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Identification and Characterization of Nuclear 3,5,3'- Triiodothyronine-Binding Sites in Fetal Human Lung^*

Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California 94143

Address requests for reprints to: Philip L. Ballard, M.D., Cardiovascular Research Institute, 1315 Moffitt, University of California, San Francisco, San Francisco, California 94143.

Thyroid hormones have been implicated in the prenatal lung development of several species. To investigate the possibility that thyroid hormones could play a role in human lung development, we examined nuclei from fetal human lung for the presence of high affinity T₃-binding sites.

A single class of high affinity (K_d = 35 ±ff 3 pM) binding sites for L-T₃ was identified in nuclei from fetuses between 12–19 weeks of gestation. The T₃-binding capacity increased 65% between 12–13 weeks (binding capacity, 0.227 and 0.282 fmol/µg DNA in two experiments) and 16–19 weeks of gestation [binding capacity, 0.420 ± 0.014 (SEM) fmol/jug DNA; n = 8]. Maximal binding was achieved after 4 h of incubation at 20 C. The halftimes for dissociation of the T₃-receptor complex were 36 h, 10.5 h, 3 h, and 23 min at 2, 20, 25, and 37 C, respectively. The relative order of potency of thyroid hormone analogs in displacing L-T,) from the receptor was: T3-proprionate > 3,3'-5-triiodothyroacetic acid > L-T₃ > D-T₃ > L-T₄ > 3,5-diethyl-3'-isopropyl- D,L-thyronine > rT₃ > 3,5-dimethyl-3'-isopropyl-L-thyronine.

Some receptors were released from the nuclei into the supernatant during incubation (7.8 ± 0.3% after 4 h at 20 C). This release increased with incubation time and temperature, but was independent of T₃ concentration, Ca²+, and gestational age. Incubation at 37 C also inactivated some of the receptors, but T₃ provided dose-dependent protection from this loss of binding activity. Our results are consistent with the proposal that nuclear receptors mediate a direct effect of thyroid hormones on developing human lung as early as the second trimester of gestation.

^* This work was supported in part by grants from the USPHS: Program Project HL-24075, Pulmonary Specialized Center of Research Grant HL-19185, and Training Grant HL-07185 (to L.W.G.).

Received November 3, 1980.

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