Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep.

Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n = 8) or 50% (NR; n = 28) of their National Research Council (NRC) recommended intake from days 35-135 of pregnancy were used to elucidate placentome transcriptome alterations at both day 70 and day 135. NR fetuses were further designated into upper (NR NonSGA; n = 7) and lower quartiles (NR SGA; n = 7) based on day 135 fetal weight. At day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene set enrichment analysis (GSEA) revealed significant overrepresentation of genes for natural-killer-cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes, and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship.

Lipid metabolism is altered in maternal, placental, and fetal tissues of ewes with small for gestational age fetuses†.

Nutrient restriction (NR) has the potential to negatively impact birthweight, an indicator of neonatal survival and lifelong health. Those fetuses are termed as small for gestational age (SGA). Interestingly, there is a spectral phenotype of fetal growth rates in response to NR associated with changes in placental development, nutrient and waste transport, and lipid metabolism. A sheep model with a maternal diet, starting at Day 35, of 100% National Research Council (NRC) nutrient requirements (n = 8) or 50% NRC (n = 28) was used to assess alterations in fetuses designated NR SGA (n = 7) or NR NonSGA (n = 7) based on fetal weight at Day 135 of pregnancy. Allantoic fluid concentrations of triglycerides were greater in NR SGA fetuses than 100% NRC and NR NonSGA fetuses at Day 70 (P < 0.05). There was a negative correlation between allantoic fluid concentrations of triglycerides (R2 = 0.207) and bile acids (R2 = 0.179) on Day 70 and fetal weight at Day 135 for NR ewes (P < 0.05). Bile acids were more abundant in maternal and fetal blood for NR SGA compared to 100% NRC and NR NonSGA ewes (P < 0.05). Maternal blood concentrations of NEFAs increased in late pregnancy in NR NonSGA compared to NR SGA ewes (P < 0.05). Protein expression of fatty acid transporter SLC27A6 localized to placentomal maternal and fetal epithelia and decreased in Day 70 NR SGA compared to 100% NRC and NR NonSGA placentomes (P < 0.05). These results identify novel factors associated with an ability of placentae and fetuses in NR NonSGA ewes to adapt to, and overcome, nutritional hardship during pregnancy.

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.