Maternal undernutrition modulates hepatic MicroRNAs expression in the early life of offspring.

Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.

Placental fatty acid transport across late gestation in a baboon model of intrauterine growth restriction.

KEY POINTS: Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and increased risk of lifelong disease, including neurodevelopmental impairment. Fatty acids (FA) are critical for normal brain development, although their transport across the placenta in IUGR pregnancies is poorly understood. The present study used a baboon model of IUGR (maternal nutrient restriction, MNR) to investigate placental expression of FA transport and binding proteins, and to determine gestational age-related changes in maternal and fetal plasma FA concentrations. We found MNR to be associated with increased placental expression of FA binding and transport proteins in late gestation, with fetal plasma FA concentrations that were similar to those of control animals. The present study is the first to report a profile of fetal and maternal plasma FA concentrations in a baboon model of growth restriction with data that suggest adaptation of placental transport to maintain delivery of critically needed FA. ABSTRACT: Intrauterine growth restriction (IUGR) is associated with specific changes in placental transport of amino acids, folate and ions. However, little is known about placental fatty acid (FA) transport in IUGR. We hypothesized that placental FA transport proteins (FATP) and FA binding proteins (FABP) are up-regulated and fetal plasma FA concentrations are decreased at term in a baboon model of IUGR. Pregnant baboons were fed control or maternal nutrient restricted (MNR) diet (70% of control calories) from gestation day (GD) 30 (term 184 days). Plasma and placental samples were collected at GD120 (control n = 8, MNR n = 9), GD140 (control n = 6, MNR n = 7) and GD170 (control n = 6, MNR n = 6). Placentas were homogenized, and syncytiotrophoblast microvillous plasma membrane (MVM) and basal plasma membranes (BM) were isolated. Protein expression of FABP1, 3, 4 and 5 (homogenate) and FATP2, 4, and 6 (MVM, BM) was determined by Western blotting. FA content in maternal and umbilical vein plasma was measured by gas chromatography-mass spectrometry. Placental FABP1 and FABP5 expression was increased in MNR compared to controls at GD170, as was MVM FATP2 and FATP6 expression at GD140 and FATP2 expression at GD170. BM FATP4 and FATP6 expression was increased in MNR at GD140. Fetal plasma FA concentrations were similar in controls and MNR. These data suggest the adaptation of placental transport when aiming to maintain delivery of critically needed FAs for fetal growth and brain development.

Maternal Nutrient Restriction and Skeletal Muscle Development: Consequences for Postnatal Health.

Severe undernutrition and famine continue to be a worldwide concern, as cases have been increasing in the past 5 years, particularly in developing countries. The occurrence of nutrient restriction (NR) during pregnancy affects fetal growth, leading to small for gestational age (SGA) or intrauterine growth restricted (IUGR) offspring. During adulthood, SGA and IUGR offspring are at a higher risk for the development of metabolic syndrome. Skeletal muscle is particularly sensitive to prenatal NR. This tissue plays an essential role in oxidation and glucose metabolism because roughly 80% of insulin-mediated glucose uptake occurs in muscle, and it represents around 40% of body weight. Alterations in myofiber number, hypertrophy and myofiber type composition, decreased protein synthesis, lower mitochondrial content and activity of oxidative enzymes, and increased accumulation of intramuscular triglycerides are among the described programming effects of maternal NR on skeletal muscle. Together, these features would add to a phenotype that is prone to insulin resistance, type 2 diabetes, obesity, and metabolic syndrome. Insights from diverse animal models (i.e. ovine, swine, and rodent) have provided valuable information regarding the molecular mechanisms behind those altered developmental pathways. Understanding those molecular signatures supports the development of efficient treatments to counteract the effects of maternal NR on skeletal muscle, and its negative implications for postnatal health.

Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons.

