Nutrient Restriction: Placental and Fetal Brain and Renal Outcomes and Mechanism

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

Significance: The overall goal of our PO1 is to extend studies on effects of global maternal nutrient restriction (NR), (MNR - mothers eat 70% feed eaten by ad lib controls (CTR). Uniquely, we will compare data in sheep (the most common fetal model) with our nonhuman primate (NHP) baboon model. Sub-optimal fetal organ growth and development are major obstetric problems associated with increased neonatal death and long term morbidity whose underlying mechanisms are poorly understood. Whilst primary causes are diverse, poor fetal development is generally secondary to fetal NR. Rodent and sheep studies provide insight but parallel NHP data are minimal. Hypothesis: exposure of fetal baboons and sheep to MNR adversely impacts growth and key cellular processes in placenta, fetal brain and fetal kidney. The placenta is the fetal supply line, fetal brain a relatively protected, and kidney an unprotected organ. We hypothesize: 30% global MNR: 1: impairs growth; 2: impairs angiogenesis; 3: impacts the IGF system; 4: impairs placental amino acid transport; 5: alters fetal steroid function; 6: alters angiotensin gene and protein expression; 7. influences apoptosis. We anticipate fetal sex and developmental stage specific effects. Approach: We use the same MNR in a group housed MNR NHP model and sheep to compare MNR with CTR mechanisms. Baboon projects evaluate 1) placental, 2) fetal brain and 3) fetal kidney effects of MNR at 0.33, 0.5. 0.66 and O.Qgestation (G) to determine developmental stage outcomes. Project IV studies sheep fetuses at 0.9G exposed to 30% MNR. Sheep are cost-effective with a large fetal data-base. These two species used in parallel facilitate extrapolation to human development. We combine 1) structural, stereological; 2) biochemical - cell signaling and gene function, with global (gene arrays, proteomics) and single gene/protein (PCR, in situ hybridization, Western blot and immunohistochemical) and in vitro and 3) in vivo approaches. Innovation: 30% MNR produces fetal NR and decreases fetahmaternal glucose, fetal blood urea nitrogen, amino acids and growth factors. No other group uses NHP combined with sheep to evaluate MNR effects on placental and fetal organ structural and functional development. These studies are not possible in human fetuses. Synergy: All projects study similar mechanisms and in vivo experiments unpractical in baboons are conducted in sheep fetuses to facilitate extrapolation of cellular data to systems function. Environment: The three Centers have collaborated for many years. We have experienced and interactive Cores. All methods are ongoing (see preliminary baboon and sheep data at 0.5 and 0.9G). Investigators: In addition to new investigators, PO1 investigators have collaborated for a total over 81 years. Summary: We apply for Years 16-20 support. We have published in major journals, presented internationally, and expanded our team showing continuity, productivity and initiative to change. We use a unique combination of species and approaches to evaluate MNR effects on development of placenta and fetal brain and kidney, key organs for adult health. This PO1 addresses the NICHD National Children's Study.