Molecular Alterations of Thyroid Hormone Metabolism in the Human Placenta due to Maternal Obesity

• Applicant: Dr. Maike Katja Kahr
• Subject Area: Gynaecology and Obstetrics
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260637721

The prevalence of obesity in pregnant women in Germany is estimated to be approximately 30% today - with a rising tendency. It is well known that obese women are at increased risk of developing gestational diabetes and preeclampsia as well as perinatal complications. In addition, maternal diet and body weight during pregnancy influence the fetal development and health negatively (higher risk for malformations, preterm, stillbirth, large for gestational age (LGA)). Studies indicate that LGA newborns develop metabolic syndrome during infancy more often, coming along with obesity, impaired glucose tolerance and insulin resistance later in life. In order to prevent health risks due to maternal obesity in the next generation it is a matter of interest to improve our understanding of the molecular mechanism that determine the observed association between excessive fetal growth and maternal obesity. Kjersti Aagaards research group has demonstrated that maternal thyroid hormones as well as the fetal hypothalamic-pituitary-thyroid axis play a major role in the regulation of fetal growth. Studies with Japanese macaques revealed that offspring of obese dams and dams with a high fat diet had significantly lower fT4 values. In coherence with these findings, a dysregulation of iodothyronin-deiodinase-genes (DIO), epigenetic modifications of alpha- and beta-thyroid-hormone-receptors along with a higher expression of their coactivators have been described. Based on the outlined results, we assume that maternal high fat diet and maternal obesity similarly alters signaling pathways in the human placenta, in addition to changes in the fetal hypothalamic-pituitary-thyroid axis. The placenta controls the passage of maternal hormones to the fetus with the help of certain mechanisms (transport proteins, deiodinases). Alterations in these mechanisms will be at the center point of my research project. The first step of the project comprises the determination of quantity and localization of thyroid hormone transporters, binding proteins, receptors and DIO-genes in the human placenta utilizing qRT-PCR and immunohistochemistry. Secondly we will isolate cytotrophoblasts from human placenta and analyze the molecular reaction of placenta tissue to thyroid hormones exposure ex vivo. For this purpose cytotrophoblast cultures will be spread and gene expression analyses as well as ChIP sequencing will be conducted. Using this approach we will be enabled to analyze the altered gene expression in cytotrophoblasts after treating the culture with triiodothyronine (T3). In addition, we hope to acquire evidence which genes are activated in obese pregnant women in comparison to a control group. Finally, we would like to obtain insight in how the occupation of promoters alters under the influence of T3 treatment.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Kjersti Aagaard