KEY POINTS: Maternal nutrient restriction induces intrauterine growth restriction (IUGR) and leads to heightened cardiovascular risks later in life. We report right ventricular (RV) filling and ejection abnormalities in IUGR young adult baboons using cardiac magnetic resonance imaging. Both functional and morphological indicators of poor RV function were seen, many of which were similar to effects of ageing, but also with a few key differences. We observed more pronounced RV changes compared to our previous report of the left ventricle, suggesting there is likely to be a component of isolated RV abnormality in addition to expected haemodynamic sequelae from left ventricular dysfunction. In particular, our findings raise the suspicion of pulmonary hypertension after IUGR. This study establishes that IUGR also leads to impairment of the right ventricle in addition to the left ventricle classically studied. ABSTRACT: Maternal nutrient restriction induces intrauterine growth restriction (IUGR), increasing later life chronic disease including cardiovascular dysfunction. Our left ventricular (LV) CMRI studies in IUGR baboons (8 M, 8 F, 5.7 years - human equivalent approximately 25 years), control offspring (8 M, 8 F, 5.6 years), and normal elderly (OLD) baboons (6 M, 6 F, mean 15.9 years) revealed long-term LV abnormalities in IUGR offspring. Although it is known that right ventricular (RV) function is dependent on LV health, the IUGR right ventricle remains poorly studied. We examined the right ventricle with cardiac magnetic resonance imaging in the same cohorts. We observed decreased ejection fraction (49 ± 2 vs. 33 ± 3%, P < 0.001), cardiac index (2.73 ± 0.27 vs. 1.89 ± 0.20 l min-1 m-2 , P < 0.05), early filling rate/body surface area (BSA) (109.2 ± 7.8 vs. 44.6 ± 7.3 ml s-1  m-2 , P < 0.001), wall thickening (61 ± 3 vs. 44 ± 5%, P < 0.05), and longitudinal shortening (26 ± 3 vs. 15 ± 2%, P < 0.01) in IUGR animals with increased chamber volumes. Many, but not all, of these changes share similarities to normal older animals. Our findings suggest IUGR-induced pulmonary hypertension should be further investigated and that atrial volume, pulmonic outflow and interventricular septal motion may provide valuable insights into IUGR cardiovascular physiology. Overall, our findings reaffirm that gestational and neonatal challenges can result in long-term programming of poor offspring cardiovascular health. To our knowledge, this is the first study reporting IUGR-induced programmed adult RV dysfunction in an experimental primate model.

Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries.

The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in the maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control [100% U.S. National Research Council (NRC)] or nutrient-restricted (60% NRC) diet from days 50 to 130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA-resistant response to bradykinin. In fetal coronary arteries from nutrient-restricted ewes, relaxation to bradykinin was fully suppressed by NLA. Large-conductance, calcium-activated potassium channel (BKCa) currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa openers, BMS 191011 and NS1619, and 14,15-epoxyeicosatrienoic acid [a putative endothelium-derived hyperpolarizing factor (EDHF)] each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by a decreased number or activity of BKCa channels or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on nitric oxide, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.

One-carbon metabolite supplementation to nutrient-restricted beef heifers affects placental vascularity during early pregnancy.

We hypothesized that restricted maternal nutrition and supplementation of one-carbon metabolites (OCM; methionine, folate, choline, and vitamin B12) would affect placental vascular development during early pregnancy. A total of 43 cows were bred, and 32 heifers successfully became pregnant with female calves, leading to the formation of four treatment groups: CON - OCM (n = 8), CON + OCM (n = 7), RES - OCM (n = 9), and RES + OCM (n = 8). The experimental design was a 2 × 2 factorial, with main factors of dietary intake affecting average daily gain: control (CON; 0.6 kg/d ADG) and restricted (RES; -0.23 kg/d ADG); and OCM supplementation (+OCM) in which the heifers were supplemented with rumen-protected methionine (7.4 g/d) and choline (44.4 g/d) and received weekly injections of 320 mg of folate and 20 mg of vitamin B12, or received no supplementation (-OCM; corn carrier and saline injections). Heifers were individually fed and randomly assigned to treatment at breeding (day 0). Placentomes were collected on day 63 of gestation (0.225 of gestation). Fluorescent staining with CD31 and CD34 combined with image analysis was used to determine the vascularity of the placenta. Images were analyzed for capillary area density (CAD) and capillary number density (CND). Areas evaluated included fetal placental cotyledon (COT), maternal placental caruncle (CAR), whole placentome (CAR + COT), intercotyledonary fetal membranes (ICOT, or chorioallantois), intercaruncular endometrium (ICAR), and endometrial glands (EG). Data were analyzed with the GLM procedure of SAS, with heifer as the experimental unit and significance at P ≤ 0.05 and a tendency at P > 0.05 and P < 0.10. Though no gain × OCM interactions existed (P ≥ 0.10), OCM supplementation increased (P = 0.01) CAD of EG, whereas nutrient restriction tended (P < 0.10) to increase CAD of ICOT and CND of COT. Additionally, there was a gain × OCM interaction (P < 0.05) for CAD within the placentome and ICAR, such that RES reduced and supplementation of RES with OCM restored CAD. These results indicate that maternal rate of gain and OCM supplementation affected placental vascularization (capillary area and number density), which could affect placental function and thus the efficiency of nutrient transfer to the fetus during early gestation.

