Funding tool: Basic research projects
Project-ID: LS15-014
Project start: 01. Dezember 2016
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 299.100,00

Brief summary:

Normal function of the placenta is pivotal for optimal fetal growth and development. The etiology of placental dysfunction is multifactorial with abundant gene and environment interactions. Placental dysfunctions are implicated in pregnancy complications such as gestational diabetes (GDM), pre-eclampsia (PE) and intrauterine growth restriction (IUGR).
We intend to examine a certain aspect of reproductive toxicology, the mercury toxicokinetics in the healthy and diseased (GDM, PE, IUGR) human placenta. Based on the available data on the involved genes/proteins in mercury toxicokinetics from the healthy placenta, we now aim to compare their role and function in healthy and diseased placentas. We are interested whether mercury toxicokinetics are altered in dysfunctional placentas, which is a relevant issue in reproduction toxicology and individualized pregnancy care.
We observed variable expression levels of placental proteins involved in mercury toxicokinetics. Our hypotheses are that 1) sequence variations in the candidate genes contribute to altered placental protein expression and as a consequence to altered toxicokinetics in the placenta, and 2) that the genetic background for mercury toxicokinetics is different between healthy and diseased placentae (GDM, PE, IUGR). The placenta is a unique organ for investigating genotype-phenotype relationship because the organ is accessible, protein levels and functions can relatively easy be determined, and also primary cells can be obtained. Methyl mercury (MeHg) is regarded as a model substrate because various amino acids, hormones, cancer drugs, and xenobiotics use at least in part the same transporter and metabolizing/detoxifying systems as the metal species. Studying transport and metabolisation/detoxification of MeHg in healthy and diseased placentas provides valuable data not only for the field of reproductive toxicology.
Three groups of proteins related to mercury toxikokinetics are involved in placental (dys)function. There is evidence that amino acid transporter levels are altered in both IUGR and fetal overgrowth and that PE goes along with an altered oxidative defense in the placenta. There is some evidence that also ABC transporters are involved in PE and IUGR. We suggest six proteins, i.e., amino acid transporters LAT1 and b0,+, GSH system related enzymes GGT1 and GSTA1 and ABC transporters MRP1 and MRP3 to be examined in the healthy and diseased placenta. In the proposed study we aim to confirm (1) whether the protein specific effects on mercury toxicokinetics observed in previous experiments are direct effects. Based on the knowledge which proteins are directly related to mercury toxicokinetics, we will determine (2) which known functional genetic variants are related to placental protein expression and mercury contents by comparing healthy and diseased (GDM, PE, IUGR) placentas.

Keywords:
Reproductive toxicology, Pregnancy diseases, Fetal-Maternal Medicine