Endocrine Abstracts

Background: Conservation of genes involved in TH transport, metabolism and action can reveal clues about the origins of TH signaling. A deiodinase homologue (DdDio) was previously identified in the social amoeba Dictyostelium discoideum (Singh, 2014). Dictyostelium cells live as single cell amoebae in soil where they feed on bacteria. However, upon starvation a developmental program is initiated that results in the formation of a multicellular fruiti...

Background: Disrupted thyroid hormone (TH) homeostasis has devastating effects on human neurodevelopment. THs are critical signaling molecules in neurodevelopment, acting on differentiation of neural cells, migration, synaptogenesis and myelination, with deiodinases governing intracellular TH concentrations in a spatiotemporal manner. It is remarkable that fetal neural cells, while being key target cells of TH, exhibit strong activity of the TH inactivating enzyme DIO3. Curren...

Background and Objective: Disrupted thyroid hormone (TH) signaling has devastating effects on human neurodevelopment. The molecular mechanisms underlying TH regulation and action are largely based on animal models. However, animal models are limited in revealing some of the most fundamental aspects of neurodevelopment that are unique to humans. We employed human induced pluripotent stem cell (iPSC) technology to study the effects of T3 on neurodevelopmental processes in a huma...

Background: Resistance to thyroid hormone (TH) alpha (RTHα), caused by heterozygous mutations in THRA, is characterized by abnormal thyroid function tests and features due to tissue-specific hypothyroidism, including disproportional short stature, variable motor and cognitive defects, macrocephaly and macroglossia, constipation and anemia. Mutant receptors display defective T3 binding resulting in impaired transcriptional activity. Dominant negative inhibition of the WT r...

Background: Over the last few decades, in vivo animal experiments have been the gold standard for the assessment of safety of chemicals and pharmaceuticals for human health. However, in vivo animal data has limited relevance for toxicity prediction in humans, especially considering species-specific issues of age, sex and exposure in different life-stages. Within the Virtual Human Platform for Safety Assessment (VHP4Safety) project we aim to develop an animal-...

Background: Disrupted thyroid hormone (TH) homeostasis has devastating effects on human neurodevelopment. THs are critical signaling molecules in neurodevelopment, acting on differentiation of neural cells, migration, synaptogenesis and myelination, with deiodinases governing intracellular TH concentrations in a spatiotemporal manner. It is remarkable that fetal neural cells, while being key target cells of TH, exhibit strong activity of the TH inactivating enzyme DIO3. Curren...

Background: Resistance to thyroid hormone (TH) beta (RTHβ), caused by mutations in THRB, is characterized by elevated serum (F)T4 accompanied by non-suppressed TSH concentrations. Disease features arise from variable resistance to TH action in tissues expressing Thyroid Hormone Receptor (TR) β (hypothalamus, pituitary, liver) and from thyrotoxic effects in tissues expressing TRα (heart, bone, brain). In symptomatic patients, treatment mainly involves be...

Background: Resistance to thyroid hormone alpha (RTHα), caused by mutations in the T3-receptor alpha 1 (TRα1) isoform, includes growth retardation, intellectual disability, and abnormal thyroid function tests. The current paradigm entails that disease features arise from decreased T3 action in TRα1-expressing tissues. However, also for patients that carry mutations that completely abolish T3-stimulated activity, neurological features vary strongly, ranging from ...

Background: Resistance to thyroid hormone (TH) beta (RTHβ), caused by mutations in the THRB gene, is characterized by elevated serum (F)T4 accompanied by non-suppressed TSH concentrations. Disease features arise from variable resistance to TH action in tissues expressing Thyroid Hormone Receptor (TR) β and from thyrotoxic effects in tissues expressing TRα1, most notably the heart. A recent clinical study showed a 3-times higher risk of cardiovascular mo...

Objectives: During prenatal neurodevelopment, maternal-to-fetal thyroxine (T4) transfer is critical, particularly during the first half of pregnancy when the fetal thyroid gland is immature. Transcellular transport of thyroid hormones (TH) is facilitated by TH transporters. Monocarboxylate transporter 8 (MCT8) is a specific TH transporter that is crucial for transport of TH with a prominent expression at the blood-brain barrier. MCT8 deficiency is a rare disorder consisting of...