In cow­calf production, periods of poor forage availability or quality can result in nutrient restriction during pregnancy. Previous studies have shown that even moderate maternal feed restriction during pregnancy, including very early in pregnancy, has profound effects on fetal and placental development, potentially having lasting impacts on calf growth and body composition later in life. One-carbon metabolites (OCM) in the diet are biomolecules required for methylation reactions and participate in the regulation of gene expression. Our objective was to evaluate the effects of nutrient restriction and OCM supplementation (specifically methionine, choline, folate, and vitamin B12) on placental vascular development during early pregnancy. Proper placental vascular development is necessary for healthy pregnancy outcomes, reflected by normal birth weight and healthy offspring. Our results indicated that maternal rate of gain and OCM supplementation affect placental vascularization, which could affect placental function and thereby fetal development throughout gestation. In the context of beef cattle production, our study sheds light on strategies that could enhance placental vascular development during early pregnancy. However, it is essential to recognize the nuances in our data, highlighting the need for further research to fully comprehend these intricate processes.

AMPK-mTORC1 pathway mediates hepatic IGFBP-1 phosphorylation in glucose deprivation: a potential molecular mechanism of hypoglycemia-induced impaired fetal growth.

Mechanisms underlying limitations in glucose supply that restrict fetal growth are not well established. IGF-1 is an important regulator of fetal growth and IGF-1 bioavailability is markedly inhibited by IGFBP-1 especially when the binding protein is hyperphosphorylated. We hypothesized that the AMPK-mTORC1 pathway increases IGFBP-1 phosphorylation in response to glucose deprivation. Glucose deprivation in HepG2 cells activated AMPK and TSC2, inhibited mTORC1 and increased IGFBP-1 secretion and site-specific phosphorylation. Glucose deprivation also decreased IGF-1 bioavailability and IGF-dependent activation of IGF-1R. AICAR (an AMPK activator) activated TSC2, inhibited mTORC1, and increased IGFBP-1 secretion/phosphorylation. Further, siRNA silencing of either AMPK or TSC2 prevented mTORC1 inhibition and IGFBP-1 secretion and phosphorylation in glucose deprivation. Our data suggest that the increase in IGFBP-1 phosphorylation in response to glucose deprivation is mediated by the activation of AMPK/TSC2 and inhibition of mTORC1, providing a possible mechanistic link between glucose deprivation and restricted fetal growth.

Influence of Maternal Protein Restriction in Primiparous Beef Heifers during Mid- and/or Late-Gestation on Progeny Feedlot Performance and Carcass Characteristics.

This study investigated the impacts of metabolizable protein (MP) restriction in primiparous heifers during mid- and/or late-gestation on progeny performance and carcass characteristics. Heifers were allocated to 12 pens in a randomized complete block design. The factorial treatment structure included two stages of gestation (mid- and late-) and two levels of dietary protein (control (CON); ~101% of MP requirements and restricted (RES); ~80% of MP requirements). Half of the pens on each treatment were randomly reassigned to the other treatment at the end of mid-gestation. Progeny were finished in a GrowSafe feeding system and carcass measurements were collected. Gestation treatment x time interactions indicated that MP restriction negatively influenced heifer body weight (BW), body condition score, and longissimus muscle (LM) area (p < 0.05), but not fat thickness (p > 0.05). Treatment did not affect the feeding period, initial or final BW, dry matter intake, or average daily gain of progeny (p > 0.05). The progeny of dams on the RES treatment in late gestation had a greater LM area (p = 0.04), but not when adjusted on a hot carcass weight basis (p > 0.10). Minimal differences in the animal performance and carcass characteristics suggest that the level of MP restriction imposed during mid- and late-gestation in this study did not have a significant developmental programming effect.

Maternal Nutrient Restriction Disrupts Gene Expression and Metabolites Associated with Urea Cycle, Steroid Synthesis, Glucose Homeostasis, and Glucuronidation in Fetal Calf Liver.

