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This version published online on October 13, 2005
Endocrinology, doi:10.1210/en.2005-0739
A more recent version of this article appeared on January 1, 2006
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Submitted on June 20, 2005
Accepted on September 26, 2005

TARGETED DISRUPTION OF THE TYPE 1 SELENODEIODINASE GENE (DIO1) RESULTS IN MARKED CHANGES IN THYROID HORMONE ECONOMY IN MICE

Mark J. Schneider, Steven N. Fiering, B. Thai, Sing-yung Wu, Emily St. Germain, Albert F. Parlow, Donald L. St. Germain, and Valerie Anne Galton*

Departments of Physiology, Microbiology, and Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA and Nuclear Medicine and Medical Services, Department of Veterans' Affairs Medical Center, Long Beach, CA 90822, USA and Harbor-UCLA Medical Center, Torrance, CA 90509, USA

* To whom correspondence should be addressed. E-mail: val.galton{at}dartmouth.edu.

The type 1 deiodinase (D1) is thought to be an important source of T3 in the euthyroid state. To explore the role of the D1 in thyroid hormone economy, a D1-deficient mouse (D1KO) was made by targeted disruption of the Dio1 gene. The general health and reproductive capacity of the D1KO mouse were seemingly unimpaired. In serum, levels of T4 and rT3 were elevated while those of TSH and T3 were unchanged, as were several indices of peripheral thyroid status. It thus appears that the D1 is not essential for the maintenance of a normal serum T3 level in euthyroid mice. However, D1 deficiency resulted in marked changes in the metabolism and excretion of iodothyronines. Fecal excretion of endogenous iodothyronines was greatly increased. Furthermore, when compared with both WT and D2-deficient mice, fecal excretion of [125I]iodothyronines was greatly increased in D1KO mice during the 48 h following injection of [125I]T4 or [125I]T3, while urinary excretion of [125I]iodide was markedly diminished. From these data it was estimated that a majority of the iodide generated by the D1 was derived from substrates other than T4. Treatment with T3 resulted in a significantly higher serum T3 level and a greater degree of hyperthyroidism in D1KO mice than in WT mice. We conclude that, while the D1 is of questionable importance to the well being of the euthyroid mouse, it may play a major role in limiting the detrimental effects of conditions that alter normal thyroid function including hyperthyroidism and iodine deficiency.




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