triiodothyronine--reverse and 3-nitrotyrosine

The present study examined human postmortem brains for changes consistent with the hypothesis of local brain TH deficiency in autism spectrum disorders (ASD). Brain levels of oxidative stress marker - 3-nitrotyrosine (3-NT), iodothyronine deiodinase type 2(D2) and type 3 (D3), 3',3,5-triiodothyronine (T3) content, mercury content and gene expression levels were analyzed and compared in the several regions of postmortem brains derived from both male and female control and ASD cases, age 4-16 years. We report that some parameters measured, such as D2 are subject to rapid postmortem inactivation, while others that were analyzed showed both brain region- and sex-dependent changes. Levels of 3-NT were overall increased, T3 was decreased in the cortical regions of ASD brains, while mercury levels measured only in the extracortical regions were not different. The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism.

Topics: Adolescent; Animals; Brain; Child; Child Development Disorders, Pervasive; Child, Preschool; Female; Gene Expression; Homeostasis; Humans; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Mercury; Rats, Sprague-Dawley; Thyroid Hormones; Triiodothyronine, Reverse; Tyrosine

The formation of DIT from T4 was quantitatively studied in thyroidectomized (T) rats given 16 micrograms synthetic T4 daily. Measurement of the elimination of radioiodinated DIT and T4 tracers from serum yielded MCRs of 19.0 ml/h X 100 g body weight for DIT and 0.65 ml/h X 100 g body weight for T4. Mean serum concentrations +/- SD (nanomoles per liter; n = 8) measured by RIA 24 and 48 h after the last T4 administration were as follows: DIT, 0.243 +/- 0.130 and 0.150 +/- 0.070, respectively; T4, 173 +/- 34 and 97 +/- 20, respectively. In T rats which had not received T4, DIT and iodothyronines in serum were undetectable. From the results of kinetic studies and RIA measurements, the fraction of circulating T4 converted to DIT was calculated to be 3.9-4.3%. After administration of the iodotyrosine inhibitor 3-nitro-L-tyrosine (MNT) to T4-treated T rats at a dosage of 50 mumol/day for 1 week or longer, it was possible to observe, on the one hand, the expected delay of DIT tracer elimination from serum resulting in a decreased MCR of 9.9 ml/h X 100 g body weight. On the other hand, MNT treatment led to a strong decline of DIT serum levels below the detection limit in all animal groups. This effect of MNT on the peripheral T4-to-DIT conversion requires further studies using other experimental systems for confirmation and elucidation of its mechanism. It is concluded that peripheral DIT formation in the animal model used occurs via ether-link cleavage of administered T4 and/or some of its iodothyronine metabolites. On the basis of data from recent studies, the peripheral DIT turnover resulting from iodothyronine degradation can be estimated to be about 35% in intact rats. Our data confirm the in vivo generation of extrathyroidal DIT from T4 in the rat. Although the experiments were performed at unphysiologically high T4 serum levels and our quantitative data, therefore, cannot be applied to euthyroid conditions with absolute certainty, the results suggest that ether-link cleavage of T4 yielding DIT is not an insignificant pathway of peripheral T4 metabolism in the rat.

Topics: Animals; Diiodotyrosine; Female; Metabolic Clearance Rate; Radioimmunoassay; Rats; Rats, Inbred Strains; Thyroidectomy; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Tyrosine

Serum concentrations and metabolic clearance rates (MCR) of diiodotyrosine (DIT) and thyroxine (T4) have been measured by radioimmunoassay and tracer kinetic technique in both normal rats and rats treated with 3-nitro-L-tyrosine (MNT), a potent inhibitor of iodotyrosine deiodinase. In normal rats, DIT serum levels were 0.27 +/- 0.12 nmol/l (mean +/- SD); MCR was 15.9 ml/h . 100 g body weight (bw), and the turnover rate was 4.3 pmol/h . 100 g bw. Inhibition of iodotyrosine deiodination by treatment with 50 mumol MNT per day for 1 week caused a highly significant elevation of DIT serum levels to 4.80 +/- 3.30 nmol/l, a decrease of MCR to 9.0 ml/h . 100 g bw and a ten-fold increase of the DIT turnover rate to 43.2 pmol/h . 100 g bw. Serum concentrations of T4 and T3 decreased slightly, whereas the T4 turnover rate (37.5 vs 37.8 pmol/h . 100 g bw) and rT3 serum levels remained unchanged under MNT treatment. The study demonstrates the presence of measurable DIT serum concentrations in the normal rat. Inhibition of intra- and extrathyroidal iodotyrosine deiodinase leads to a situation in which circulating iodotyrosines play an equally important role in peripheral iodine turnover as the iodothyronines. Since DIT serum levels in normal and enzyme-blocked rats were comparable to those in normal human subjects and patients with iodotyrosine deiodinase defect respectively, MNT-treated rats afford a suitable experimental model for this disease.

Topics: Animals; Diiodotyrosine; Female; Iodide Peroxidase; Kinetics; Metabolic Clearance Rate; Peroxidases; Rats; Rats, Inbred Strains; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse; Tyrosine