The metabolome of human placental tissue: Investigation of first trimester tissue and changes related to preeclampsia in late pregnancy

Unique biochemical and physical challenges to both mother and fetus are observed during human pregnancy, and the placenta plays an important role in protecting the fetus and supporting its development. Consequently, many pregnancy complications are associated with altered placental biochemistry and structure. Here we have further developed a combination of analytical tools for determining the tissue metabolome of placental tissue by applying a methanol/water/chloroform extraction method followed by analysis of the polar fraction (methanol/water) using GC-ToF-MS and of the non-polar fraction (chloroform) using UPLC-LTQ-Orbitrap-MS. This combination maximises the number of different metabolites detected and is the first holistic investigation of placental tissue applying UPLC-MS. Placental tissue differs between early and late first trimester pregnancies in that the developing placenta is exposed to significantly different oxygen tensions and undergoes a change from histiotrophic to haemotrophic nutrition. Application of these metabolomic methods detected 156 unique and chemically identified metabolites that showed statistically significant differences (P <0.05). These included changes in di- and triglycerides, phospholipids, sphingolipids, fatty acids and fatty acid carnitines. This is the first metabolomics study to identify these changes that potentially show the initiation or switch to fatty acid beta-oxidation for mitochondrial ATP production. A separate study showed a small number of changes that were related to the position of sampling of the placental tissue and to the type of delivery from pregnancy. This result indicates that variations associated with sampling position and delivery type are small compared to between-subject variation. However, the authors recommend robust experimental design which may include sampling from the same position of the placenta and from the same delivery type. When comparing tissue from term-uncomplicated pregnancies with those exhibiting preeclampsia at term, 86 unique and chemically identified metabolites showed statistically significant differences (P <0.05). Potential changes in metabolism operating in the mitochondria, in vitamin D metabolism and in oxidative and nitrative stress were observed. These proof-of-principle studies demonstrate the sensitivity of placental tissue metabolomics to define changes related to alterations in environment and perfusion and related to diseases of pregnancy including preeclampsia. Data are available on request.