American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment ap-proaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothy-roidism, hyperthyroidism, or thyroid cancer, are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a se-ries of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes

Environmental toxicants and white matter composition: Understanding the role of thyroid disruption

It is becoming increasingly clear that chemicals present in the environment can interfere with thyroid hormone (TH) action and signaling. This is of great concern because TH is critical for normal brain development and recent evidence suggests that the developing brain is exquisitely sensitive to perturbations in TH action. Developmental exposure to the ubiquitous environmental toxicants, polychlorinated biphenyls (PCBs), is associated with neurological deficits that may be related to ability of these chemicals to alter TH-mediated brain development by interfering with TH action. Thyroid hormone plays an important role of is on the development and maturation of white matter tracts and its glial constituents. Because PCBs are suspected of interfering with thyroid hormone (TH) signaling in the developing brain, and because TH is important in white matter development, this dissertation set-out to critically test the hypothesis that developmental exposure to PCBs alters white matter development by interfering with TH action. In testing this hypothesis, we addressed four main questions: (1) Do PCBs perturb white matter development by causing a relative state of hypothyroidism? (2) Is the severity of TH insufficiency associated with different effects on white matter? (3) Do PCBs have a TH-like effect on white matter composition? (4) Do PCBs and TH insufficiency alter white matter by affecting the same signaling networks? We focused our experiments on postnatal day 15, a time when both myelination and TH levels are at their peak during development, and effects of hypothyroidism on white matter development have been documented. We evaluated the effect of developmental exposure to the commercial PCB mixture Aroclor 1254, TH insufficiency, and TH excess on markers of oligodendrocyte and astrocytes in two white matter tracts, the corpus callosum (CC) and anterior commissure (AC). The results described in this dissertation are consistent with the idea that developmental exposure to PCBs alters white matter composition independent of ability to interfere with TH action. Furthermore, the nature of the experimental designs used in testing our hypothesis provided fundamental information on the role of TH in the differentiation of oligodendrocytes and astrocyte from common precursors

Analóg-digitális televízió átállás, HDTV rendszer, kábel TV-hálózatok terjeszkedése, piaci alakulás

Transmembrane proteins that mediate the cellular uptake or efflux of thyroid hormone potentially provide a key level of control over neurodevelopment. In humans, defects in one such protein, solute carrier SLC16A2 (MCT8) are associated with psychomotor retardation. Other proteins that transport the active form of thyroid hormone triiodothyronine (T3) or its precursor thyroxine (T4) have been identified in vitro but the wider significance of such transporters in vivo is unclear. The development of the auditory system requires thyroid hormone and the cochlea is a primary target tissue. We have proposed that the compartmental anatomy of the cochlea would necessitate transport mechanisms to convey blood-borne hormone to target tissues. We report hearing loss in mice with mutations in Slc16a2 and a related gene Slc16a10 (Mct10, Tat1). Deficiency of both transporters results in retarded development of the sensory epithelium similar to impairment caused by hypothyroidism, compounded with a progressive degeneration of cochlear hair cells and loss of endocochlear potential. Administration of T3 largely restores the development of the sensory epithelium and limited auditory function, indicating the T3-sensitivity of defects in the sensory epithelium. The results indicate a necessity for thyroid hormone transporters in cochlear development and function

Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Mutations of SLC26A4 cause an enlarged vestibular aqueduct, nonsyndromic deafness, and deafness as part of Pendred syndrome. SLC26A4 encodes pendrin, an anion exchanger located in the cochlea, thyroid, and kidney. The goal of the present study was to determine whether developmental delays, possibly mediated by systemic or local hypothyroidism, contribute to the failure to develop hearing in mice lacking Slc26a4 (Slc26a4−/−). We evaluated thyroid function by voltage and pH measurements, by array-assisted gene expression analysis, and by determination of plasma thyroxine levels. Cochlear development was evaluated for signs of hypothyroidism by microscopy, in situ hybridization, and quantitative RT-PCR. No differences in plasma thyroxine levels were found in Slc26a4−/− and sex-matched Slc26a4+/− littermates between postnatal day 5 (P5) and P90. In adult Slc26a4−/− mice, the transepithelial potential and the pH of thyroid follicles were reduced. No differences in the expression of genes that participate in thyroid hormone synthesis or ion transport were observed at P15, when plasma thyroxine levels peaked. Scala media of the cochlea was 10-fold enlarged, bulging into and thereby displacing fibrocytes, which express Dio2 to generate a cochlear thyroid hormone peak at P7. Cochlear development, including tunnel opening, arrival of efferent innervation at outer hair cells, endochondral and intramembraneous ossification, and developmental changes in the expression of Dio2, Dio3, and Tectb were delayed by 1–4 days. These data suggest that pendrin functions as a HCO3− transporter in the thyroid, that Slc26a4−/− mice are systemically euthyroid, and that delays in cochlear development, possibly due to local hypothyroidism, lead to the failure to develop hearing