Low Thyroid Hormone Levels Disrupt Thyrotrope Development.

Low thyroid hormone (TH) conditions caused by a variety of prenatal and perinatal problems have been shown to alter postnatal regulatory thyrotropin (TSH) responsiveness to TH in humans and rodents. The mechanisms underlying this pituitary TH resistance remain unknown. Here we use the evolutionarily conserved zebrafish model to examine the effects of low TH on thyrotrope development and function. Zebrafish were exposed to the goitrogen 6-propyl-2-thiouracil (PTU) to block TH synthesis, and this led to an approximately 50% increase in thyrotrope numbers and an 8- to 10-fold increase in tshb mRNA abundance in 2-week-old larvae and 1-month-old juveniles. Thyrotrope numbers returned to normal 3 weeks after cessation of PTU treatment, demonstrating that these effects were reversible and revealing substantial plasticity in pituitary-thyroid axis regulation. Using a T4 challenge assay, we found that development under low-TH conditions did not affect the ability of T4 to suppress tshb mRNA levels despite the thyrotrope hyperplasia that resulted from temporary low-TH conditions. Together, these studies show that low developmental TH levels can lead to changes in thyrotrope number and function, providing a possible cellular mechanism underlying elevated TSH levels seen in neonates with either permanent or transient congenital hypothyroidism.

Embryonic exposure to excess thyroid hormone causes thyrotrope cell death.

Central congenital hypothyroidism (CCH) is more prevalent in children born to women with hyperthyroidism during pregnancy, suggesting a role for thyroid hormone (TH) in the development of central thyroid regulation. Using the zebrafish embryo as a model for thyroid axis development, we have characterized the ontogeny of negative feedback regulation of thyrotrope function and examined the effect of excess TH on thyrotrope development. We found that thyroid-stimulating hormone ß subunit (tshb) and type 2 deiodinase (dio2) are coexpressed in zebrafish thyrotropes by 48 hours after fertilization and that TH-driven negative feedback regulation of tshb transcription appears in the thyroid axis by 96 hours after fertilization. Negative feedback regulation correlated with increased systemic TH levels from the developing thyroid follicles. We used a transgenic zebrafish that expresses GFP under the control of the tshb promoter to follow thyrotrope fates in vivo. Time-lapse imaging revealed that early exposure to elevated TH leads to thyrotrope cell death. Thyrotrope numbers slowly recovered following the removal of excess TH. These data demonstrate that transient TH exposure profoundly impacts the thyrotrope population during a critical period of pituitary development and may have long-term implications for the functional reserve of thyroid-stimulating hormone (TSH) production and the TSH set point later in life.

Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene-specific effects on thyroid hormone signaling during development.

Polychlorinated biphenyls (PCB) are industrial chemicals linked to developmental deficits that may be caused in part by disrupting thyroid hormone (TH) action by either reducing serum TH or interacting directly with the TH receptor (TR). Individual PCB congeners can activate the TR in vitro when the metabolic enzyme cytochrome P4501A1 (CYP1A1) is induced, suggesting that specific PCB metabolites act as TR agonists. To test this hypothesis in vivo, we compared two combinations of PCB congeners that either activate the TR (PCB 105 and 118) or not (PCB 138 and 153) in the presence or absence of a PCB congener (PCB 126) that induces CYP1A1 in vitro. Aroclor 1254 was used as a positive control, and a group treated with propylthiouracil was included to characterize the effects of low serum TH. We monitored the effects on TH signaling in several peripheral tissues by measuring the mRNA expression of well-known TH-response genes in these tissues. Aroclor 1254 and its component PCB 105/118/126 reduced total T(4) to the same extent as that of propylthiouracil but increased the expression of some TH target genes in liver. This effect was strongly correlated with CYP1A1 expression supporting the hypothesis that metabolism is necessary. Effects were gene and tissue specific, indicating that tissue-specific metabolism is an important component of PCB disruption of TH action and that PCB metabolites interact in complex ways with the TR. These are essential mechanisms to consider when evaluating the health risks of contaminant exposures, for both PCB and other polycyclic compounds known to interact with nuclear hormone receptors.