This study aimed to understand the mechanisms underlying the effects of maternal undernutrition (MUN) on liver growth and metabolism in Japanese Black fetal calves (8.5 months in utero) using an approach that integrates metabolomics and transcriptomics. Dams were fed 60% (low-nutrition; LN) or 120% (high-nutrition; HN) of their overall nutritional requirements during gestation. We found that MUN markedly decreased the body and liver weights of the fetuses; metabolomic analysis revealed that aspartate, glycerol, alanine, gluconate 6-phosphate, and ophthalmate levels were decreased, whereas UDP-glucose, UDP-glucuronate, octanoate, and 2-hydroxybutyrate levels were decreased in the LN fetal liver (p ≤ 0.05). According to metabolite set enrichment analysis, the highly different metabolites were associated with metabolisms including the arginine and proline metabolism, nucleotide and sugar metabolism, propanoate metabolism, glutamate metabolism, porphyrin metabolism, and urea cycle. Transcriptomic and qPCR analyses revealed that MUN upregulated QRFPR and downregulated genes associated with the glucose homeostasis (G6PC, PCK1, DPP4), ketogenesis (HMGCS2), glucuronidation (UGT1A1, UGT1A6, UGT2A1), lipid metabolism (ANGPTL4, APOA5, FADS2), cholesterol and steroid homeostasis (FDPS, HSD11B1, HSD17B6), and urea cycle (CPS1, ASS1, ASL, ARG2). These metabolic pathways were extracted as relevant terms in subsequent gene ontology/pathway analyses. Collectively, these results indicate that the citrate cycle was maintained at the expense of activities of the energy metabolism, glucuronidation, steroid hormone homeostasis, and urea cycle in the liver of MUN fetuses.

Effect of maternal nutrient restriction on expression of glucose transporters (SLC2A4 and SLC2A1) and insulin signaling in skeletal muscle of SGA and Non-SGA sheep fetuses.

Maternal nutrient restriction (NR) causes small for gestational age (SGA) offspring, which are at higher risk for accelerated postnatal growth and developing insulin resistance in adulthood. Skeletal muscle is essential for whole-body glucose metabolism, as 80% of insulin-mediated glucose uptake occurs in this tissue. Maternal NR can alter fetal skeletal muscle mass, expression of glucose transporters, insulin signaling, and myofiber type composition. It also leads to accumulation of intramuscular triglycerides (IMTG), which correlates to insulin resistance. Using a 50% NR treatment from gestational day (GD) 35 to GD 135 in sheep, we routinely observe a spectral phenotype of fetal weights within the NR group. Thus, we classified those fetuses into NR(Non-SGA; n = 11) and NR(SGA; n = 11). The control group (n = 12) received 100% of nutrient requirements throughout pregnancy. At GD 135, fetal plasma and gastrocnemius and soleus muscles were collected. In fetal plasma, total insulin was lower in NR(SGA) fetuses compared NR(Non-SGA) and control fetuses (P < 0.01), whereas total IGF-1 was lower in NR(SGA) fetuses compared with control fetuses (P < 0.05). Within gastrocnemius, protein expression of insulin receptor (INSRB; P < 0.05) and the glucose transporters, solute carrier family 2 member 1 and solute carrier family 2 member 4, was higher (P < 0.05) in NR(SGA) fetuses compared with NR(Non-SGA) fetuses; IGF-1 receptor protein was increased (P < 0.01) in NR(SGA) fetuses compared with control fetuses, and a lower (P < 0.01) proportion of type I myofibers (insulin sensitive and oxidative) was observed in SGA fetuses. For gastrocnemius muscle, the expression of lipoprotein lipase (LPL) messenger RNA (mRNA) was upregulated (P < 0.05) in both NR(SGA) and NR(Non-SGA) fetuses compared with control fetuses, whereas carnitine palmitoyltransferase 1B (CPT1B) mRNA was higher (P < 0.05) in NR(Non-SGA) fetuses compared with control fetuses, but there were no differences (P > 0.05) for protein levels of LPL or CPT1B. Within soleus, there were no differences (P > 0.05) for any characteristic except for the proportion of type I myofibers, which was lower (P < 0.05) in NR(SGA) fetuses compared with control fetuses. Accumulation of IMTG did not differ (P > 0.05) in gastrocnemius or soleus muscles. Collectively, the results indicate molecular differences between SGA and Non-SGA fetuses for most characteristics, suggesting that maternal NR induces a spectral phenotype for the metabolic programming of those fetuses.

Maternal Undernutrition during Pregnancy Alters Amino Acid Metabolism and Gene Expression Associated with Energy Metabolism and Angiogenesis in Fetal Calf Muscle.

