# Placental Transcriptome Adapations to Maternal Nutrient Restriction in Sheep
## 3 Discussion  
Nutrient restriction during pregnancy reshapes the interaction between, and function of, the maternal, placental, and fetal compartments. Previous studies have indicated that the placenta--specifically the placentome in sheep--is not only nutrient-sensitive, but may be able to adapt to nutrient restriction as measured by the growth of the fetus [5; 6]. Because placental growth precedes fetal growth, a major limitation in placental biology research--including previous studies on sheep--has been the inability to conduct a retrospective assessment of placental development responses that give rise to a spectrum of fetal growth outcomes. Using the pregnant sheep as our model organism, we developed a surgical technique to remove a single placentome during mid-gestation, and then allowed the pregnancy to proceed, which has provided the opportunity for a retrospective assessment of the early and late placental transcriptome based on late gestation fetal weight. Results from these analyses have revealed that a relatively low number of genes are differentially expressed between placentomes from well-fed ewes, NR ewes with NonSGA fetuses, and NR ewes with SGA fetuses--especially in comparison to the number of genes that are differentially expressed over time in the placentome--but those genes are involved in a variety of functions that lead to a broader impact later in pregnancy. Additionally, GSEA analyses have revealed a small number of unique pathways at day 70--including natural-killer-cell-mediated cell toxicity in SGA fetuses--that have interesting implications for placental development and function. A previous study in our laboratory used a microarray analysis to identify transcriptomic changes between SGA and NonSGA placentomes from NR pregnancies at day 125 of pregnancy [6]. Major findings of that study included differentially expressed gene clusters involved in immune response, cell signaling, nutrient response, and nutrient transport [6]. These placentomes also showed histological differences, including decreased placentome volume and total maternal/fetal interface surface area in SGA pregnancies compared to NonSGA pregnancies from NR ewes [5]. The current study showed similar functional differences between SGA and NonSGA placentomes, with chemokine binding and cytokine activity altered at day 135 in addition to signaling receptor binding, nutrient transporter activity, and cell structure molecules. Indeed, certain genes-such as _CD86_, _CXCL10_, and _DYYD_--were differentially expressed in both studies, even with the small difference in timing [6]. Similar observations in late pregnancy between the two studies demonstrate that the model is reproducible, and provide confidence that DEGs identified in mid-gestation are inducing changes in placental function that lead to divergent patterns of fetal growth. In the same cohort of animals as the current study, we previously found that triglycerides and bile acids were accumulating in allanotic fluid during mid-gestation of SGA fetuses from NR ewes, but not in allanotic fluid of NonSGA fetuses, suggesting impaired placental transport. We next found that SLC27A6 protein levels were reduced in mid-gestation placentomes from NR sheep with SGA fetuses, but not in NonSGA fetuses [9]. Interestingly, SLC27A6 is robustly expressed during placental growth, but is only modestly expressed during late gestation, highlighting a potentially novel role for this member of the fatty acid transport family in supporting early placental growth during nutritional hardship. This particular transporter family also has adaptive potential in other species, as both SLC27A2 and SLC27A6 were increased in the late-gestation baboon placenta in response to maternal nutrient restriction [14].