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Preferential Saturation of Brain 3,5,3'-Triiodothyronine Receptor during Development in Fetal Lambs^*

Unidad de Endocrinologia Experimental, Instituto de Investigaciones Biomedicas, CSIC, Facultad de Medicina, UAM (B.F., J.B., G.M.d.E.) 28029 Madrid, Spain
CSIRO Division of Human Nutrition (B.J.P.) Adelaide, South Australia, Australia

Address all correspondence and requests for reprints to: Dr. Juan Bernal, Instituto de Investigaciones Biomedicas, Facultad de Medicina, UAM, Arzobispo Morcillo 4, 28029 Madrid, Spain.

Abstract

The concentrations of T₄ and T₃ were measured in brain, liver, and lung of fetal lambs at 100 days gestational age. The highest concentrations of T₄ were found in lung (26.8 ng/g). Brain T₄ (8.8 ng/g) was only 30% of lung T₄. In contrast, higher concentrations of T₃ were found in brain (1.8 ng/g) than in lung (0.39 ng/g) or liver (0.36 ng/g). Nuclear T₃ was 16% of the total T₃ in brain and 44% of that in lung. The degree of saturation of the nuclear T₃ receptor was estimated from the concentrations of nuclear T₃ and nuclear receptor. Receptor saturation was low in liver and lung (10%) and high in brain (74%). Receptor occupancy was also measured directly in vitro by comparing the binding of [^l25I]T₃ in nuclear extracts at 0 and 20 C. This method is based on the different rates of dissociation of the T₃-receptor complex at these temperatures (0.045 and 0.618 h^-1, respectively). Therefore, [¹²⁵I]T₃ was bound mainly to unoccupied sites at 0 C, whereas at 20 C it bound to unoccupied sites plus a fraction (70%) of endogenously occupied sites. There was no difference in binding at the two temperatures using lung extract, reflecting a very low occupancy. Data from brain suggested 61% receptor saturation. Total and free T₃ were measured in plasma and in lung and brain cytosols, and the figures were compared to the intranuclear free T₃ calculated by the law of mass action, from the affinity and saturation of receptor. In lung, the concentrations of cytosolic (5.4 ± 1.9 pM) and nuclear (8.6 pM) free T₃ were similar to that of plasma T₃ (3.7 ± 0.99 pM). In contrast, brain cytosolic (14.9 ± 1.2 pM) and nuclear (203 pM) free T₃ revealed the presence of free T₃ gradients from cytosol to plasma (4-fold) and from nucleus to cytosol (13.6- fold). The data suggest that the sheep brain is a major target of thyroid hormone action at the end of the neuroblast proliferation period. Mechanisms are locally present in the brain at this stage of development to ensure a high saturation of the nuclear T₃ receptor. (Endocrinology 122: 438–443, 1988)

Footnotes

^* This work was supported by grants from the Comision Asesora de Investigation Cientifica y Tecnica and the Fondo de Investigaciones Sanitarias de la Seguridad Social.

Received February 11, 1987.

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