To elucidate the mechanisms underlying maternal undernutrition (MUN)-induced fetal skeletal muscle growth impairment in cattle, the longissimus thoracis muscle of Japanese Black fetal calves at 8.5 months in utero was analyzed by an integrative approach with metabolomics and transcriptomics. The pregnant cows were fed on 60% (low-nutrition, LN) or 120% (high-nutrition, HN) of their overall nutritional requirement during gestation. MUN markedly decreased the bodyweight and muscle weight of the fetus. The levels of amino acids (AAs) and arginine-related metabolites including glutamine, gamma-aminobutyric acid (GABA), and putrescine were higher in the LN group than those in the HN group. Metabolite set enrichment analysis revealed that the highly different metabolites were associated with the metabolic pathways of pyrimidine, glutathione, and AAs such as arginine and glutamate, suggesting that MUN resulted in AA accumulation rather than protein accumulation. The mRNA expression levels of energy metabolism-associated genes, such as PRKAA1, ANGPTL4, APLNR, CPT1B, NOS2, NOS3, UCP2, and glycolytic genes were lower in the LN group than in the HN group. The gene ontology/pathway analysis revealed that the downregulated genes in the LN group were associated with glucose metabolism, angiogenesis, HIF-1 signaling, PI3K-Akt signaling, pentose phosphate, and insulin signaling pathways. Thus, MUN altered the levels of AAs and expression of genes associated with energy expenditure, glucose homeostasis, and angiogenesis in the fetal muscle.

Effect of maternal nutrient restriction on skeletal muscle mass and associated molecular pathways in SGA and Non-SGA sheep fetuses.

Maternal nutrient restriction causes small for gestational age (SGA) offspring, which exhibit a higher risk for metabolic syndrome in adulthood. Fetal skeletal muscle is particularly sensitive to maternal nutrient restriction, which impairs muscle mass and metabolism. Using a 50% nutrient restriction treatment from gestational day (GD) 35 to GD 135 in sheep, we routinely observe a spectral phenotype of fetal weights within the nutrient-restricted (NR) group. Thus, our objective was to evaluate the effect of maternal NR on muscle mass, myofiber hypertrophy, myonuclear dotation, and molecular markers for protein synthesis and degradation, while accounting for the observed fetal weight variation. Within the NR group, we classified upper-quartile fetuses into NR(Non-SGA) (n = 11) and lower-quartile fetuses into NR(SGA) (n = 11). A control group (n = 12) received 100% of nutrient requirements throughout pregnancy. At GD 135, fetal plasma and organs were collected, and gastrocnemius and soleus muscles were sampled for investigation. Results showed decreased (P < 0.05) absolute tissue/organ weights, including soleus and gastrocnemius muscles, in NR(SGA) fetuses compared to NR(Non-SGA) and control. Myofiber cross-sectional area was smaller in NR(SGA) vs control for gastrocnemius (P = 0.0092) and soleus (P = 0.0097) muscles. Within the gastrocnemius muscle, the number of myonuclei per myofiber was reduced (P = 0.0442) in NR(SGA) compared to control. Cortisol may induce protein degradation. However, there were no differences in fetal cortisol among groups. Nevertheless, for gastrocnemius muscle, cortisol receptor (NR3C1; P = 0.0124), and FOXO1 (P = 0.0131) were upregulated in NR(SGA) compared to control while NR(Non-SGA) did not differ from the other 2 groups. KLF15 was upregulated (P = 0.0002) in both NR(SGA) and NR(Non-SGA); while FBXO32, TRIM63, BCAT2 or MSTN did not differ. For soleus muscle, KLF15 mRNA was upregulated (P = 0.0145) in NR(SGA) compared to control, and expression of MSTN was increased (P = 0.0259) in NR(SGA) and NR(Non-SGA) compared to control. At the protein level, none of the mentioned molecules nor total ubiquitin-labeled proteins differed among groups (P > 0.05). Indicators of protein synthesis (total and phosphorylated MTOR, EI4EBP1, and RPS6KB1) did not differ among groups in either muscle (P > 0.05). Collectively, results highlight that maternal NR unequally affects muscle mass in NR(SGA) and NR(Non-SGA) fetuses, and alterations in myofiber cross-sectional area and myonuclei number partially explain those differences.

Effects of maternal nutrient restriction followed by realimentation during early and mid-gestation in beef cows. II. Placental development, umbilical blood flow, and uterine blood flow responses to diet alterations.

