| Potential Mechanisms of Thyroid Disruption in Humans: Interaction of Organochlorine Compounds with Thyroid Receptor, Transthyretin, and Thyroid-binding Globulin Ann Oliver Cheek,1,2 Kelvin Kow,1 Jian Chen,1 and John A. McLachlan1,3 1Tulane/Xavier Center for Bioenvironmental Research; 2Department of Ecology, Evolution, and Organismal Biology; 3Department of Pharmacology, Tulane University, New Orleans, LA 70402 USA Abstract
Organochlorine compounds, particularly polychlorinated biphenyls (PCBs) , alter serum thyroid hormone levels in humans. Hydroxylated organochlorines have relatively high affinities for the serum transport protein transthyretin, but the ability of these compounds to interact with the human thyroid receptor is unknown. Using a baculovirus expression system in insect cells (Sf9 cells) , we produced recombinant human thyroid receptor ß (hTRß) . In competitive binding experiments, the recombinant receptor had the expected relative affinity for thyroid hormones and their analogs. In competitive inhibition experiments with PCBs, hydroxylated PCBs (OH-PCBs) , DDT and its metabolites, and several organochlorine herbicides, only the OH-PCBs competed for binding. The affinity of hTRß for OH-PCBs was 10,000-fold lower (Ki = 20-50 µM) than its affinity for thyroid hormone (3,3´,5-triiodothyronine, T3 ; Ki = 10 nM) . Because their relative affinity for the receptor was low, we tested the ability of OH-PCBs to interact with the serum transport proteins--transthyretin and thyroid-binding globulin (TBG) . With the exception of one compound, the OH-PCBs had the same affinity (Ki = 10-80 nM) for transthyretin as thyroid hormone (thyroxine ; T4) . Only two of the OH-PCBs bound TBG (Ki = 3-7 µM) , but with a 100-fold lower affinity than T4. Hydroxylated PCBs have relatively low affinities for the human thyroid receptor in vitro, but they have a thyroid hormonelike affinity for the serum transport protein transthyretin. Based on these results, OH-PCBs in vivo are more likely to compete for binding to serum transport proteins than for binding to the thyroid receptor. Key words: endocrine disruption, PCB, thyroid-binding globulin, thyroid receptor, transthyretin. Environ Health Perspect 107:273-278 (1999) . [Online 9 March 1999] http://ehpnet1.niehs.nih.gov/docs/1999/107p273-278cheek/ abstract.html Address correspondence to A.O. Cheek, Department of Biology, Southeastern Louisiana University, SLU 10736, Room 205 Mead Hall, North Pine Extension, Hammond, LA 70402 USA. Many thanks to P. Vonier for teaching techniques in cell culture and baculovirus expression and to A. Holstein for performing preliminary Western blot analysis. This study was supported by Department of Energy grant DE-FG07-96ER62308. Received 21 September 1998 ; accepted 21 December 1998.
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