids, particularly allopregnanolone, are important in protecting the developing brain and promoting many essential neurodevelopmental processes. Individually, IUGR and prenatal stress (PS) reduce myelination and neurogenesis within affected fetal brains, however less information is available on the combined effects of these two disorders on the term fetal brain. This study aimed to investigate how IUGR and PS impairs the neurosteroid pathway when combined using a guinea pig model, and how these then disrupt the neurodevelopment of the fetus. Uterine artery blood flow restriction was performed at GA30-35 to induce growth restriction, whilst PS was induced by exposure of the dam to a strobe light during gestation commencing GA40 and repeated every 5 days. Exposure in this model caused reductions in hippocampal CA1 MBP immunostaining of male fetuses in both IUGR alone and IUGR+PS paradigms but only by IUGR in the subcortical white mater, compared with control males. Plasma allopregnanolone was reduced by both stressors irrespective of sex, whereas GFAP or MAP2 expression were not affected by either stressor. Female neurodevelopment, as assessed by these markers, was unimpeded by these compromises. The addition of prenatal stress did not further compound these deficits.

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic–pituitary–adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.

It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.

Intrauterine growth restriction has been noted to adversely impact morbidity and mortality in the neonatal period as well as cardiovascular well-being in adolescence and adulthood. Recent data based on a wide range of ultrasound parameters during fetal and neonatal life has noted early and persistent involvement of the cardiovascular system. Some of these measures are predictive of long-term morbidities. Assessment of vascular mechanics is a new and novel concept in this population, and opens up avenues for diagnosis, monitoring and evaluation of the likely effectiveness of interventions. Prevention of these adverse vascular and cardiac outcomes secondary to fetal growth restriction may be feasible and of clinical relevance. This review focuses on growth restriction in humans with respect to cardiovascular remodeling and dysfunction during fetal life, persistence of functional cardiac impairment during early childhood and adolescence, and possible preventive strategies.

Hypoxia is the primary stimulus for the production of erythropoietin (EPO) in both fetal and adult life. Here, we investigated fetal plasma EPO concentrations in monochorionic (MC) twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery (UA) Doppler. We diagnosed sIUGR in presence of (1) birth-weight discordance >20% and (2) either twin with a birth weight <10th percentile. An abnormal UA Doppler was defined as a persistent absent-reverse end diastolic flow (AREDF). The intertwin EPO ratio was calculated as the plasma EPO level of the smaller (or small-for-gestational-age) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin. Thirty-two MC twin pairs were included. Of these, 17 pairs were normal twins (Group 1), seven pairs were twins with sIUGR without UA Doppler abnormalities (Group 2), and eight pairs were twins with sIUGR and UA Doppler abnormalities (Group 3). The highest EPO ratio was identified in Group 3 (p < .001) but no significant differences were observed between Groups 1 and 2. Fetal hemoglobin levels did not differ significantly in the three groups, and fetal EPO concentration did not correlate with gestational age at birth. We conclude that fetal plasma EPO concentrations are selectively increased in MC twin pregnancies with sIUGR and abnormal UA Doppler, possibly as a result of uncompensated hypoxia.

The objective of the present study was to investigate the intestinal development of newborn intrauterine growth-restricted (IUGR) piglets subjected to normal nutrient intake (NNI) or restricted nutrient intake (RNI). Newborn normal birth weight (NBW) and IUGR piglets were allotted to NNI or RNI levels for 4 weeks from day 8 postnatal. IUGR piglets receiving NNI had similar growth performance compared with that of NBW piglets. Small intestine length and villous height were greater in IUGR piglets fed the NNI than that of piglets fed the RNI. Lactase activity was increased in piglets fed the NNI compared with piglets fed the RNI. Absorptive function, represented by active glucose transport by the Ussing chamber method and messenger RNA (mRNA) expressions of two main intestinal glucose transporters, Na+-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), were greater in IUGR piglets fed the NNI compared with piglets fed the RNI regimen. The apoptotic process, characterized by caspase-3 activity (a sign of activated apoptotic cells) and mRNA expressions of p53 (pro-apoptotic), bcl-2-like protein 4 (Bax) (pro-apoptotic) and B-cell lymphoma-2 (Bcl-2) (anti-apoptotic), were improved in IUGR piglets fed the NNI regimen. To test the hypothesis that improvements in intestinal development of IUGR piglets fed NNI might be mediated through circulating glucagon-like peptide-2 (GLP-2), GLP-2 was injected subcutaneously to IUGR piglets fed the RNI from day 8 to day 15 postnatal. Although the intestinal development of IUGR piglets fed the RNI regimen was suppressed compared with those fed the NNI regimen, an exogenous injection of GLP-2 was able to bring intestinal development to similar levels as NNI-fed IUGR piglets. Collectively, our results demonstrate that IUGR neonates that have NNI levels could improve intestinal function via the regulation of GLP-2.

In today's world, there is an unprecedented rise in the prevalence of chronic metabolic diseases, including obesity, insulin resistance and type 2 diabetes (T2D). The pathogenesis of T2D includes both genetic and environmental factors, such as excessive energy intake and physical inactivity. It has recently been suggested that environmental factors experienced during early stages of development, including the intrauterine and neonatal periods, might play a major role in predisposing individuals to T2D. Furthermore, several studies have shown that such early environmental conditions might even contribute to disease risk in further generations. In this review, we summarise recent data describing how parental nutrition during development increases the risk of diabetes in the offspring. We also discuss the potential mechanisms underlying transgenerational inheritance of metabolic disease, with particular emphasis on epigenetic mechanisms.