Thyroid Hormone Levels and Expression of Genes Involved in Regulation of Thyroid System Activity in Male Rats Exposed to Prolonged Low Temperatures, and the Effect of a Thyroid-Stimulating Hormone Receptor Antagonist on These Parameters

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Abstract Mechanisms of adaptation to prolonged low temperature exposures, aimed at increasing thermogenesis and altering metabolism, include an increase in the activity of the hypothalamic-pituitary-thyroid (HPT) axis. Therefore, it remains a relevant task to explore the balance of thyroid hormones (THs), expression and activity of enzymes responsible for their synthesis in the thyroid gland (TG), expression of the main components of the HPT axis, as well as to investigate the effect of thyroid stimulating hormone (TSH) receptor antagonists on these indices when administered to animals exposed to cold. This work was aimed to study blood TSH and TH levels and the expression of hypothalamic, pituitary and thyroid genes involved in their synthesis and secretion in male rats exposed to low temperatures (5°C) for 10 days, as well as to assess the effect of a single treatment of animals with the thieno[2,3-d]-pyrimidine derivative TPY1, an original allosteric TSH receptor antagonist, on these indices. Cold-exposed rats developed T3 hyperthyroidism, which was associated with a decrease in the thyroxine level due to an increase in its conversion to T3, as indicated by an increase in the T3/T4 ratio and type 2 deiodinase (DIO2) expression in the TG. Compared to controls, the expression of thyroidal Tg and Nis genes, encoding thyroglobulin and Na+/I– symporter, increased in the TG of hyperthyroid rats. TPY1 normalized the T3 level and decreased Tg and Nis expression, suggesting a TPY1-induced decrease in the TSH-stimulated TSH receptor activity. TPY1 also increased the gene expression of the TSH β-subunit and thyroliberin receptor genes in the pituitary gland, which may be due to a higher threshold of sensitivity of thyrotrophs to the inhibitory effect of T3 under conditions of long-term T3 hyperthyroidism. A distinctive feature of cold-induced T3 hyperthyroidism in rats was the tissue specificity of changes in DIO2 gene expression, namely its increase in the TG and a decrease in the hypothalamus, as well as the retention of elevated DIO2 gene expression in the TG after TPY1 treatment. Thus, prolonged exposure of rats to cold leads to the development of pronounced T3 hyperthyroidism with increased expression of genes responsible for TH synthesis, while the treatment with an allosteric TSH receptor antagonist significantly normalizes these indices.

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