The objectives were to examine the effects of maternal nutrient restriction followed by realimentation during early to mid-gestation on placental development and uterine and umbilical hemodynamics in the beef cow. On day 30 of pregnancy, multiparous, non-lactating beef cows (620.5 ±â€¯11.3 kg) were assigned to 1 of 2 dietary treatments: control (C; 100% National Research Council [NRC] recommendations; n = 18) and restricted (R; 60% NRC; n = 30). On day 85, cows were slaughtered (C, n = 6; R, n = 6), remained on control (CC; n = 12) and restricted (RR; n = 12), or were realimented to control (RC; n = 11). On day 140, cows were slaughtered (CC, n = 6; RR, n = 6; RC, n = 5), remained on control (CCC, n = 6; RCC, n = 5), or were realimented to control (RRC, n = 6). On day 254, all remaining cows were slaughtered. Heart rate and umbilical and uterine hemodynamics [blood flow, resistance index (RI), and pulsatility index (PI)] were determined via Doppler ultrasonography. As expected umbilical blood flow increased and fetal heart rate decreased as gestation advanced. Umbilical PI in RRC cows was less (P = 0.01) compared to RCC and CCC. During late gestation, RCC cows had greater (P = 0.02) ipsilateral and total uterine blood flow vs. CCC and RRC. There was an increase in the number and weight of placentomes from R cows (P ≤ 0.02) compared to C cows (i.e. day 85). There were more placentomes (P = 0.03) in RR vs. CC and RC cows, but placentome weight was not affected (P = 0.18) by maternal dietary treatment at day 140. Maternal nutrient restriction during early to mid-gestation increased the weight (by day 85) and number (day 85 and 140) of placentomes, and did not reduce fetal weight compared to control cows. A longer realimentation period may enhance uterine blood flow and individual placentome size during later gestation, which may compensate for reduced nutrients experienced early in gestation.

Poor perinatal growth impairs baboon aortic windkessel function.

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/m2 v. 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.

The use of ultrasound to assess fetal growth in a guinea pig model of fetal growth restriction.

Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar between the species. Nutrient restriction of the dam creates growth-restricted fetuses while leaving an intact uteroplacental circulation, vital for evaluating novel therapies for FGR. Growth-restricted fetuses were generated by feeding Dunkin Hartley guinea pig dams 70% of ad libitum intake from four weeks before and throughout pregnancy. The effect of maternal nutrient restriction (MNR) on dams and fetuses was carefully monitored, and ultrasound measurements of pups collected. There was no difference in maternal weight at conception, however by five weeks post conception MNR dams were significantly lighter ( P < 0.05). MNR resulted in significantly smaller pup size from 0.6-0.66 gestation. Ultrasound is a powerful non-invasive tool for assessing the effect of therapeutic interventions on fetal growth, allowing longitudinal measurement of fetuses. This model and method yield data applicable to the human condition without the need for animal sacrifice and will be useful in the translation of therapies for FGR into the clinic.

Premature Brain Aging in Baboons Resulting from Moderate Fetal Undernutrition.

Contrary to the known benefits from a moderate dietary reduction during adulthood on life span and health, maternal nutrient reduction during pregnancy is supposed to affect the developing brain, probably resulting in impaired brain structure and function throughout life. Decreased fetal nutrition delivery is widespread in both developing and developed countries, caused by poverty and natural disasters, but also due to maternal dieting, teenage pregnancy, pregnancy in women over 35 years of age, placental insufficiency, or multiples. Compromised development of fetal cerebral structures was already shown in our baboon model of moderate maternal nutrient reduction. The present study was designed to follow-up and evaluate the effects of moderate maternal nutrient reduction on individual brain aging in the baboon during young adulthood (4-7 years; human equivalent 14-24 years), applying a novel, non-invasive neuroimaging aging biomarker. The study reveals premature brain aging of +2.7 years (p < 0.01) in the female baboon exposed to fetal undernutrition. The effects of moderate maternal nutrient reduction on individual brain aging occurred in the absence of fetal growth restriction or marked maternal weight reduction at birth, which stresses the significance of early nutritional conditions in life-long developmental programming. This non-invasive MRI biomarker allows further longitudinal in vivo tracking of individual brain aging trajectories to assess the life-long effects of developmental and environmental influences in programming paradigms, aiding preventive and curative treatments on cerebral atrophy in experimental animal models and humans.