Die Rolle von Schilddrüsenhormon-Transmembrantransportern und des lokalen Schilddrüsenhormonmetabolismus für den testikulären Schilddrüsenhormonstatus unter besonderer Betrachtung der testikulären Entwicklung
Endokrinologie, Diabetologie, Metabolismus
Zusammenfassung der Projektergebnisse
This pilot project was initiated to gain insight in the role of thyroid hormone transmembrane transporters and local thyroid hormone metabolism in the regulation of testicular thyroid hormone concentrations and testis development. In case of continuous hypothyroidism, low circulating thyroid hormone concentrations, the development of the rodent testis is delayed, but does not come to a complete halt. In a rat model, we show that transient pre‐pubertal hypothyroidism, induced by administering sodium perchlorate to the diet, leads to a marginal increase in seminiferous tubule diameter and testis weights in adulthood. This effect could be due to the increased proliferative activity of both the Sertoli as well as Leydig cells a few days after the hypothyroidism is alleviated. We showed that the use of sodium perchlorate as a model to induce (transient) hypothyroidism can form a valuable alternative to the use of the goitrogen propylthiouracil, which inhibits the thyroid hormone converting enzyme deiodinase type 1 and interacts with the androgen receptor. For thyroid hormones to enter the cell, the presence of transmembrane thyroid hormone transporters plays an essential role. In rodent testes and the murine Leydig tumor cell line‐1 (MLTC‐ 1) we confirmed the presence of a wide variety of transmembrane TH transporters. The prominent expression of the Lat1 and Lat2 in the rat and mouse testis, the Lat2 more specifically in the Leydig cell, could provide an efficient uptake of the so‐called metabolically active 3,3’,5‐triiodothyronine (T3). In our Lat2 knockout mouse model however, the histological changes were limited, suggestive of compensatory mechanisms by other transmembrane thyroid hormone transporters. With the arrival of more sensitive LC‐MS/MS machines, the concentration of a wide variety of thyroid hormone metabolites in tissues and cells can be determined. To prepare the sample for accurate examination of its thyroid hormone concentrations, a reproducible extraction method with a good capacity to remove interfering compounds, high yields and absent molecular alterations is needed. This pilot project contributed to the development of a thyroid hormone extraction protocol for culture media and cultured Leydig cells, which has a better recovery and reduced alteration (acetylation or deiodination) of the thyroid hormone metabolites, than the protocol in use before. We used this new protocol to examine thyroid hormone metabolite uptake in MLTC‐1 as an alternative for using radiolabelled thyroid hormones, which is limited to the availability of radiolabelled metabolites. We have shown that the MLTC‐1 line is able to take up thyroid hormone metabolites with different efficiencies, preferring thyroxine above T3. In combination with human chorionic gonadotropin (hCG) stimulation thyroxine was even able to induce steroidogenic enzyme expression. We are currently revisiting the extraction protocols for tissue. The experiences collected in our current pilot project will be, and are already currently used in this process. As soon as these validations are completed, we will determine the endogenous thyroid hormone concentrations in the testis of the rats and our different knockout mouse models.
Projektbezogene Publikationen (Auswahl)
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The mouse Leydig cell line MLTC‐1 prefers L‐thyroxine over 3,3’,5‐triiodo‐L‐thyronine in transport across plasma membrane and shows steroidogenesis response to thyroid hormone treatment. 57. Symposium Deutsche Gesellschaft für Endokrinologie, 19‐22.03.2014, Dresden
Eddy Rijntjes, Anna Dresler, Eva Wirth, Daniel Rathmann, Josef Köhrle
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Transient Hypothyroidism: Dual Effect on Adult-Type Leydig Cell and Sertoli Cell Development. Frontiers in Physiology Vol 8, 2017, 323
Eddy Rijntjes, Marcos Gomes, Nina Zupanič, Hans Swarts, Jaap Keijer, Katja Teerds
