Chorionic somatomammotropin impacts early fetal growth and placental gene expression.

Several developmental windows, including placentation, must be negotiated to establish and maintain pregnancy. Impaired placental function can lead to preeclampsia and/or intrauterine growth restriction (IUGR), resulting in increased infant mortality and morbidity. It has been hypothesized that chorionic somatomammotropin (CSH) plays a significant role in fetal development, potentially by modifying maternal and fetal metabolism. Recently, using lentiviral-mediated in vivo RNA interference in sheep, we demonstrated significant reductions in near-term (135 days of gestation; dGA) fetal and placental size, and altered fetal liver gene expression, resulting from CSH deficiency. We sought to examine the impact of CSH deficiency on fetal and placental size earlier in gestation (50 dGA), and to examine placental gene expression at 50 and 135 dGA. At 50 dGA, CSH-deficient pregnancies exhibited a 41% reduction (P ≤ 0.05) in uterine vein concentrations of CSH, and significant (P ≤ 0.05) reductions (≈21%) in both fetal body and liver weights. Placentae harvested at 50 and 135 dGA exhibited reductions in IGF1 and IGF2 mRNA concentrations, along with reductions in SLC2A1 and SLC2A3 mRNA. By contrast, mRNA concentrations for various members of the System A, System L and System y+ amino acid transporter families were not significantly impacted. The IUGR observed at the end of the first-third of gestation indicates that the near-term IUGR reported previously, began early in gestation, and may have in part resulted from deficits in the paracrine action of CSH within the placenta. These results provide further compelling evidence for the importance of CSH in the progression and outcome of pregnancy.

Specificity protein-1 and -3 trans-activate the ovine placental lactogen gene promoter.

The proximal promoter (-383/+16) of the ovine placental lactogen (oPL) gene provides trophoblast-specific expression in vitro. Footprint 6 (FP6; -319/-349) lies within this region, and transfection of two-base pair mutations across FP6 into BeWo cells identified potential binding sites for CCAAT-enhancer binding protein (CEBP) and specificity proteins (Sp). Transfection of CEBP dominant negative or over-expression constructs did not impact transactivation of the proximal promoter. However, Sp1 and Sp3 over-expression constructs increased (p

Transcriptional regulation in the placenta during normal and compromised fetal growth.

The placenta synthesizes a number of cytokines and growth factors that are involved in the establishment, maintenance or regulation of pregnancy. Included are interferons, placental lactogens, other members of the growth hormone/prolactin gene family, leptin, and an array of angiogenic growth factors. While their roles in pregnancy differ, in their absence pregnancy is either lost or compromised. Therefore an understanding of the cell-specific transcriptional regulation of these genes is imperative if we are ever to alter their expression to benefit pregnancy progression. Our understanding of transcriptional regulation in the placenta is still in its infancy, and there appears to be considerable divergence in the transcriptional regulation of these genes between species, as well as between the various cytokine genes being examined. For example, while there are some commonalities in the regulation of human, rodent and ruminant placental lactogens, there are differences that require the study of placental lactogen gene regulation across species. However, one common theme that is emerging with the angiogenic growth factors, such as vascular endothelial growth factor and the angiopoietins, is the transcriptional control of these genes by oxygen tension within the placenta. Examination of transcriptional regulation in normal and compromised pregnancies will provide additional insight in this area.