The role of transmembrane thyroid hormone transporters and local metabolism of thyroid hormone on testicular thyroid hormone levels in relation to testicular development

• Applicant: Dr. Eddy Rijntjes
• Subject Area: Reproductive Medicine, Urology ; Endocrinology, Diabetology, Metabolism
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240906641

Alterations in thyroid hormone (TH) levels are well known to influence key functions in growth and development. The testis has been identified as an organ, whose development depends on the thyroid status. Earlier animal studies used 6-propyl-2-thiouracil (PTU) from partus to weaning to induce hypothyroidism, which resulted in increased testis weights in adulthood. PTU is an antithyroid drug with dual action on TH synthesis and deiodination. In our preliminary work we have set up an animal model to induce chronic hypothyroidism in rats using an iodide poor diet in combination with sodium perchlorate, which inhibits iodide uptake by the thyroid. Our preliminary results indicate that a condition of continuous hypothyroidism delays Leydig and Sertoli cell proliferation and differentiation, but does not lead to an absolute increase in testis weight in adulthood. If these effects are due to changes in local testicular TH levels is unknown, since local TH levels have never been determined. We hypothesise that altered local availability of active TH, depending on transmembrane TH transporters and local TH metabolism by deiodinases, can partially compensate for the decreased plasma triiodothyronine and thyroxine levels during hypothyroidism, thus limiting the local consequences of systemic hypothyroidism in the testis. The objective of the project is to determine local testicular TH levels using LC-MS/MS in the developing hypothyroid and euthyroid rat testis, and in transmembrane TH transporter knockout mouse models (Lat2 and Mct8). These two transporter knockout mouse models will interrogate the importance of TH transport for testicular and especially Leydig and Sertoli cell development and their relative contributions to the tissue-specific compensatory mechanisms counteracting systemic hypothyroidism. TH uptake-assays in Leydig- and Sertoli- cell lines will give valuable insights into the role of transmembrane TH transporters while deiodinase activity assays will indicate potential local TH conversion. Using our novel LC-MS/MS techniques, we will even be able to identify TH metabolite profiles generated by the cell lines, including the recently re-discovered class of TH counteracting thyronamines. These findings will be related to the proliferation and differentiation of Leydig and Sertoli cells in vivo.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Participating Person: Dr. Katja Teerds