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<p>Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) that have been heavily used in consumer products such as furniture foams, plastics, and textiles since the mid-1970’s. BFRs are added to products in order to meet state flammability standards intended to increase indoor safety in the event of a fire. The three commercial PBDE mixtures, Penta-, Octa-, and DecaBDE, have all been banned in the United States, however, limited use of DecaBDE is still permitted. PBDEs were phased out of production and added to the Stockholm Convention due to concerns over their environmental persistence and toxicity. Human exposure to PBDEs occurs primarily through the inadvertent ingestion of contaminated house dust, as well as though dietary sources. Despite the phase-out and discontinued use of PBDEs, human exposure to this class of chemicals is likely to continue for decades due to the continued use of treated products and existing environmental reservoirs of PBDEs. Extensive research over the years has shown that PBDEs disrupt thyroid hormone (TH) levels and neurodevelopmental endpoints in rodent and fish models. Additionally, there is growing epidemiological evidence linking PBDE exposure in humans to altered TH homeostasis and neurodevelopmental impairments in children. Due to the importance of THs throughout gestation, there is a great need to understand the effects of BFRs on the developing fetus. Specifically, the placenta plays a critical role in the transport, metabolism, and delivery of THs to the fetal compartment during pregnancy and is a likely target for BFR bioaccumulation and endocrine disruption. The central hypothesis of this dissertation research is that BFRs disrupt the activity of TH sulfotransferase (SULT) enzymes, thereby altering TH concentrations in the placenta.</p><p>In the first aim of this dissertation research, the concentrations of PBDEs and 2,4,6-TBP were measured in a cohort of 102 placenta tissue samples from an ongoing pregnancy cohort in Durham, NC. Methods were developed for the extraction and analysis of the BFR analytes. It was found that 2,4,6-TBP was significantly correlated with all PBDE analytes, indicating that 2,4,6-TBP may share common product applications with PBDEs or that 2,4,6-TBP is a metabolite of PBDE compounds. Additionally, this was the first study to measure 2,4,6-TBP in human placenta tissues.</p><p>In the second aim of this dissertation research, the placenta tissue concentrations of THs, as well as the endogenous activity of deiodinase (DI) and TH SULT enzymes were quantified using the same cohort of 102 placenta tissue samples. Enzyme activity was detected in all samples and this was the first study to measure TH DI and SULT activity in human placenta tissues. Enzyme activities and TH concentrations were compared with BFR concentrations measured in Aim 1. There were few statistically significant associations observed for the combined data, however, upon stratifying the data set based on infant sex, additional significant associations were observed. For example, among males, those with the highest concentrations of BDE-99 in placenta had T3 levels 0.80 times those with the lowest concentration of BDE-99 (95% confidence interval (CI): 0.59, 1.07). Whereas females with the highest concentrations of BDE-99 in placenta had T3 levels 1.50 times those with the lowest concentration of BDE-99 (95% CI: 1.10, 2.04). Additionally, all BFR analyte concentrations were higher in the placenta of males versus females and they were significantly higher for 2,4,6-TBP and BDE-209. 3,3’-T2 SULT activity was significantly higher in female placenta tissues, while type 3 DI activity was significantly higher in male placenta tissues. This research is the first to show sex-specific differences in the bioaccumulation of BFRs in human placenta tissue, as well as differences in TH concentrations and endogenous DI and SULT activity. The underlying mechanisms of these observed sex differences warrant further investigation. </p><p>In the third aim of this dissertation research, the effects of BFRs were examined in a human choriocarcinoma placenta cell line, BeWo. Michaelis-Menten parameters and inhibition curves were calculated for 2,4,6-TBP, 3-OH BDE-47, and 6-OH BDE-47. 2,4,6-TBP was shown to be the most potent inhibitor of 3,3’-T2 SULT activity with a calculated IC50 value of 11.6 nM. It was also shown that 2,4,6-TBP and 3-OH BDE-47 exhibit mixed inhibition of 3,3’-T2 sulfation in BeWo cell homogenates. Next, a series of cell culture exposure experiments were performed using 1, 6, 12, and 24 hour exposure durations. Once again, 2,4,6-TBP was shown to be the most potent inhibitor of basal 3,3’-T2 SULT activity by significantly decreasing activity at the high and medium dose (1 M and 0.5 M, respectively) at all measured time points. Interestingly, BDE-99 was also shown to inhibit basal 3,3’-T2 SULT activity in BeWo cells following the 24 hour exposure, despite exhibiting no inhibitory effects in the BeWo cell homogenate experiments. This indicates that BDE-99 must act through a pathway other than direct enzyme inhibition. Following exposures, the TH concentrations in the cell culture growth media and mRNA expression of TH-related genes were also examined. There was no observed effect of BFR treatment on these endpoints. Future work should focus on determining the downstream biological effects of TH SULT disruption in placental cells, as well as the underlying mechanisms of action responsible for reductions in basal TH SULT activity following BFR exposure. </p><p>This was one of the first studies to measure BFRs in a cohort of placenta tissue samples from the United States and the first study to measure THs, DI activity, and SULT activity in human placenta tissues. This research provides a novel contribution to our growing understanding of the effects of BFRs on TH homeostasis within the human placenta, and provides further evidence for sex-specific differences within this important organ. Future research should continue to investigate the effects of environmental contaminants on TH homeostasis within the placenta, as this represents the most critical and vulnerable stage of human development.</p> / Dissertation

