Embryonic exposure to excess thyroid hormone causes thyrotrope cell death
Ksenia N. Tonyushkina, … , Theresa Ortiz-Toro, Rolf O. Karlstrom
Ksenia N. Tonyushkina, … , Theresa Ortiz-Toro, Rolf O. Karlstrom
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):321-327. https://doi.org/10.1172/JCI70038.
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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 4

Lasting effects of T4 exposure on thyrotrope numbers.

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Lasting effects of T4 exposure on thyrotrope numbers. (A) Approximately ...
(A) Approximately 10 thyrotropes were present in the pituitary by 72 hpf in DMSO-treated control embryos, as visualized by GFP fluorescence in the Tg(tshb:EGFP) line. (B) Example of decreased thyrotrope numbers by 72 hpf immediately following a 24-hour exposure to 300 nM T4. (C) Approximately 13 thyrotropes were present by 14 dpf in DMSO-treated control embryos. (D) Example of a 14-dpf larva with 4 thyrotropes that was treated with 300 nM T4 from 48 to 72 hpf, followed by an 11-day washout period. (E) Approximately 10 thyrotropes were present in the pituitary by 18 dpf in DMSO-treated control embryos. (F) Example of a larva with normal thyrotrope numbers that was treated with 300 nM T4 from 48 to 72 hpf, followed by a 15-day washout period. (G) Graph showing thyrotrope numbers, with a minimum of 20 embryos scored for each treatment. ***P < 0.001. (A–F) Ventral views of pituitary in the left anterior forebrain. Scale bar: 25 μm.