Exposure to Legacy and Alternative Brominated Flame Retardants During Pregnancy and Associations with Placental Thyroid Hormones

Abstract

Brominated flame retardants (BFRs) are a class of synthetic chemicals that have been used for decades due to their ability to hinder combustion by quenching free radicals using bromine radicals. These compounds are added to various materials used in consumer and construction products, including polyurethane foams in furniture, textiles, electronics, and even baby products. Many of these BFRs, such as polybrominated diphenyl ethers (PBDEs), are used in an additive fashion, meaning they are not bound to materials they are applied to and can leach out over time and enter the environment. Studies have demonstrated that BFR exposure can result in neurotoxicity, hepatotoxicity, reproductive toxicity, and thyroid toxicity and endocrine disruption. Thyroid hormones (TH) are particularly important for growth and development, cognitive function, metabolism and homeostasis, as well as regulating the progression of pregnancy and placental growth. Due to the high impact of THs during gestation, it is crucial to understand how exposure to environmental contaminants that may impact THs can adversely impact fetal growth and development. Importantly, PBDEs and other BFRs have been demonstrated to dysregulate THs, and in utero BFR-mediated TH disruption is associated with a number of negative fetal birth outcomes, including altered birth weight (BW) and length, intrauterine growth restriction, and reduced cognitive function and IQ.The primary focus of this dissertation was to assess concentrations of legacy and replacement BFRs and THs in maternally- and fetally-derived placental tissue in rats and in humans. Few studies have measured contaminants and hormones separately in the two placental layers, despite evidence that there are differences in chemical accumulation and transporter and enzymes expression and activity, potentially resulting in differential fetal exposure than predicted from whole placental measurements. Therefore, this work sought to not only characterize differences in the two placental layers, but to also determine whether maternal and fetal BFR and TH concentrations were differentially associated with fetal birth outcomes. Additionally, we assessed sex-specific concentrations and associations in order to determine if fetal sex impacts placental BFR and TH levels. Finally, this work aimed to understand the translatability of maternal and fetal placental TH and BFR trends in rodent and human tissue. In Chapter 2, we explored the relationship between maternal and fetal placental PBDE concentrations and between TH levels in a controlled animal dosing study. Pregnant Wistar rats were gestationally exposed to an environmentally relevant mixture of PBDEs commonly detected in U.S. house dust. At mid- and late-gestational time points, dams were sacrificed, and dam serum and maternal and fetal placental tissue were collected. Paired placental tissues and dam serum were extracted for 1) PBDEs and 2) rT3, T3, and T4, and analyte concentrations were determined using gas- and liquid-chromatography mass spectrometry. We reported that there is timepoint-specific differential accumulation of the PBDEs in the two placental layers that appears to be driven by changes in placental structure. Additionally, we found that there were tissue-specific (i.e. maternal or fetal placenta) and timepoint-specific differences in TH sensitivity to gestational PBDE exposure. In Chapter 3, we measured legacy and alternative BFRs and THs concentrations in paired maternal and fetal placental samples, and assessed associations with fetal birth outcomes, including z-score adjusted BW and gestational age. Placentas from 200 participants were collected through Duke Hospital as part of a prospective birth cohort, and maternal and fetal layers were separated prior to BFR and TH extraction and quantification. We identified several novel findings, including the detection of several alternative BFRs in placental tissue. Maternal and fetal placental concentrations of all frequently detected analytes were significantly positively correlated with each other. We also reported differential maternal and fetal concentrations of placental BDE 47, BDE 153, and rT3, as well as overall declining detection and concentrations of legacy BFRs. Additionally, we identified several tissue-and sex-specific impacts, including a positive association with male-associated placental rT3 and z-score BW and a negative association with female-associated placental T4 and gestational age. Overall, this work highlights differences in maternal and fetal placental concentrations of both BFRs and THs and contributes several novel timepoint- and sex-specific findings that offer insights into the implications of in utero BFR exposure for fetal birth outcomes.