OR23-6 The Impact of PBDE Exposure, Fetal Sex, and Gestational Day on Thyroid Hormone Regulation in the Placenta

Abstract

During pregnancy, supply of thyroid hormone (TH) is critically important for fetal growth, neural development, metabolism and maintenance of pregnancy. However, when circulating levels of THs in maternal serum are disrupted, there is an increased risk of several adverse pregnancy outcomes, such as neurodevelopmental delays. It is unclear what may be disrupting TH homeostasis, however, numerous studies have shown that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs) could be playing a role. Exposure to PBDEs have been shown to lower circulating free T4 and T3 in animal studies and their metabolites can be inhibitors of deiodinase enzymes. However, no studies to date have investigated potential changes in TH levels in paired maternal serum, placenta, and fetal tissues following exposure to PBDEs during development. Although it is well known that the rat fetus relies on maternal synthesis and delivery of TH until gestational day (GD) 18, it is unclear how levels of TH fluctuate in paired maternal serum, placenta and fetus prior to GD 18 and if there are any sex differences. In this study, pregnant Wistar rats were dosed daily from GD 6 to 15 with a mixture of PBDEs ranging in concentration from 5.3 - 30.4 ug/kg/day. After 10 days, two fetuses per sex per treatment, their paired micro-dissected placenta (isolated fetal and maternal placental tissue) and dam serum were collected. The tissues were extracted, purified and quantified for TH’s (T4, T3, rT3) and PBDE’s. We also examined gene expression of TH transporters in the fetal portion of the placenta using qPCR. Circulating T3 levels in the dosed dams were lower relative to controls, but not significantly different (p=0.1). However, we detected a significant increase in T3 levels in the maternal placental tissues of the dosed dams relative to controls (p=0.037), suggesting the tissue sampled has a significant impact on the direction of TH disruption. Furthermore, we found that the sex of the fetus influenced the levels of T3 in the fetal placental tissues (increased levels of T3 from female fetuses, decreased levels from male fetuses). Preliminary data on TH levels in the fetus thus far suggest changes in TH levels are influenced by both sex and exposure. For example, rT3 levels were lower in females compared to males (p<0.001) and was not influenced by exposure. T3 was also lower in females compared to males (p<0.001) and was significantly reduced by exposure to PBDEs (p=0.027). Furthermore, we observed an upregulation in gene expression for TH transporter MCT8 in the fetal portion of the placenta in males relative to females. Lastly, we also observed significant differences in TH levels based on GD, with levels decreasing from GD 12-15 (p<0.001). This study suggests that even though there are no significant effects of dose on maternal TH levels, there is significant disruption of TH homeostasis in the placenta as well as the fetus.