Potential mechanisms of thyroid disruption in humans: Interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin

Organochlorine compounds, particularly polychlorinated biphenyls (PCBs), al ter serum thyroid hormone levels in humans. Hydroxylated organochlorines ha ve relatively high affinities for the serum transport protein transthyretin , but the ability of these compounds to interact with the human thyroid rec eptor is unknown. Using a baculovirus expression system in insect cells (Sf 9 cells), we produced recombinant human thyroid receptor beta (hTR beta). I n competitive binding experiments, the recombinant receptor had the expecte d 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 compet ed for binding. The affinity of hTR beta for OH-PCBs was 10,000-fold lower (K-i = 20-50 mu M) than its affinity for thyroid hormone (3,3',5-triiodothy ronine, T-3; K-i = 10 nM). Because their relative affinity for the receptor was low, we tested the ability of OH-PCBs to interact with the serum trans port proteins-transthyretin and thyroid-binding globulin (TBG). With the ex ception of one compound, the OH-PCBs had the same affinity (K-i = 10-80 nM) for transthyretin as thyroid hormone (thyroxine; T-4). Only two Of the OH- PCBs bound TBG (K-i = 3-7 mu M), but with a 100-fold lower affinity than T- 4. Hydroxylated PCBs have relatively low affinities for the human thyroid r eceptor bt vitro, but they have a thyroid hormonelike affinity for the seru m 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.