Placental adaptation to maternal malnutrition.

Maternal malnutrition gives rise to both short- and long-term consequences for the survival and health of the offspring. As the intermediary between mother and fetus, the placenta has the potential to interpret environmental signals, such as nutrient availability, and adapt to support fetal growth and development. While this potential is present, it is clear that at times placental adaptation fails to occur resulting in poor pregnancy outcomes. This review will focus on placental responses to maternal undernutrition related to changes in placental vascularization and hemodynamics and placental nutrient transport systems across species. While much of the available literature describes placental responses that result in poor fetal outcomes, novel models have been developed to utilize the inherent variation in fetal weight when dams are nutrient restricted to identify placental adaptations that result in normal-weight offspring. Detailed analyses of the spectrum of placental responses to maternal malnutrition point to alternations in placental histoarchitectural and vascular development, amino acid and lipid transport mechanisms, and modulation of immune-related factors. Dietary supplementation with selected nutrients, such as arginine, has the potential to improve placental growth and function through a variety of mechanisms including stimulating cell proliferation, protein synthesis, angiogenesis, vasodilation, and gene regulation. Improved understanding of placental responses to environmental cues is necessary to develop diagnostic and intervention strategies to improve pregnancy outcomes.

Obesity increases hepatic glycine dehydrogenase and aminomethyltransferase expression while dietary glycine supplementation reduces white adipose tissue in Zucker diabetic fatty rats.

Obesity is associated with altered glycine metabolism in humans. This study investigated the mechanisms regulating glycine metabolism in obese rats. Eight-week-old Zucker diabetic fatty rats (ZDF; a type-II diabetic animal model) received either 1% glycine or 1.19% L-alanine (isonitrogenous control) in drinking water for 6 weeks. An additional group of lean Zucker rats also received 1.19% L-alanine as a lean control. Glycine concentrations in serum and liver were markedly lower in obese versus lean rats. Enteral glycine supplementation restored both serum and hepatic glycine levels, while reducing mesenteric and internal white fat mass compared with alanine-treated ZDF rats. Blood glucose and non-esterified fatty acid (NEFA) concentrations did not differ between the control and glycine-supplemented ZDF rats (P > 0.10). Both mRNA and protein expression of aminomethyltransferase (AMT) and glycine dehydrogenase, decarboxylating (GLDC) were increased in the livers of obese versus lean rats (P < 0.05). In contrast, glycine cleavage system H (GCSH) hepatic mRNA expression was downregulated in obese versus lean rats, although there was no change in protein expression. These findings indicate that reduced quantities of glycine observed in obese subjects likely results from an upregulation of the hepatic glycine cleavage system and that dietary glycine supplementation potentially reduces obesity in ZDF rats.

Identification of Pathways Associated with Placental Adaptation to Maternal Nutrient Restriction in Sheep.

Maternal nutrient restriction impairs placental growth and development, but available evidence suggests that adaptive mechanisms exist, in a subset of nutrient restricted (NR) ewes, that support normal fetal growth and do not result in intrauterine growth restriction (IUGR). This study utilized Affymetrix GeneChip Bovine and Ovine Genome 1.0 ST Arrays to identify novel placental genes associated with differential fetal growth rates within NR ewes. Singleton pregnancies were generated by embryo transfer and, beginning on Day 35 of pregnancy, ewes received either a 100% National Research Council (NRC) (control-fed group; n = 7) or 50% NRC (NR group; n = 24) diet until necropsy on Day 125. Fetuses from NR ewes were separated into NR non-IUGR (n = 6) and NR IUGR (n = 6) groups based on Day 125 fetal weight for microarray analysis. Of the 103 differentially expressed genes identified, 15 were upregulated and 88 were downregulated in NR non-IUGR compared to IUGR placentomes. Bioinformatics analysis revealed that upregulated gene clusters in NR non-IUGR placentomes associated with cell membranes, receptors, and signaling. Downregulated gene clusters associated with immune response, nutrient transport, and metabolism. Results illustrate that placentomal gene expression in late gestation is indicative of an altered placental immune response, which is associated with enhanced fetal growth, in a subpopulation of NR ewes.

Adaptive responses to maternal nutrient restriction alter placental transport in ewes.

INTRODUCTION: Maternal nutrient partitioning, uteroplacental blood flow, transporter activity, and fetoplacental metabolism mediate nutrient delivery to the fetus. Inadequate availability or delivery of nutrients results in intrauterine growth restriction (IUGR), a leading cause of neonatal morbidity and mortality. Maternal nutrient restriction can result in IUGR, but only in an unforeseeable subset of individuals. METHODS: To elucidate potential mechanisms regulating fetal nutrient availability, singleton sheep pregnancies were generated by embryo transfer. Pregnant ewes received either a 50% NRC (NR; n = 24) or 100% NRC (n = 7) diet from gestational Day 35 until necropsy on Day 125. Maternal weight did not correlate with fetal weight; therefore, the six heaviest (NR Non-IUGR) and five lightest (NR IUGR) fetuses from nutrient-restricted ewes, and seven 100% NRC fetuses, were compared to investigate differences in nutrient availability. RESULTS: Insulin, multiple amino acids, and their metabolites, were reduced in fetal circulation of NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. In contrast, glucose in fetal fluids was not different between groups. There was a nearly two-fold reduction in placentome volume and fetal/maternal interface length in NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. Changes in amino acid concentrations were associated with altered expression of cationic (SLC7A2, SLC7A6, and SLC7A7) and large neutral (SLC38A2) amino acid transporters in placentomes. DISCUSSION: Results establish a novel approach to study placental adaptation to maternal undernutrition in sheep and support the hypothesis that amino acids and polyamines are critical mediators of placental and fetal growth in sheep.

Development of a surgical procedure for removal of a placentome from a pregnant ewe during gestation.

BACKGROUND: In recent decades, there has been a growing interest in the impact of insults during pregnancy on postnatal health and disease. It is known that changes in placental development can impact fetal growth and subsequent susceptibility to adult onset diseases; however, a method to collect sufficient placental tissues for both histological and gene expression analyses during gestation without compromising the pregnancy has not been described. The ewe is an established biomedical model for the study of fetal development. Due to its cotyledonary placental type, the sheep has potential for surgical removal of materno-fetal exchange tissues, i.e., placentomes. A novel surgical procedure was developed in well-fed control ewes to excise a single placentome at mid-gestation. RESULTS: A follow-up study was performed in a cohort of nutrient-restricted ewes to investigate rapid placental changes in response to undernutrition. The surgery averaged 19 min, and there were no viability differences between control and sham ewes. Nutrient restricted fetuses were smaller than controls (4.7 ± 0.1 kg vs. 5.6 ± 0.2 kg; P < 0.05), with greater dam weight loss (- 32.4 ± 1.3 kg vs. 14.2 ± 2.2 kg; P < 0.01), and smaller placentomes at necropsy (5.7 ± 0.3 g vs. 7.2 ± 0.9 g; P < 0.05). Weight of sampled placentomes and placentome numbers did not differ. CONCLUSIONS: With this technique, gestational studies in the sheep model will provide insight into the onset and complexity of changes in gene expression in placentomes resulting from undernutrition (as described in our study), overnutrition, alcohol or substance abuse, and environmental or disease factors of relevance and concern regarding the reproductive health and developmental origins of health and disease in humans and in animals.