Altered selenium transport and distribution influences thyroid hormone metabolism in transgenic SePP-KO mice

Selenium (Se) is an essential trace element for mammals and highly enriched in brain, the reproductive and endocrine organs. We have genetically inactivated the gene for the Se-transport protein selenoprotein P (SePP). SePP-KO mice are characterised by a growth defect, a disturbed Se distribution and an altered expression of selenoproteins. Since activation of the prohormone T4 and inactivation of biologically active T3 and T4 are mediated by Se-dependent enzymes, we studied expression of Type I (5’DIO1) and Type II (5’DIO2) 5’deiodinase activities using 125-I-labeled rT3 as substrate. In parallel, serum thyroid hormone and TSH concentrations were analysed by RIAs adapted to mouse serum and Se concentrations were analysed by the DAN-fluorimetric method. The 5’DIO1 activity was significantly reduced in SePP-KO mice to 48.6% of wild-type (wt) levels in kidneys and to 20.5% of wt in liver (P<0.001). Activity of 5’DIO2 in brain did not differ among the genotypes. Reduced renal 5’DIO1 expression corresponded to diminished Se-content in kidney (64% of wt levels). In contrast, liver Se content was elevated 1.5 fold compared to wt. Hepatic reduction of 5’DIO1 activity was accompanied by drastically reduced mRNA levels indicative of pretranslational control mechanisms. Despite these diminished expressions of 5’-DIO1 in kidney and liver, plasma concentrations of T4 (ranging from 3.5 to 4.4µg/dl), T3 (from 0.98 to 1.16 ng/ml) or TSH (from 153 to 194 ng/ml) were not strikingly different between the genotypes. Moreover, the thyroid glands from SePP-KO mice appeared normal in size and morphology. We conclude that a disturbed distribution and transport of Se in SePP-KO mice impacts negatively on 5’DIO1 expression in liver and kidney, but that thyroid hormone feedback and backup systems efficiently counteract this defect in the living organism. Supported by the Deutsche Krebshilfe and the DFG. Dr. Parlow, NHPP kindly provided TSH reagents.