Martinez M Elena, Karaczyn Aldona, Stohn J Patrizia, Donnelly William T, Croteau Walburga, Peeters Robin P, Galton Valerie A, Forrest Douglas, St Germain Donald, Hernandez Arturo
Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
Endocrinology. 2016 Mar;157(3):1276-88. doi: 10.1210/en.2015-1910. Epub 2016 Jan 4.
Timely and appropriate levels of thyroid hormone (TH) signaling are necessary to ensure normal developmental outcomes in many tissues. Studies using pharmacological models of altered TH status have revealed an influence of these hormones on testis development and size, but little is known about the role of endogenous determinants of TH action in the developing male gonads. Using a genetic approach, we demonstrate that the type 3 deiodinase (D3), which inactivates TH and protects developing tissues from undue TH action, is a key factor. D3 is highly expressed in the developing testis, and D3-deficient (D3KO) mice exhibit thyrotoxicosis and cell proliferation arrest in the neonatal testis, resulting in an approximately 75% reduction in testis size. This is accompanied by larger seminiferous tubules, impaired spermatogenesis, and a hormonal profile indicative of primary hypogonadism. A deficiency in the TH receptor-α fully normalizes testis size and adult testis gene expression in D3KO mice, indicating that the effects of D3 deficiency are mediated through this type of receptor. Similarly, genetic deficiencies in the D2 or in the monocarboxylate transporter 8 partially rescue the abnormalities in testis size and gonadal axis gene expression featured in the D3KO mice. Our study highlights the testis as an important tissue in which determinants of TH action coordinately converge to ensure normal development and identifies D3 as a critical factor in testis development and in testicular protection from thyrotoxicosis.
适时且适量的甲状腺激素（TH）信号对于确保许多组织的正常发育结果至关重要。使用改变TH状态的药理学模型进行的研究揭示了这些激素对睾丸发育和大小的影响，但对于TH作用的内源性决定因素在发育中的雄性性腺中的作用知之甚少。我们采用遗传学方法证明，使TH失活并保护发育中的组织免受过度TH作用的3型脱碘酶（D3）是一个关键因素。D3在发育中的睾丸中高度表达，D3基因缺陷（D3KO）小鼠表现出甲状腺毒症以及新生睾丸中的细胞增殖停滞，导致睾丸大小减少约75%。这伴随着更大的生精小管、精子发生受损以及表明原发性性腺功能减退的激素谱。TH受体-α的缺陷使D3KO小鼠的睾丸大小和成年睾丸基因表达完全恢复正常，表明D3缺陷的影响是通过这种类型的受体介导的。同样，D2或单羧酸转运体8的基因缺陷部分挽救了D3KO小鼠中睾丸大小和性腺轴基因表达的异常。我们的研究强调睾丸是一个重要组织，其中TH作用的决定因素协同汇聚以确保正常发育，并确定D3是睾丸发育以及睾丸免受甲状腺毒症影响的关键因素。
