Embryonic exposure to excess thyroid hormone causes thyrotrope cell death
Ksenia N. Tonyushkina, Meng-Chieh Shen, Theresa Ortiz-Toro, Rolf O. Karlstrom
Ksenia N. Tonyushkina, Meng-Chieh Shen, Theresa Ortiz-Toro, Rolf O. Karlstrom
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Research Article

Embryonic exposure to excess thyroid hormone causes thyrotrope cell death

Abstract

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 β 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.

Authors

Ksenia N. Tonyushkina, Meng-Chieh Shen, Theresa Ortiz-Toro, Rolf O. Karlstrom

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Figure 2

Embryonic exposure to elevated T4 reduces the number of cells expressing tshb and dio2.

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Embryonic exposure to elevated T4 reduces the number of cells expressing...
(A–D) tshb- and dio2-expressing thyrotropes by 48 hpf following exposure to 300 nM T4 or DMSO (carrier) starting at 24 hpf, as visualized by ISH. (E) Graph showing decreases in tshb- (blue) and dio2-labeled (green) cells. (F and G) tshb-expressing thyrotropes by 72 hpf following a 24-hour exposure to 300 nM T4 or DMSO. (H) Graph showing decreases in tshb- (blue) and dio2-labeled (green) cells after a 24-hour exposure to T4 and T3. (I) Graph showing a decrease in tshb-labeled (blue) cells and no changes in gh- and prl-labeled cells after a 48-hour exposure to 100 nM T4 or DMSO (carrier) started 24 hpf. *P < 0.05; **P < 0.01; ***P < 0.001. (A–D, F, and G) Ventral views of the left anterior head; red dashed lines outline the left half of the pituitary placode. Scale bars: 25 μm.