国立情報学研究所で電子化したコンテンツを使用している。

INTRODUCTION Impaired sensitivity to thyroid hormone is described as any process that interferes with the effectiveness of thyroid hormone and includes defects in thyroid hormone action, transport, or metabolism. Here we present a case of a 60-year-old man with resistance to thyroid hormone (RTH), the most common form of impaired sensitivity. CASE A 60-year-old male presented to the endocrinology clinic with complaints of fatigue, decreased concentration, and impaired memory. He denied neck swelling, neck pain, peripheral edema, or any significant changes in weight, temperature sensitivity, bowel habits, and mood. His family history was significant for difficult to control thyroid disease in his brother and son. Thyroid exam was normal. Seven years ago, he was diagnosed with hypothyroidism of undetermined etiology with an elevated Thyroid Stimulating Hormone (TSH) and started on Levothyroxine. TSH was within normal limits in the first 3 years of therapy but TSH and free T4 remained high since then. MRI of the brain could not be done to rule out TSH secreting adenoma as he had pieces of metal in his face. In the absence of overt signs or symptoms of hyperthyroidism except atrial fibrillation, and a normal alpha subunit, IGF1, and prolactin, a TSH secreting adenoma is considered less likely. Levothyroxine was stopped and thyroid hormone levels were rechecked in 1 month that revealed elevated TSH with normal T3 and T4, representing compensated RTH. Genetic counseling was provided to the patient but he refused genetic testing. DISCUSSION The incidence of RTH is approximately 1 in 50,000 live births. In approximately 85 percent of cases it is due to mutations in the gene encoding the thyroid hormone receptor beta (TR-beta), while the other 15% are yet to be determined. It is characterized by reduced responsiveness of target tissue to thyroid hormones. The hallmark of RTH is the paucity of signs and symptoms of thyroid dysfunction despite the presence of high serum T4 and T3 concentrations. Clinical features include goiters, hyperactivity, and tachycardia. It can be diagnosed after other causes of hyperthyroxinemia are ruled out and confirmed with genetic testing.

Thesis advisor: Sarah K. McMenamin / Thesis advisor: Vicki Losick / Proper bone development requires coordination and timing of specific morphogenetic events, and relative shifts in these temporal processes can change morphology. Thyroid hormone (TH) plays an important role in regulating the timing of vertebrate skeletogenesis, and the hormone induces the profound skeletal shape changes that occur during amphibian metamorphosis. Like humans, zebrafish do not undergo an ecological metamorphosis; yet TH is essential in coordinating postembryonic developmental processes. In particular, several elements of the craniofacial skeleton that continue to ossify and remodel during later stages of development are sensitive to TH titer. My aims focus on the role of TH in regulating skeletal growth and shape changes in zebrafish. To examine changes in the entire zebrafish skeleton during normal postembryonic development, I generated a skeletal reference of microCT scans of zebrafish ranging from early juvenile through adult stages (Chapter 2). After defining the normal changes that wild-type zebrafish undergo, I hypothesized that TH coordinates the developmental shape changes and determined the role of TH in stimulating developmental shape change in zebrafish skulls and its effects on skeletogenic cell populations (Chapter 3). Finally, I investigated whether phenotypes induced by altered TH levels mirror some of the evolutionary diversity seen across Danioninae craniofacial skeletons (Chapter 4). My research elucidates the role of TH in the regulation of bone growth and shape change in a vertebrate system and provides new insights into the natural craniofacial diversity of Danioninae. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 3 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

For nearly a century, amphibian metamorphosis has served as an important model of how thyroid hormones regulate vertebrate development. Consequently metamorphosis has been studied in a number of ways including: morphologically, developmentally, ecologically, and from an endocrine perspective. Over the last two decades, much has been learned about the molecular basis of anuran (frog) metamorphosis. However, very little is known about the molecular underpinnings of urodele (salamander) metamorphosis. Using the axolotl and axolotl hybrids as models, I present some of the first studies on the gene expression changes that occur during urodele metamorphosis. In Chapter 1, the motivation for the research described in the subsequent chapters is presented and the literature is briefly reviewed. In Chapter 2, the first microarray analysis of urodele metamorphosis is presented. This analysis shows that hundreds of genes are differentially expressed during thyroid hormone-induced metamorphic skin remodeling. Chapter 3 extends the analysis presented in Chapter 2 by showing that the transcriptional patterns associated with metamorphic skin remodeling are robust even when the concentration of thyroid hormone used to induce metamorphosis is varied by an order of magnitude. Chapter 4 makes use of the differentially expressed genes identified in Chapters 2 and 3 to articulate the first model of urodele metamorphosis to integrate changes in morphology, gene expression, and histology. In addition, Chapter 4 outlines a novel application for piecewise linear regression. In turn, Chapter 5 makes use of the model presented in Chapter 4 to demonstrate that full siblings segregating profound variation in metamorphic timing begin to diverge in phenotype early during larval development. In Chapter 6 the conclusions drawn from the research are summarized and future directions are suggested.